Reimbursement Review

Momelotinib (Ojjaara)

Sponsor: GlaxoSmithKline Inc.

Therapeutic area: Myelofibrosis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Myelofibrosis (MF) is a rare, chronic, and progressive bone marrow disorder categorized as a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN).^1,2 Characterized by the excessive production of reticulin and collagen fibres, MF leads to bone marrow fibrosis, bone marrow failure, systemic inflammation, and splenomegaly.³ MF can develop as primary myelofibrosis (PMF) or as secondary forms following essential thrombocythemia (ET) or polycythemia vera (PV). PMF is the most aggressive type and has the potential to progress into acute myeloid leukemia (AML).³ The incidence of PMF in Canada is estimated at 0.80 per 100,000 person-years,⁴ with approximately 200 new cases diagnosed annually, accounting for 1% of all hematological malignancies.⁵ Key clinical manifestations of MF include severe anemia, thrombocytopenia, marked hepatosplenomegaly, and constitutional symptoms such as fatigue, night sweats, and unintentional weight loss. Current treatment options primarily include Janus kinase (JAK) inhibitors like ruxolitinib, which are aimed at reducing splenomegaly and managing symptoms.^6-9 However, unmet needs remain, especially for patients who experience disease progression after JAK inhibitor therapy.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of momelotinib, administered orally at a dosage of 200 mg once daily, for the treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate-risk or high-risk PMF, post-PV MF, or post-ET MF who have moderate to severe anemia. Momelotinib, which also inhibits ACVR1, may provide additional benefits, particularly in managing anemia, by restoring iron homeostasis and reducing the need for RBC transfusions. This drug has not been previously reviewed by Canada’s Drug Agency (CDA-AMC).

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of the input provided by the patient and clinician groups who responded to the CDA-AMC call for input and from the clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

The Leukemia & Lymphoma Society of Canada (LLSC) and the Canadian MPN Network (CMPNN) jointly provided patient input for this review, sourcing information from 3 online surveys conducted between March 2024 and May 2024, with a total of 73 respondents. Heal Canada also provided input for this review, sourcing information mainly from surveys and interviews. The surveys included in both inputs gathered insights from patients with MF and their caregivers, focusing on their lived experiences and specific interactions with the drug under review, momelotinib. MF profoundly impacts patients and their families, affecting physical, emotional, and financial aspects of daily life. Many patients reported relying heavily on caregiver support, which placed significant burdens on both parties. Key outcomes important to patients include the management of fatigue, anemia, and spleen size, with a particular emphasis on reducing symptom burden, improving quality of life, and decreasing the need for blood transfusions. Notably, 73% of respondents with experience using momelotinib felt it improved their quality of life.

Clinician Input

Input From Clinical Experts

Clinical experts consulted by CDA-AMC identified significant unmet needs in the current treatment landscape for MF. While existing JAK inhibitors like ruxolitinib and fedratinib effectively address symptoms such as splenomegaly and constitutional symptoms, they do not modify the underlying disease or delay its progression. Additionally, hematopoietic stem cell transplant (HSCT), the only potentially curative treatment, is viable for less than 10% of patients due to its high associated morbidity and mortality. Experts emphasized the need for therapies that provide more durable responses, better management of anemia, and potential modification of disease progression.

Experts suggested that momelotinib could be an important option for patients with MF who require JAK inhibitor therapy and have clinically significant anemia. Momelotinib would be particularly beneficial for patients not previously treated with JAK inhibitors or who have developed anemia or intolerance on existing JAK inhibitor therapy. The experts noted that momelotinib could be used in first-line settings and as a second-line or third-line treatment for patients with clinically relevant anemia and MPN symptoms. However, the experts noted that momelotinib might be less suitable for patients whose primary issue is symptomatic splenomegaly in the context of ruxolitinib resistance or intolerance.

Based on the input provided by the clinical experts, the patient population most likely to benefit from momelotinib includes those with MF who have not been previously treated with JAK inhibitors and have splenomegaly or MPN symptoms and clinically relevant anemia, as well as those experiencing anemia or intolerance on other JAK inhibitor therapies. Patients whose main issue is splenomegaly without accompanying anemia or MPN symptoms may be less likely to benefit from momelotinib.

The experts recommended assessing the response to momelotinib through patient-reported outcomes, physical examinations (including spleen size), and anemia parameters such as hemoglobin levels and transfusion frequency. The experts suggested that responses should be evaluated approximately every 3 months, with a clinically meaningful response being indicated by subjective improvements, reduced spleen size, and improved anemia metrics. Treatment discontinuation should be considered if there is no response after about 6 months, if there is a loss of a prior response, or if the patient experiences grade 3 adverse events (AEs) that do not resolve with dose modification.

The experts advised that momelotinib should be prescribed and monitored by hematologists or oncologists with expertise in MF, ideally in hospital outpatient clinics or specialty settings where appropriate expertise is available. Regional access to such specialists should be considered when prescribing momelotinib.

Clinician Group Input

Clinician group input on the review of momelotinib was provided by 15 clinicians from LLSC and the CMPNN Clinician Group, as well as the Ontario Health – Cancer Care Ontario (OH-CCO) Hematology Disease Site Drug Advisory Committee. Both clinician groups emphasized the significant unmet need for effective treatments to manage anemia in MF, aligning with the clinical experts consulted by CDA-AMC, who also identified anemia management as a critical challenge. The clinician groups and the clinical experts all recognized the potential of momelotinib to benefit patients with MF-associated anemia; the clinician groups noted, however, a lack of evidence on the reduction in the risk of progression to acute leukemia associated with momelotinib. The clinician groups highlighted that assessment of response to momelotinib in clinical practice should include improvements in hemoglobin, reductions in transfusions, and stable disease or improvement in symptom burden, which are also consistent with the views of the clinical experts consulted by CDA-AMC. These clinician groups believe that momelotinib could be relevant to clinical practice, especially for patients who experience anemia and transfusion dependence, although the clinician groups also caution that it does not address all aspects of disease progression.

Drug Program Input

The drug plans submitted questions relating to the initiation and generalizability of momelotinib and the associated funding algorithm.

Clinical Evidence

Systematic Review

Description of Studies

Three pivotal randomized controlled trials (RCTs) were included in the sponsor’s submission to assess the efficacy and safety of momelotinib for MF in adults. The SIMPLIFY-1 trial (N = 432) was a phase III, double-blind, multicentre study that compared momelotinib with ruxolitinib in patients with PMF, post-PV MF, or post-ET MF who had not previously been treated with JAK inhibitors. The primary end point was the splenic response rate (SRR) at week 24, defined as a reduction of 35% or more in spleen volume from baseline. The secondary outcomes included the total symptom score (TSS) response rate, defined as the proportion of patients experiencing a reduction of 50% or more from baseline in symptom burden, and transfusion independence, defined as the proportion of patients who do not require any red blood cell (RBC) transfusions for a period of 12 weeks while maintaining hemoglobin levels at or more than 8 g/dL. The SIMPLIFY-2 trial (N = 156) was a phase III, open-label, multicentre study that evaluated the efficacy of momelotinib versus the best available therapy (BAT) — 88.5% of patients received ruxolitinib as the BAT of choice — in patients with MF who had been previously treated with ruxolitinib but experienced either an inadequate response or intolerance. The primary end point was the SRR at week 24, with the secondary outcomes including the TSS response rate and overall survival (OS). The MOMENTUM trial (N = 195) was a phase III, double-blind, multicentre study that focused on patients with symptomatic and anemic MF who had received prior JAK inhibitor therapy. The trial compared momelotinib with danazol, with the primary end point being the TSS response rate at week 24. The secondary outcomes included SRR, transfusion independence, and OS.

Baseline characteristics across the studies showed a population predominantly composed of patients with intermediate-2–risk or high-risk MF. Across the 3 trials, more than one-half of patients were male, the majority were white, and the mean age was mid-to-late 60s. In the SIMPLIFY-1 trial, 56.5% of patients were male and 43.5% were female, with 9.2% identifying as Asian, 0.9% as Black, 82.6% as white, and 7.9% as “other” or “not reported.” In the SIMPLIFY-2 trial, 59.6% of patients were male and 40.4% were female, with 3.8% identifying as Black, 81.4% as white, and 14.7% as “other” or “not reported.” In the MOMENTUM trial, 63.1% of patients were male and 36.9% were female, with 9.2% identifying as Asian, 2.1% as Black, 80.5% as white, and 6.2% as “other.” With the exception of anemia-related characteristics in the MOMENTUM trial, where only patients with a hemoglobin level of less than 10 g/dL were included, the rest of the baseline characteristics were relatively consistent across the 3 trials, with relatively balanced demographic and clinical characteristics between treatment arms.

Efficacy Results

In the SIMPLIFY-1 trial, 66.5% of patients treated with momelotinib experienced transfusion independence at week 24, compared to 49.3% in the ruxolitinib group, with a proportion difference of 0.18 (95% confidence interval [CI], 0.09 to 0.26). In the SIMPLIFY-2 trial, 43.3% of patients in the momelotinib group experienced transfusion independence at week 24, compared with 21.2% in the BAT group, with a proportion difference of 0.23 (95% CI, 0.09 to 0.37). In the MOMENTUM study, 30.8% of patients treated with momelotinib experienced transfusion independence at week 24, compared to 20.0% in the danazol group (proportion difference = 10.99%; 95% CI, –0.80% to 22.77%), with an adjusted proportion difference noninferiority test, which targeted 80% retention of the effect of danazol, at 14.77% (95% CI, 3.13% to 26.41%; P = 0.0064).

The mean rate of RBC transfusions at week 24 in the SIMPLIFY-1 trial was 0.5 units per patient-month in the momelotinib group, versus 1.0 unit in the ruxolitinib group, with a transfusion rate ratio of 0.28 (95% CI, 0.19 to 0.43). In the SIMPLIFY-2 trial, the mean transfusion rate was 1.6 units in the momelotinib group, compared to 1.8 units in the BAT group (transfusion rate ratio = 0.80; 95% CI, 0.49 to 1.31). In the MOMENTUM trial, patients in the momelotinib group received a mean 6.6 units, compared with a mean 10.9 units in the danazol group, with a treatment difference of –5.66 units (95% CI, –10.65 to –0.68 units).

In the SIMPLIFY-1 trial, 26.5% of patients in the momelotinib group experienced a splenic response at week 24, compared to 29.5% in the ruxolitinib group. Momelotinib met the noninferiority criterion, with an adjusted proportion difference (targeting 60% retention of the effect of ruxolitinib) of 0.09 (95% CI, 0.02 to 0.16; P = 0.014), but it did not demonstrate superiority (proportion difference = –0.03; 95% CI, –0.12 to 0.05; P = 0.45). In the SIMPLIFY-2 trial, the SRR was 6.7% in the momelotinib group and 5.8% in the BAT group (proportion difference = 0.01; 95% CI, –0.09 to 0.10; P = 0.90). In the MOMENTUM trial, the SRR was 23.1% in the momelotinib group versus 3.1% in the danazol group (proportion difference = 19.37%; 95% CI, 10.96% to 27.77%; P = 0.001).

In the SIMPLIFY-1 trial, 28.4% of patients in the momelotinib group experienced a TSS response at week 24, compared to 42.2% in the ruxolitinib group (proportion difference = –14.0%; 95% CI, –23.0% to –5.0%; P = 0.9985). A noninferiority test that targeted 67% retention of ruxolitinib failed to the predefined noninferiority margin, where the lower bound of the 2-sided 95% CI should be greater than 0. Specifically, the adjusted proportion difference noninferiority testing was 0.00 (95% CI, –0.08 to 0.08; P = 0.98). In the SIMPLIFY-2 trial, 26.2% of patients in the momelotinib group experienced a TSS response, compared to 5.9% in the BAT group, with a proportion difference of 0.20 (95% CI, 0.09 to 0.32). In the MOMENTUM study, 24.6% of patients in the momelotinib group experienced a TSS response, compared to 9.2% in the danazol group, with a proportion difference of 15.67% (95% CI, 5.54% to 25.81%; P = 0.0095).

Harms Results

Across the trials, most patients treated with momelotinib experienced at least 1 AE. In the SIMPLIFY-1 trial, 92.5% of patients in the momelotinib group experienced at least 1 AE, compared to 95.4% in the ruxolitinib group. In the SIMPLIFY-2 trial, the rates were 97.1% in the momelotinib group and 88.5% in the BAT group. For the MOMENTUM study, 93.8% of patients in the momelotinib group reported at least 1 AE, compared to 95.4% in the danazol group. Thrombocytopenia and anemia were commonly reported AEs across these trials. In the SIMPLIFY-1 trial, thrombocytopenia occurred in 18.7% of patients in the momelotinib group and 29.2% of patients in the ruxolitinib group, while anemia was reported in 14.5% of patients in the momelotinib group and 37.5% of patients in the ruxolitinib group. In the SIMPLIFY-2 trial, thrombocytopenia was observed in 10.6% of patients in the momelotinib group and 5.8% of patients in the BAT group, and anemia was reported in 13.5% of patients in the momelotinib group, compared to 17.3% in the BAT group. In the MOMENTUM study, thrombocytopenia was seen in 22.3% of patients in the momelotinib group versus 10.8% of patients in the danazol group, while anemia was observed in 7.7% of patients in the momelotinib group and 6.2% of patients in the danazol group.

Grade 3 or 4 AEs were observed in a proportion of patients across all studies. In the SIMPLIFY-1 trial, 34.6% of patients in the momelotinib group experienced grade 3 or 4 AEs, compared to 43.5% in the ruxolitinib group. In the SIMPLIFY-2 trial, 54.8% of patients in the momelotinib group experienced grade 3 or 4 AEs versus 42.3% in the BAT group. In the MOMENTUM trial, 48.5% of patients in the momelotinib group reported grade 3 or 4 AEs, compared to 63.1% in the danazol group. Thrombocytopenia and anemia were the most common grade 3 or 4 AEs. In the SIMPLIFY-1 trial, grade 3 or 4 thrombocytopenia was reported in 7.0% of patients in the momelotinib group and 4.6% of patients in the ruxolitinib group, while grade 3 or 4 anemia was reported in 6.1% of patients in the momelotinib group and 22.7% of patients in the ruxolitinib group. In the SIMPLIFY-2 trial, grade 3 or 4 thrombocytopenia was observed in 10.6% of patients in the momelotinib group versus 5.8% of patients in the BAT group, and grade 3 or 4 anemia was reported in 13.5% of patients in the momelotinib group compared to 17.3% in the BAT group. In the MOMENTUM trial, grade 3 or 4 thrombocytopenia was seen in 16.9% of patients in the momelotinib group and 7.7% of patients in the danazol group, while grade 3 or 4 anemia was reported in 7.7% of patients in the momelotinib group and 6.2% of patients in the danazol group.

Serious AEs (SAEs) were frequent across the trials. In the SIMPLIFY-1 trial, 22.9% of patients in the momelotinib group experienced at least 1 SAE, compared to 18.1% in the ruxolitinib group. In the SIMPLIFY-2 trial, 35.6% of patients in the momelotinib group experienced at least 1 SAE versus 23.1% in the BAT group. In the MOMENTUM trial, 34.6% of patients in the momelotinib group reported at least 1 SAE, compared to 40.0% in the danazol group. Common SAEs included anemia, pneumonia, and sepsis. In the SIMPLIFY-1 trial, anemia was observed in 1.9% of patients in the momelotinib group and 3.7% of patients in the ruxolitinib group, and pneumonia was reported in 1.9% of patients in the momelotinib group and 1.4% of patients in the ruxolitinib group. In the SIMPLIFY-2 trial, sepsis was observed in 2.9% of patients in the momelotinib group; no cases were reported in the BAT group. In the MOMENTUM trial, anemia was seen in 3.8% of patients in the momelotinib group versus 4.6% in the danazol group, and pneumonia was reported in 2.3% of patients in the momelotinib group and 9.2% of patients in the danazol group.

Discontinuations due to AEs were relatively common. In the SIMPLIFY-1 trial, 12.6% of patients in the momelotinib group discontinued treatment due to AEs, compared to 5.6% in the ruxolitinib group. In the SIMPLIFY-2 trial, discontinuation rates were 21.2% in the momelotinib group versus 1.9% in the BAT group. In the MOMENTUM trial, 17.7% of patients in the momelotinib group discontinued treatment, compared to 23.1% in the danazol group. Thrombocytopenia was a key reason for discontinuation, especially in the SIMPLIFY-2 trial, where it led to treatment cessation in 4.8% of patients in the momelotinib group; there were no reported cases in the BAT group. In the MOMENTUM trial, thrombocytopenia caused discontinuation in 0.8% of patients in the momelotinib group versus 3.1% of patients in the danazol group.

Mortality rates varied across the studies. In the SIMPLIFY-1 trial, 3.7% of patients in the momelotinib group died, compared to 2.8% of patients in the ruxolitinib group. In the SIMPLIFY-2 trial, mortality was 7.7% in the momelotinib group and 9.6% in the BAT group. In the MOMENTUM trial, 29.2% of patients in the momelotinib group died, compared to 30.8% in the danazol group. In the SIMPLIFY-1 trial, most deaths in the momelotinib group were due to treatment-emergent AEs (TEAEs), while in the MOMENTUM trial, a notable number of deaths were linked to TEAEs in both the momelotinib and danazol groups.

Notable harms included peripheral neuropathy, reported in 10.3% of patients in the momelotinib group in the SIMPLIFY-1 trial and 11.5% in the SIMPLIFY-2 trial, with fewer cases in the comparator groups (5.6% in the ruxolitinib group in the SIMPLIFY-1 trial and none reported in the BAT group in the SIMPLIFY-2 trial). In the MOMENTUM trial, infections were prevalent, affecting 33.8% of patients in the momelotinib group and 35.4% of patients in the danazol group. Other significant AEs in the MOMENTUM trial included hemorrhage (21.5% in the momelotinib group versus 18.5% in the danazol group), malignancies (5.4% in the momelotinib group versus 9.2% in the danazol group), thromboembolism (3.8% in the momelotinib group versus 9.2% in the danazol group), and transformation to AML (3.1% in the momelotinib group versus 4.6% in the danazol group).

Critical Appraisal

The studies included in this review are generally well designed, with RCTs and active comparator arms, which strengthen their internal validity. The SIMPLIFY-1 and MOMENTUM trials were double-blind studies, while the SIMPLIFY-2 trial was open label, increasing the potential for bias, particularly in subjective outcomes like the TSS. The studies used robust randomization and allocation concealment methods, with noninferiority to be met if the lower 95% CI did not go below the null; this margin was established based on prior evidence, which was supported by clinical experts. However, limited clinical rationale was provided for the threshold used to determine the comparator efficacy preservation. The open-label design of the SIMPLIFY-2 trial introduces a risk of bias in favour of momelotinib, especially for patient-reported outcomes. A significant limitation across all studies is the high rate of treatment discontinuation, which was particularly imbalanced in the MOMENTUM trial, where more patients discontinued treatment in the danazol group than in the momelotinib group. Additionally, the lack of adjustment for type I error (multiple testing) in several efficacy outcomes further complicates the interpretation of these results, particularly in the SIMPLIFY-2 trial, where the primary objectives were not met, rendering subsequent analyses nominal and unadjusted.

The external validity of the studies is supported by their attempt to capture a representative population of patients with MF, including those who have not previously been treated with a JAK inhibitor, those who have previously been treated with a JAK inhibitor, and those who have anemia. The baseline characteristics of the study populations were consistent with those seen in clinical practice in Canada, according to the clinical experts. However, the studies have limitations in generalizability due to the lack of comparisons against certain relevant treatments, such as fedratinib or hydroxyurea, particularly in the Canadian context. The use of danazol in the MOMENTUM trial, which is uncommon in Canadian practice, further limits the applicability of the results. Additionally, the short 24-week duration of the studies is insufficient to assess long-term outcomes such as survival and disease progression, which are critical in MF management. The high rates of treatment discontinuation also limit the generalizability of the findings to patients who are likely to remain on therapy, potentially skewing results toward those who respond well to treatment. Lastly, the absence of established minimal important differences for key outcomes diminishes the ability to interpret the clinical significance of the differences observed between momelotinib and comparators.

Table 2: Summary of Findings for Momelotinib vs. Ruxolitinib for Patients With Myelofibrosis Not Previously Treated With JAK Inhibitors

CDA-AMC = Canada’s Drug Agency; CI = confidence interval; JAK = Janus kinase; MID = minimal important difference; MPN-SAF = Myeloproliferative Neoplasm Symptom Assessment Form; NR = not reported; RBC = red blood cell; RCT = randomized controlled trial; SD = standard deviation; TSS = total symptom score; vs. = versus.

Notes: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Did not rate down for imprecision; a between-group difference of larger than the null and a CI that excludes the null suggest benefit as judged by the CDA-AMC review team.

^bEnd point not adjusted for multiple testing, thus should be used as supportive evidence.

^cResults for absolute between-group difference with 95% CI for the full study population were not available. Furthermore, no MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects. Therefore, the null was used in relation to the relative treatment effect. Did not rate down for imprecision; a relative treatment effect larger than the null and a CI that excludes the null suggest benefit as judged by the CDA-AMC review team.

^dNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Rated down 1 level for serious imprecision as the lower bound of the CI suggests harm and the upper bound of the 95% CI suggests benefit and/or little-to-no difference.

^eNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects. Rated down 2 levels for very serious imprecision as the lower bound of the CI suggests benefit and the upper bound of the 95% CI suggests harm.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Table 3: Summary of Findings for Momelotinib vs. Best Available Therapy for Patients With Myelofibrosis Previously Treated With JAK Inhibitors

CDA-AMC = Canada’s Drug Agency; CI = confidence interval; JAK = Janus kinase; MID = minimal important difference; MPN-SAF = Myeloproliferative Neoplasm Symptom Assessment Form; NR = not reported; RBC = red blood cell; RCT = randomized controlled trial; SD = standard deviation; TSS = total symptom score; vs. = versus.

^aNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Did not rate down for imprecision; a between-group difference of larger than the null and a CI that excludes the null suggest benefit as judged by the CDA-AMC review team. Rated down 1 level for serious risk of bias due to missing data and the lack of a washout period.

^bResults for absolute between-group difference with 95% CI for the full study population were not available. Furthermore, no MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects Rated down 2 levels for very serious imprecision as the lower bound of the CI suggests comparative harm and the upper bound of the 95% CI suggests comparative benefit.

^cEnd point not adjusted for multiple testing, thus should be used as supportive evidence.

^dNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Rated down 2 levels for very serious imprecision as the lower bound of the 95% CI suggests serious harm and the upper bound of the 95% CI suggests serious benefit. Rated down 1 level for serious risk of bias due to missing data and lack of a washout period.

^eNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Rated down 2 levels for very serious risk of bias due to open-label design in a subjective outcome, missing data, and lack of a washout period.

^fNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects. Rated down 2 levels for very serious imprecision as the lower bound of the CI suggests benefit and the upper bound of the 95% CI suggests harm.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Table 4: Summary of Findings for Momelotinib vs. Danazol for Patients With Myelofibrosis Previously Treated With JAK Inhibitors and Who Have Anemia

CDA-AMC = Canada’s Drug Agency; CI = confidence interval; JAK = Janus kinase; MFSAF = Myelofibrosis Symptom Assessment Form; MID = minimal important difference; NR = not reported; RBC = red blood cell; RCT = randomized controlled trial; SD = standard deviation; TSS = total symptom score; vs. = versus.

^aNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Rated down 1 level for serious imprecision as the lower bound of the 95% CI suggests minimal harm and/or no difference and the upper bound of the 95% CI suggests benefit. Rated down 1 level for serious risk of bias due to missing data.

^bEnd point not adjusted for multiple testing, thus should be used as supportive evidence.

^cNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Rated down 1 level for serious risk of bias due to the large and imbalanced number of treatment discontinuations and the lack of data imputation methods for this outcome.

^dNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects; therefore, the null was used. Did not rate down due to imprecision. Rated down 1 level for serious risk of bias due to the large and imbalanced number of treatment discontinuations.

^eNo published between-group MID was identified, and the clinical experts consulted by CDA-AMC were unable to estimate a threshold for clinically important effects. Rated down 2 levels for very serious imprecision as the lower bound of the CI suggests benefit and the upper bound of the 95% CI suggests harm.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• Transfusion independence response rate — follow-up: week 24

• Rate of RBC transfusion — follow-up: week 24

• SRR — follow-up: week 24

• TSS response rate — follow-up: week 24

• SAEs — follow-up: week 24.

Long-Term Extension Studies

This section summarizes the open-label extension studies of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials.

Description of Studies

The open-label long-term extension of the SIMPLIFY-1 trial evaluated the open-label treatment with momelotinib for up to 216 weeks (i.e., through week 240) after the randomized, double-blind phase. The open-label extension of the SIMPLIFY-2 trial evaluated the open-label treatment with momelotinib for up to 204 weeks (i.e., through week 228) after the randomized treatment phase. All patients who completed the 24-week randomized treatment phase in the SIMPLIFY-1 and SIMPLIFY-2 trials were eligible to participate in the extended treatment phases.

The open-label extension of the MOMENTUM trial evaluated the open-label treatment with momelotinib for up to 180 weeks (i.e., through week 204) or with danazol for up to 24 weeks after the randomized, double-blind phase. Patients who completed the 24-week randomized treatment phase in the MOMENTUM trial, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through week 24 had the option to continue on momelotinib.

The median total duration of follow-up (combined randomized and open-label extension phases) was 35.3 months (range, 0.4 to 59.3 months) in the SIMPLIFY-1 trial and 28.2 months (range, 0.3 to 50.4 months) in the SIMPLIFY-2 trial. In the open-label extension phase of the SIMPLIFY-1 trial, the majority of patients in the continuing momelotinib and switch to momelotinib treatment groups (40.4% and 48.7%, respectively) had high-risk MF per the International Prognostic Scoring System (IPSS) criteria and a positive JAK2V617F mutation status (58.5% and 64.0% in the continuing momelotinib and switch to momelotinib treatment groups, respectively) at baseline. The proportion of patients with a hemoglobin level less than 10 g/dL was higher in the switch to momelotinib treatment group (56.3%) than in the continuing momelotinib group (37.4%).

In the SIMPLIFY-2 trial, the majority of patients in the continuing momelotinib group (64.1%) and the switch to momelotinib treatment group (55.0%) had intermediate-2–risk MF per the Dynamic International Prognostic Scoring System (DIPSS) criteria, and more than 60% of patients in both treatment groups had a positive JAK2V617F mutation status (60.9% versus 72.5% in the continuing momelotinib group and switch to momelotinib treatment group, respectively). A numerically larger proportion of patients in the continuing momelotinib group (57.8%) were transfusion dependent than in the switch to momelotinib treatment group (50.0%). The proportion of patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 1 was higher in the continuing momelotinib group (64.1%) than in the switch to momelotinib treatment group (47.5%). A numerically smaller proportion of patients in the continuing momelotinib group (4.7%) had an ECOG PS of 2 than in the switch to momelotinib treatment group (15.0%). There were no patients with an ECOG PS of 3 in the continuing momelotinib group; 5% of patients in the switch to momelotinib treatment group had an ECOG PS of 3. The proportion of patients with a hemoglobin level less than 8 g/dL was higher in the continuing momelotinib group (28.1%) than in the switch to momelotinib treatment group (7.5%).

Efficacy Results

██ ███████████ ██ ███████ ██ ███ ███ ████████ ██ ███ ███████████ █████ ███ █ ███████ ████████ ██ ███ ████ ██████ ███ ████████████ ██ ██████████ █████████ ██████ ██ ██████████ ██ ███████ █████████ ████ ████████ ██ ███ ██████████████████████ █████ █████████ █████████ ██ ███████████ ██ ███ ██████████ █████████ ██████ ██ ███ █████ ███████████ ████████ ███████ ███ ███████ ██ ███ ████████ ███ █ ███████ ████████ ██ ███ █████ ██ ███████████ ██ ███████ ██ ███ ███ ████████ ██ ███ ███████████ █████ ███ █ ███████ ██ ██ ████████ ██ ███ ███ █████ ██████████ ████████ ███ ████████ ████ ███ ██ ████████████ ███ █ ███████ ████████ ██ ███ ████ ██ ███ ██████████ ██ ██████████ █████████ ██████ █████ ███████ ██ ██ ████████ ██████████ ██ ███ ███ ████████ ████ ███ ██ ███████████ ██████ ███ ██████████ █████████ █████ ████ ██████████ ██ ███ ██████████ In the MOMENTUM trial, most patients (n = 19 of 24; 79.2%) in the continuing momelotinib group and 50.0% of patients (n = 1 of 2) in the switch to momelotinib treatment group who experienced splenic response at week 24 were also classified as experiencing splenic response at week 48. Of those not experiencing splenic response at week 24 in the continuing to momelotinib group (n = 43) and the switch to momelotinib treatment group (n = 28), 23.3% and 10.7%, respectively, were classified as experiencing a splenic response at week 48.

In the MOMENTUM trial, the majority of patients were transfusion independent at week 24 and at week 48, including 88.2% of patients (n = 30 of 34) in the continuing momelotinib group and 80.0% of patients (n = 8 of 10) in the switch to momelotinib treatment group. A majority of patients with at least a 50% reduction from baseline Myelofibrosis Symptom Assessment Form (MFSAF) TSS at week 24 were also experiencing a TSS response at week 48, including 72.0% (n = 18 of 25) in the continuing momelotinib group and all patients (n = 5 of 5; 100%) in the switch to momelotinib treatment group.

Harms Results

In the SIMPLIFY-1 trial, the overall frequencies of TEAEs were numerically higher in patients who switched from ruxolitinib to momelotinib than those who continued on momelotinib (89.8% versus 78.4%, respectively) after 24 weeks of treatment with momelotinib in the open-label extension phase. Similar trends were observed for the most common grade 3 or 4 AEs (37.6% versus 27.5%), for SAEs (23.4% versus 15.8%), and for TEAEs leading to treatment discontinuation (14.7% versus 8.8%), with numerically higher proportions for patients who switched from ruxolitinib to momelotinib than for those who continued on momelotinib. The most reported AEs in both groups, occurring in at least 10% of patients, were diarrhea, thrombocytopenia, anemia, fatigue, nausea, and cough. The most common AEs leading to treatment discontinuation were thrombocytopenia, fatigue, and peripheral sensory neuropathy (no events in the continuing momelotinib group and relatively few [2.0% to 2.5% of patients] in the switch to momelotinib treatment group). Among the continuing momelotinib group and the switch to momelotinib treatment group, the following AEs of special interest (AESIs) were reported: peripheral neuropathy (5.3% versus 7.6% of patients), nonhematological AEs (77.2% versus 87.3% of patients), cataract (4.7% versus 3.6% of patients), and first dose effect (not reported [NR] versus 2.0% of patients). In the continuing momelotinib group, 10.5% of patients died from TEAEs not related to disease progression; in the switch to momelotinib treatment group, this percentage was 8.6%.

In the SIMPLIFY-2 trial, the overall frequencies of the following were numerically higher in patients who switched from BAT to momelotinib than in those who continued on momelotinib: TEAEs (100% versus 93.8%), grade 3 or 4 AEs (55.0% versus 28.1%), SAEs (27.5% versus 20.3%), TEAEs leading to treatment discontinuation (37.5% versus 7.8%), and AEs leading to treatment interruption and/or dose reduction (19.2% versus 16.3%). The most commonly reported AEs occurring in at least 15% of patients were cough and diarrhea in patients who continued momelotinib in the extended treatment phase, and asthenia, pyrexia, diarrhea, thrombocytopenia, cough, and anemia in patients who switched from BAT to momelotinib. The most reported SAEs occurring in at least 5% of patients were anemia, pyrexia, and confusional state in patients who switched from BAT to momelotinib. No patient in the continuing momelotinib group experienced any of these SAEs. The most common AEs leading to treatment discontinuation were thrombocytopenia, diarrhea, and headache (no events in the continuing momelotinib group and events affecting 5.0% to 7.5% of patients in the switch to momelotinib treatment group). Among the continuing momelotinib group and the switch to momelotinib treatment group, the following AESIs were reported: peripheral neuropathy (10.9% versus 20.0%), nonhematological AEs (98.4% versus 100%), cataract (1.6% versus 0%), and first-dose effect (NR versus 7.5%). Deaths due to TEAEs not related to disease progression were reported in 21.9% of patients who continued treatment with momelotinib and 7.5% of patients who switched from BAT to momelotinib.

In the MOMENTUM trial, after 24 weeks of treatment with momelotinib in the open-label treatment phase, the overall frequencies of TEAEs (89.2% versus 85.4%), grade 3 or higher TEAEs (51.6% versus 48.8%), and serious TEAEs (32.3% versus 29.3%) were slightly higher in patients who continued on momelotinib than in those who switched from danazol to momelotinib. The most reported AEs occurring in at least 10% of patients were diarrhea, thrombocytopenia, pyrexia, asthenia, and anemia in patients who continued momelotinib, and thrombocytopenia and diarrhea in those who switched from danazol to momelotinib. The most commonly reported SAEs occurring in at least 2% of patients were urinary tract infection, acute kidney injury, febrile neutropenia, and squamous cell carcinoma of the skin in patients who continued momelotinib, and acute kidney injury and urinary tract infection in those who switched from danazol to momelotinib. The most common AEs leading to treatment discontinuation were anemia, AML, and transformation to AML (no events in the continuing momelotinib group for AML or transformation to AML, and no events in the switch from danazol to momelotinib group for anemia). No deaths due to TEAE not related to disease progression were reported in either of the treatment groups.

Critical Appraisal

Internal Validity

The open-label extension phase design of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials may have biased the reporting of some end points because awareness of the study treatment received may have influenced the perception of improvement and/or harms by patients and clinicians, particularly for outcomes that are subjective in measurement and interpretation (e.g., TSS response rate and subjective AEs). In the open-label extension phases, all patients were taking momelotinib. As such, there was no relevant randomized comparison group (i.e., for any active comparator of interest), which precludes causal conclusions. In terms of protocol deviations, for the SIMPLIFY-2 trial, the proportion of patients with at least 1 important protocol violation was higher in the continuing momelotinib group (20.3%) than in the switch to momelotinib treatment group (10.0%) in the extended treatment phase. No information on protocol deviation for the open-label extension phase of the MOMENTUM study was reported separately; as such, the risk of bias due to deviations from the intended interventions is uncertain. The results are reflective of patients who were able to tolerate and stay on momelotinib (in the continuing momelotinib group). No information on missing data imputations was reported for the open-label extension phase in the SIMPLIFY-1, SIMPLIFY-2, or MOMENTUM Clinical Study Reports provided by the sponsor. In the SIMPLIFY-1 and SIMPLIFY-2 trials, the number of patients who discontinued treatment before week 24 of the open-label treatment phase was higher among those who switched from ruxolitinib to momelotinib or from BAT to momelotinib than among those who continued on momelotinib. The main reason behind this imbalance in both groups was AEs. This imbalance may potentially bias the safety results as patients who were still continuing the open-label extension phase had better tolerability of momelotinib than those who had discontinued.

External Validity

Because the patients who took part in the open-label extension phases were originally from the pivotal trials and the eligibility criteria remained the same, it is reasonable to expect that the same limitations to generalizability are relevant to the open-label extension phases for all 3 studies as were identified for the randomized phases. The trials included patients who were transfusion dependent and patients who were transfusion independent, making the results generalizable to more patients.

Indirect Comparisons

None submitted.

Studies Addressing Gaps in the Evidence From the Systematic Review

The sponsor submitted 2 retrospective analyses and the interim results of 1 ongoing extended access study to address gaps related to long-term survival by baseline transfusion independence status.^1,13,14 These studies were not included in the clinical review report as they provided supplementary evidence rather than addressing specific gaps in the evidence.

Conclusions

Three pivotal RCTs informed the efficacy and safety of momelotinib for the treatment of MF in adults compared to the following: ruxolitinib in patients not previously treated with a JAK inhibitor (SIMPLIFY-1 trial), BAT (which was mostly ruxolitinib) in patients who had been previously treated with a JAK inhibitor (SIMPLIFY-2 trial), and danazol in patients who had been previously treated with a JAK inhibitor and who had anemia (MOMENTUM trial). In patients not previously treated with a JAK inhibitor, momelotinib, as compared to ruxolitinib, resulted in an increased number of patients who were transfusion independent, likely led to little-to-no difference in SRR, but resulted in a decrease in the number of patients with a TSS response. In patients who had been previously treated with a JAK inhibitor, the evidence on the effect of momelotinib compared to BAT on the outcome of SRR was uncertain but showed that momelotinib may increase TSS response and may be likely to result in more patients who are transfusion independent. In patients who had been previously treated with a JAK inhibitor and who had anemia, compared to danazol, momelotinib may result in an increased number of patients with transfusion independence and is likely to increase the SRR and TSS response. As such, it is unclear if momelotinib offers an advantage over existing therapies in SRR or offers better symptom resolution compared to ruxolitinib in patients not previously treated with a JAK inhibitor. However, momelotinib is likely to result in an improvement in blood transfusion outcomes when compared to ruxolitinib.

The safety of momelotinib is in line with that of other JAK inhibitors. There is low-certainty evidence that momelotinib will lead to an increase or decrease in patients with SAEs compared to ruxolitinib, BAT, or danazol.

There is no evidence to inform the comparative efficacy and safety of momelotinib versus fedratinib, and there remains no long-term comparative data on important clinical outcomes such as survival and leukemia progression.

The results available from the long-term extension studies suggest that more than two-thirds of patients experienced sustained efficacy with momelotinib over extended periods. In the open-label extension phases of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, momelotinib appeared to provide ongoing benefits in terms of transfusion independence, splenic response, and symptom relief. Splenic responses were observed in a proportion of patients, particularly those continuing momelotinib treatment, and the majority of patients who were transfusion independent at week 24 maintained this status through extended follow-up.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of momelotinib, 200 mg, administered orally once daily, with 150 mg and 100 mg alternative strengths, for the treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate-risk or high-risk PMF, post-PV MF, or post-ET MF who have moderate to severe anemia.

Disease Background

The contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CDA-AMC review team.

MF is a rare, chronic, and progressive bone marrow disorder classified as a Philadelphia chromosome-negative MPN.^1,2 It is characterized by excessive production of reticulin and collagen fibres in the bone marrow.³ MF can present de novo as PMF or secondary to other conditions, such as ET and PV, termed post-ET MF and post-PV MF, respectively.^1,2 PMF is the most aggressive form of MF and can progress into AML.³ The 10-year risk of transformation to AML for patients with PMF ranges from 10% to 20%.¹⁵

MF originates from acquired mutations targeting hematopoietic stem cells, leading to dysregulation of kinase signalling, clonal myeloproliferation, and abnormal cytokine expression. A mutation in the JAK2 gene is found in nearly all patients (95%) with post-PV MF and approximately 50% to 60% of those with post-ET MF or PMF.^16-18

Diagnosis of MF is based on the 2017 WHO criteria and involves a combination of physical examination, blood tests, imaging, bone marrow biopsy, and molecular testing.⁴ The median age at diagnosis for patients with MF is 67 years.¹⁹ Approximately 30% of patients are asymptomatic at the time of diagnosis, but as the disease progresses, all patients eventually develop symptoms due to bone marrow fibrosis, bone marrow failure, systemic inflammation, and splenomegaly.¹⁹ Key clinical manifestations include severe anemia, thrombocytopenia, marked hepatosplenomegaly, and constitutional symptoms such as fatigue, night sweats, low-grade fevers, itching, bone pain, unintentional weight loss, and cachexia.^16-18 Splenomegaly, a common feature in MF, can result in several complications, including pressure and pain in the left upper quadrant of the abdomen, pain in the left shoulder, early satiety, portal hypertension, splanchnic vein thrombosis, hepatic extramedullary hematopoiesis, and obliterative portal venopathy.²⁰ Massive splenomegaly can lead to severe sequelae, like lower extremity edema and painful splenic infarctions, significantly impacting patients’ quality of life.²¹

MF prognosis can be estimated using scoring systems such as the IPSS and the DIPSS.^17,18,22 These systems evaluate risk factors including age, constitutional symptoms, hemoglobin levels, white blood cell count, and blood blasts. The median OS varies significantly: patients considered to be at low risk have a median OS of 11.3 years, patients considered to be at intermediate-1 risk have a median OS of 7.9 years, patients considered to be at intermediate-2 risk have a median OS of 4 years, and patients considered to be at high risk have a median OS of 1.5 to 2.3 years. Approximately 70% of patients with MF fall into the intermediate-2–risk or high-risk categories.^17,18,22

Anemia and transfusion dependence are negative prognostic factors in MF.²³ At diagnosis, about 40% of patients have moderate anemia (hemoglobin level < 10 g/dL), and nearly all patients develop anemia over time.²⁰ Anemia’s multifactorial pathophysiology in MF can be driven by the disease itself or by myelosuppressive treatments such as JAK inhibitors.^16-18 The median OS for patients with even mild anemia is significantly lower (4.9 years) than for patients without anemia (6 years).²⁰ Transfusion dependence further worsens survival outcomes, with a median survival of 2.6 years for patients who are transfusion dependent versus 8 years for those not requiring transfusions at diagnosis.²³

There is limited evidence on the incidence of MF in Canada. In 2016, approximately 200 individuals were diagnosed with MF in Canada, accounting for 1% of all hematological malignancies.⁵ A Canadian study estimated that between 2011 and 2015, the age-standardized incidence rate of PMF in Canada was 0.80 per 100,000 person-years.⁴ Data from the Ontario Cancer Registry shows that between 2004 and 2016, 1,031 patients were diagnosed with PMF in Ontario, which increased to 1,385 between 2004 and 2019.^24,25 The incidence rates are slightly higher among males than among females.²⁴ As with incidence, the prevalence estimates of PMF in Canada are limited. The prevalence of MF in Canada is estimated to be 6.2 per 100,000 person-years.⁵ In 2016, an estimated 1,800 people in Canada were living with MF, with estimates ranging from 1,400 to 2,177.²⁶ The proportion of patients with intermediate-risk and high-risk MF is estimated to be 15% to 37% and 33% to 37%, respectively.^27,28

Standards of Therapy

The contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CDA-AMC review team.

The only curative treatment option for MF is allogenic HSCT; however, patient eligibility for this treatment is limited, and the procedure is associated with morbidity and mortality.²¹ JAK inhibitors are the current standard of care for MF, with demonstrated efficacy in improving splenomegaly and constitutional symptoms.^6-9 International and national guidelines recommend that patients with HSCT-ineligible intermediate-risk to high-risk MF receive a JAK inhibitor as initial therapy, and ruxolitinib has become standard of care for patients not previously treated with JAK inhibitors who have sufficient platelet and RBC levels.²⁰ In Canada, the treatment recommendation after ruxolitinib is to offer patients HSCT (if eligible), administer a second-line JAK inhibitor (i.e., fedratinib), or enrol patients in a clinical trial.^6-9 However, although fedratinib is approved for patients not previously treated with JAK inhibitors and those previously treated with ruxolitinib, reimbursement is limited to patients who are intolerant of ruxolitinib or for whom ruxolitinib is contraindicated and whose MF did not progress while receiving ruxolitinib.²⁹ Patients who do not have access to fedratinib or another JAK inhibitor after ruxolitinib are treated with suboptimal doses of ruxolitinib or other therapies (i.e., hydroxyurea, steroids, palliative splenectomy, or radiation).

Several supportive therapies are used to address symptomatic anemia in MF, such as androgens (danazol), erythropoiesis-stimulating agents (ESAs), immunomodulating drugs (thalidomide or lenalidomide), corticosteroids (prednisone or prednisolone), and chronic RBC transfusions.²⁰ However, these supportive therapies have demonstrated limited clinical activity in MF-related anemia, and in Canada these supportive therapies are used off-label for managing anemia in MF.

Relief of symptoms and improved health-related quality of life (HRQoL) are important goals for all patients with PMF.²¹ Before the introduction of JAK inhibitors, conventional cytoreductive therapies for patients with symptomatic splenomegaly included hydroxyurea and interferon therapy.^6-9 Hydroxyurea is an oral ribonucleotide reductase inhibitor and is often employed as first-line cytoreductive therapy in post-PV MF and post-ET MF, while for patients with PMF, hydroxyurea is typically reserved for those who have hyperproliferative features including splenomegaly, leukocytosis, and constitutional symptoms who are not eligible for JAK2 inhibitors.³⁰ Adverse effects related to the use of hydroxyurea include dose-limiting cytopenias and oral and lower extremity skin ulcers.³⁰

Currently, the mainstay of pharmacologic-induced spleen reduction in MF is the use of JAK1 and JAK2 inhibitors, such as ruxolitinib. Ruxolitinib is a JAK1- and JAK2-selective inhibitor and is indicated for the treatment of splenomegaly and/or its associated symptoms in adult patients with PMF, post-PV MF, or post-ET MF. The effects of ruxolitinib in reducing spleen volume and improving disease-related symptoms have been demonstrated in clinical trials involving patients with intermediate-risk and high-risk MF, as well as patients who did not experience response with or were intolerant of hydroxyurea.⁸ Although the initial response rate to ruxolitinib therapy is high, patients eventually develop intolerance due to dose-dependent drug-related cytopenias or resistance to ruxolitinib after 2 to 3 years of therapy.^2,8 After ruxolitinib failure, strategies to overcome ruxolitinib resistance or intolerance are limited and mainly involve different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. The goals of treatment are to reduce the symptoms of MF, reduce splenomegaly, and improve OS. Before ruxolitinib becoming the standard of care, patients were treated with hydroxyurea or interferons. These treatments may still be used in select groups of patients (e.g., interferon for patients with the potential to become pregnant, hydroxyurea for patients with severe thrombocytopenia).^2,8

Despite effective pharmacologic options, there are patients who have experienced disease progression but have limited treatment options; more invasive treatment modalities may then be given. Splenectomy, splenic irradiation, and partial splenic artery embolization remain valid therapeutic tools to consider in the management of MF-related splenomegaly.^31-33 Another treatment option for patients with intermediate-risk or high-risk MF is HSCT, but this requires an appropriate donor, and the associated rates of morbidity and mortality limit eligibility.^14,15,33 AEs related to HSCT include treatment-related mortality, graft failure, graft versus host disease, and infection.³⁴

Drug Under Review

Key characteristics of momelotinib are summarized in Table 5, along with other treatments available for MF.

Momelotinib is an orally bioavailable, small-molecule inhibitor of JAK1 and JAK2, and the first JAK1 and JAK2 inhibitor with a differentiated mechanism of action that also inhibits ACVR1.^35-37 Details included in the table are from the sponsor’s summary of clinical evidence. Momelotinib’s mechanism of action involves inhibition of JAK1 and JAK2 signalling, which reduces constitutional symptoms and splenomegaly through decreased inflammatory cytokine signalling, hematopoietic stem cell proliferation, and RBC sequestration. Inhibition of ACVR1 decreases hepcidin expression, restores iron homeostasis, increases serum iron availability for erythropoiesis, facilitates improvements in hemoglobin levels, and decreases the need for RBC transfusion, thus improving anemia.^35-37

Momelotinib is indicated for the treatment of disease-related splenomegaly or symptoms and anemia in adult patients with PMF, post-PV MF, or post-ET MF who have or have not been previously treated with a JAK inhibitor.^35-37 The recommended starting dosage for momelotinib is 200 mg administered once daily, with 150 mg and 100 mg strengths available for dose modification. Momelotinib can be taken with or without food. The sponsor’s reimbursement request is aligned with this proposed indication. Momelotinib received a Notice of Compliance from Health Canada on November 8, 2024.

Table 5: Key Characteristics of Momelotinib, Ruxolitinib, and Fedratinib

b.i.d. = twice daily; ET = essential thrombocythemia; JAK = Janus kinase; JAKi = Janus kinase inhibitor; MF = myelofibrosis; PMF = primary myelofibrosis; PV = polycythemia vera; q.d. = once daily.

^aHealth Canada–approved indication.

Sources: Novartis Pharmaceuticals Canada Inc., 2023 (Health Canada product monograph for ruxolitinib);³⁸ Celgene Inc., 2020 (Health Canada product monograph for fedratinib);³⁹ GSK Data on File draft product monograph momelotinib.⁴⁰

Perspectives of Patients, Clinicians, and Drug Programs

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups. The full original patient input(s) have been included in the Perspectives of Patients, Clinicians, and Drug Programs section of this report.

Two patient groups, LLSC and CMPNN, provided a joint input for this review. Another patient group, Heal Canada, also provided input. Information from the joint input was sourced from 3 online surveys conducted between March 2024 and May 2024. Two surveys (survey 1 and survey 2) were developed by CMPNN and were distributed by both CMPNN and LLSC. Another survey (survey 3) was developed and distributed by both CMPNN and LLSC. Survey 1 (33 respondents) and survey 3 (29 respondents) gathered input from patients and caregivers who had lived experience with MF; survey 2 (11 respondents) was intended to gather information on patient experience with the drug under review. LLSC also conducted 1-on-1 interviews with 2 patients currently living with MF and being treated with momelotinib. Most respondents (70.37%) in survey 3 indicated that they were a patient (past or present), and 25.93% of respondents indicated that they were a caregiver. All respondents from survey 1 and survey 3 were living in Canada; survey 2 received responses from patients living in Canada as well as patients living in the US and Germany. Heal Canada gathered information from Cheryl Petruk, who was a former caregiver of a patient with post-ET MF and the founder of CMPNN. She was also involved in the international MPN landmark survey conducted in 2016, she also supported the recruitment of 64 patients living in Canada, including 28 patients with MF. A total of 174 patients participated in this survey. Other information was gathered from interviews with patients living in Canada being treated for MF (10 respondents), from an online survey conducted in 2024 to assess the impact of frequent transfusion on patients living in Canada (24 respondents), and from literature review.

The joint input from LLSC and CMPNN highlighted that patients often rely heavily on caregiver support to navigate daily life and manage their symptoms, which puts a significant burden on both patients and their caregivers. Caregivers for this input stated that witnessing the decline in their loved one’s health and daily functioning caused substantial stress and anxiety. Patients with MF in this joint input noted that fatigue, enlarged spleen, anemia, night sweats, bone or joint pain, weight loss, early satiety, brain fog, itching or pruritus, gout, and frequent infections were some of the side effects of MF that affected them. Fifty-five percent of respondents mentioned losing income due to MF treatment. When asked about the impact of MF, 85% respondents replied that it had a negative to extremely negative impact on their personal or home life and social life and 65% replied that it had a negative to extremely negative impact on their mental health. Respondents highlighted that low energy, symptom burden, depression and anxiety, fear of infections, and frequent hospital visits were some of the factors that contributed to these negative impacts. Respondents in the Heal Canada landmark survey expressed similar concerns regarding symptom frequency and severity, with 83% of respondents stating that MPN symptoms impacted their quality of life and 58% particularly mentioned bone pain.

Many respondents in the joint input indicated that expenses to attend treatments (e.g., parking, travel) had an impact on them (20 of 33, 60.6%), as did the need to take time off work for treatments (13 of 33; 39.4%); difficulties taking treatments, such as the transfusion process, swallowing pills, and injections (11 of 33; 33.3%); and transfusion dependency (6 of 33; 18.2%). Respondents in the Heal Canada landmark survey also reported a high impact of MF on ability to work, with only 14% of patients being able to work full-time and 11% being able to work part-time. In the 2024 online survey conducted by Heal Canada, 75% of respondents mentioned experiencing or caring for adverse reactions during and after blood transfusion. All respondents from this survey added that the benefits of blood transfusion wear off before the next transfusion. One-half of the respondents from this survey also indicated that receiving regular transfusion had impacted their and their caregivers’ working status.

When respondents in the joint input were asked to choose the top 3 factors that are most important to them when considering new MF treatment options, most respondents (94.74%) selected the amount and severity of side effects as the most important factor, followed by quality of life during treatment (84.21%), the length of time in potential remission (63.16%), financial costs (31.58%), the length and frequency of hospital visits or stays (26.32%), outpatient treatment options (21.05%), distance from home (15.79%), number of treatments (10.53%), and physician recommendation (10.53%).

The joint input highlighted that MPN specialists are not universally available at every community cancer centre, which means some patients and caregivers may need to travel outside their local area to access health care services for MF. The patient groups noted that despite the availability of the current treatment options for MF, not all patients may respond adequately, and even those who do may experience only temporary benefits. Additionally, many patients may not qualify for a potentially curative stem cell transplant. Considering patient responses and health status, along with patient preference, the joint input highlighted that the range of currently available treatment options may be quite limited.

The joint input noted that managing anemia was a significant challenge for patients living with MF, with 63% of respondents receiving blood or platelet transfusions due to MF. When asked about the desired improvements they would like to experience from new treatments, the respondents highlighted reducing symptom burden, enhancing quality of life, and reducing the need for transfusions as some of the desired factors. When respondents were asked about the aspects of the disease they felt were important to control, 58% noted fatigue, 54% noted anemia or need for transfusions, and 37% noted spleen size. The majority of respondents (73%) from survey 2 who had experience with the drug under review stated that they felt momelotinib treatment improved their quality of life.

Clinician Input

Input From Clinical Experts

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of MF.

Unmet Needs

According to the clinical experts, current treatments for MF, including JAK inhibitors like ruxolitinib and fedratinib, address symptoms such as splenomegaly and constitutional symptoms but do not modify the underlying disease or delay its progression. It was noted that the only potentially curative therapy, HSCT, is applicable to less than 10% of patients due to significant associated morbidity and mortality. Not all patients experience a response to available therapies, with only approximately 30% experiencing a splenic response to JAK inhibitors and up to 50% experiencing a response to ESAs for anemia. The experts noted that even when responses are experienced, they are often not durable, with a median response duration of 3 years for ruxolitinib and 2 years for ESAs. Therefore, there is an unmet need for therapies that can provide durable responses, better manage anemia, and possibly modify disease progression.

Place in Therapy

According to the clinical experts, momelotinib would fit into the current treatment paradigm for MF as an option for patients who require JAK inhibitor therapy and have clinically significant anemia. It would be particularly beneficial for patients who have not previously been treated with JAK inhibitors and those who have experienced intolerance or ongoing symptomatic or transfusion-dependent anemia on existing JAK inhibitor therapy. The experts noted that momelotinib could be used both in the first-line setting and as a second-line or third-line treatment, especially in patients with clinically relevant anemia and MPN symptoms. However, it may not be the best option for patients whose primary clinical issue is symptomatic splenomegaly in the context of ruxolitinib resistance or intolerance.

Patient Population

According to the clinical experts, the patients most suited for treatment with momelotinib include those with MF who have not previously been treated with JAK inhibitors and have splenomegaly or MPN symptoms and clinically relevant anemia, those who have experienced intolerance or anemia on JAK inhibitor therapy, and those in whom JAK inhibitor therapy has failed, particularly if anemia or MPN symptoms are present. The experts noted that the patients best suited for treatment can be identified through clinical examination, spleen palpation or measurement, and assessment of anemia parameters such as hemoglobin levels and frequency of RBC transfusions. Patients whose main clinical issue is splenomegaly without anemia or MPN symptoms may be less suitable for momelotinib.

Assessing the Response Treatment

In clinical practice, according to the clinical experts consulted by the review team, response to momelotinib is assessed through a combination of patient-reported outcomes (e.g., improvement in anemia or spleen symptoms), physical examination (including spleen size), and anemia parameters (e.g., hemoglobin levels, transfusion frequency). Response assessments should be conducted approximately every 3 months. A clinically meaningful response includes subjective improvements reported by the patient, objective reduction in spleen size, and improved anemia metrics. The experts noted that the magnitude of the response considered necessary to continue treatment is likely to vary among physicians but that consistency in monitoring is key.

Discontinuing Treatment

According to the clinical experts, treatment with momelotinib should be discontinued if there is no evidence of response after approximately 6 months, if there is a loss of previous response (e.g., worsening of symptoms, spleen size, or anemia), or if grade 3 AEs occur that do not resolve with dose interruption or reduction.

Prescribing Considerations

Momelotinib, as noted by the clinical experts, should be prescribed and monitored by hematologists or oncologists specializing in the treatment of MF. The administration and continued monitoring of patients receiving momelotinib should occur in a hospital outpatient clinic or a specialty clinic setting where appropriate expertise is available. Consideration should also be given to potential regional variations in access to such specialists.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups. The full original clinician group inputs have been included in the Perspectives of Patients, Clinicians, and Drug Programs section of this report.

Clinician group input on the review of momelotinib was received from 2 clinician groups: a joint input from LLSC and the CMPNN Clinician Group, and another input from the OH-CCO Hematology Cancer Disease Site Drug Advisory Committee. A total of 15 clinicians (9 from LLSC and the CMPNN Clinician Group, and 6 from OH-CCO’s drug advisory committees) provided input for this submission.

LLSC and the CMPNN Clinician Group emphasized that the management of anemia remains a critical challenge in MF care. While discussing the unmet needs of patients, the groups highlighted that while the currently available JAK inhibitors can be effective in addressing some symptoms and splenomegaly, they may fail to improve anemia and may exacerbate anemia as an on-target side effect. The groups also noted the lack of approved treatments for MF-associated anemia. They pointed out that anemia, as well as the need for life-saving transfusions, significantly impact patients’ quality of life. The groups further stated that treatments that can decrease the need for transfusions are highly desired in this patient population. The groups noted that for patients considered to be at high risk who are eligible for allogeneic stem cell transplant, fewer transfusions may lead to better outcomes, whereas for patients who are not transplant eligible or who have low-risk MF, the focus is on improving quality of life. In addition, the OH-CCODrug Advisory Committee highlighted that current treatments for this patient population are designed to reduce symptoms, improve blood counts or splenomegaly, and reduce transfusion requirements. Both groups agreed that some treatments are not well tolerated and may not be very effective.

Both clinician groups agreed that patients with MF-associated anemia may benefit from momelotinib in comparison to other available therapies. However, LLSC and the CMPNN Clinician Group added that momelotinib has not yet demonstrated a reduction in the risk of transformation to acute leukemia or mitigated the need for curative allogeneic stem cell transplant in eligible patients. The OH-CCO Drug Advisory Committee noted that treatment responses with momelotinib are based on symptom burden, blood counts, and splenomegaly, whereas LLSC and the CMPNN Clinician Group noted stable disease or improvement in symptom burden, decrease in spleen volume, improvement in hemoglobin, and/or reduction in transfusions as determining factors for outcome assessment. LLSC and the CMPNN Clinician Group elaborated that at least 6 months may be required for assessment of the efficacy of the drug under review. They also added some factors to consider in determining lack of efficacy or deciding on discontinuation of treatment; these factors were increase in transfusion requirement, symptom burden, spleen volume, or severe therapy-related thrombocytopenia or neutropenia. Significant intolerance and clear worsening or lack of response were some factors noted by the OH-CCO Drug Advisory Committee to be considered in deciding on discontinuation of treatment.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Response

Clinical Evidence

The objective of the CDA-AMC clinical review is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of oral momelotinib 200 mg once daily for the treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate-risk or high-risk PMF, post-PV MF, or post-ET MF who have moderate to severe anemia. The focus will be placed on comparing momelotinib to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of momelotinib is presented in 4 sections, with critical appraisal of the evidence by CDA-AMC included at the end of each section. The first section, the systematic review, includes the pivotal studies and RCTs selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section would include indirect evidence from the sponsor (none submitted). The fourth section would include additional studies considered by the sponsor to address important gaps in the systematic review evidence. The sponsor submitted 2 retrospective analyses and 1 set of interim results of an ongoing extended access study to address gaps related to long-term survival by baseline transfusion independence status; however, these were not included in the clinical review report.

Included Studies

Clinical evidence from the following are included in the CDA-AMC review and appraised in this document:

• 3 pivotal studies or RCTs identified in the systematic review

• 3 long-term extension studies.

Systematic Review

The contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CDA-AMC review team.

Description of Studies

Characteristics of the included studies are summarized in Table 7.

The clinical efficacy and safety of momelotinib were assessed in 3 international phase III trials — the SIMPLIFY-1 trial (patients not previously treated with JAK inhibitors) and the SIMPLIFY-2 and MOMENTUM trials (patients previously treated with JAK inhibitors) — in patients with symptomatic PMF, post-ET MF, or post-PV MF and anemia.^{10-12,43,44,49}

SIMPLIFY-1 Trial

The SIMPLIFY-1 trial was a randomized, double-blind study of momelotinib versus ruxolitinib in patients with symptomatic PMF, post-ET MF, or post-PV MF who had not previously received a JAK inhibitor therapy.^10,43 The study was conducted in 112 sites across 22 countries, including Edmonton, Vancouver, Hamilton, and Toronto in Canada (Table 7). Thirteen of the enrolled patients were living in Canada.^10,51 The study design of the SIMPLIFY-1 trial is presented in Figure 1.

Patients were randomly assigned in a 1:1 ratio to receive oral momelotinib plus ruxolitinib placebo or ruxolitinib plus momelotinib placebo for 24 weeks, following 5 weeks of screening.¹⁰ Randomization was stratified by transfusion dependence (presence or absence; defined as ≥ 4 units of RBC transfusions or hemoglobin levels < 8 g/dL in the 8 weeks before randomization, excluding patients with clinically overt bleeding) and by platelet count (< 100 × 10⁹/L, ≥ 100 × 10⁹/L and ≤ 200 × 10⁹/L, or > 200 × 10⁹/L). At the time of the SIMPLIFY-1 study initiation, ruxolitinib was the only approved JAK inhibitor indicated for the treatment of intermediate-risk or high-risk MF in adults and therefore was chosen as the active control for this trial.^10,38,56

Following the completion of the double-blind treatment phase, patients treated with momelotinib or ruxolitinib were eligible to receive momelotinib as an open-label treatment for up to 216 weeks (i.e., through week 240).¹⁰ The planned overall study duration, including screening, double-blind randomized treatment, open-label treatment, and survival follow-up periods, was approximately 5 years.¹⁰

Figure 1: Study Design of the SIMPLIFY-1 Trial

BID = twice daily; ET = essential thrombocythemia; JAK = Janus kinase; MF = myelofibrosis; MMB = momelotinib; QD = once daily; PMF = primary myelofibrosis; PV = polycythemia vera; R = randomization; RUX = ruxolitinib.

Source: GSK Data on File 2021 (SIMPLIFY-2 Clinical Study Report).¹⁰

Table 7: Details of Studies Included in the Systematic Review

AE = adverse event; ALT = alanine transaminase; ANC = absolute neutrophil count; ASCT = allogenic stem cell transplant; AST = aspartate transaminase; BAT = best available therapy; b.i.d. = twice daily; CR = complete remission; CrCl = creatinine clearance; DAN = danazol; DIPSS = Dynamic International Prognostic Scoring System; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ELN = European Leukemia Net; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EMH = extramedullary hematopoiesis; ESA = erythropoiesis-stimulating agent; ET = essential thrombocythemia; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HRQoL = health-related quality of life; ICT = iron chelation therapy; IWG-MRT = International Working Group for Myelofibrosis Research and Treatment; JAK = Janus kinase; LCM = Left Coastal Margin; LFS = leukemia-free survival; MF = myelofibrosis; MF-8D = Myelofibrosis 8 dimensions; MFSAF = Myelofibrosis Symptom Assessment Form; MMB = momelotinib; MPN-SAF = Myeloproliferative Neoplasm Symptom Assessment Form; ORR = overall response rate; OS = overall survival; PBC = peripheral blast count; PBO = placebo; PGI-C = Patient Global Impressions — Change; PMF = primary myelofibrosis; PR = partial remission; PRO = patient-reported outcome; PROMIS = Patient-Reported Outcomes Measurement Information System; PV = polycythemia vera; q.d. = once daily; RBC = red blood cell; RCT = randomized controlled trial; RUX = ruxolitinib; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; SRR = splenic response rate; TD = transfusion dependence; TEAE = treatment-emergent adverse event; TI = transfusion independence; TSS = total symptom score; ULN = upper limit of normal; VAS = visual analogue scale.

Sources: ClinicalTrials.gov 2023 [MOMENTUM];⁵⁰ ClinicalTrials.gov 2023 [SIMPLIFY-1];⁵¹ ClinicalTrials.gov 2023 [SIMPLIFY-2];⁵² GSK Data on File 2016 [SIMPLIFY-1 statistical analysis plan];³⁵ GSK Data on File 2016 [SIMPLIFY-2 statistical analysis plan];³⁶ GSK Data on File 2017 [SIMPLIFY-1 clinical study protocol];⁵³ GSK Data on File 2017 [SIMPLIFY-2 clinical study protocol];⁵⁴ GSK Data on File 2020 [MOMENTUM clinical study protocol];⁵⁵ GSK Data on File 2021 [SIMPLIFY-1 Clinical Study Report];¹⁰ GSK Data on File 2021 [SIMPLIFY-2 Clinical Study Report];¹¹ GSK Data on File 2021 [MOMENTUM statistical analysis plan];³⁷ GSK Data on File 2023 [MOMENTUM Clinical Study Report];¹² Harrison et al. (2018); Mesa et al. (2017); Verstovsek et al. (2023).⁴⁵ Details included in the table are from the sponsor’s summary of clinical evidence.

SIMPLIFY-2 Trial

The SIMPLIFY-2 trial was a randomized, open-label study of momelotinib versus BAT in patients with PMF, post-ET MF, or post-PV MF who experienced suboptimal responses or hematological toxic effects after treatment with ruxolitinib and who experienced National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 anemia, thrombocytopenia, or hematoma during ruxolitinib treatment.^11,44 The study was conducted in 55 sites across 8 countries, including Edmonton, Toronto, and Montreal in Canada (Table 7). Ten of the enrolled patients were living in Canada.^11,52 The study design of the SIMPLIFY-2 trial is presented in Figure 2.

Patients were randomly assigned in a 2:1 ratio to receive oral momelotinib or BAT for 24 weeks, following 30 days of screening.¹¹ Randomization was stratified based on transfusion dependence (presence or absence; defined as ≥ 4 units of RBC transfusions or hemoglobin levels < 8 g/dL in the 8 weeks before randomization) and by baseline TSS (< 18 or ≥ 18).¹¹

Following the completion of the open-label treatment phase, patients treated with momelotinib or BAT were eligible to receive momelotinib as an open-label treatment for up to 204 weeks (i.e., through week 228) in the open-label extension phase.¹¹ The planned overall study duration, including screening, randomized treatment, posttreatment follow-up, and survival follow-up periods, was approximately 5 years.¹¹

Figure 2: Study Design of the SIMPLIFY-2 Trial

BAT = best available therapy; ET = essential thrombocythemia; MF = myelofibrosis; MMB = momelotinib; QD = once daily; PMF = primary myelofibrosis; PV = polycythemia vera; R = randomization.

Source: GSK Data on File 2021 (SIMPLIFY-2 Clinical Study Report).¹¹

MOMENTUM Trial

The MOMENTUM trial was a randomized, double-blind study of momelotinib versus danazol in patients with symptomatic PMF, post-ET MF, or post-PV MF who had anemia (hemoglobin levels < 10 g/dL) and had previously received JAK inhibitor therapy.⁴⁵ The study was conducted in 107 sites across 21 countries, including Vancouver, Halifax, Hamilton, Toronto, Montreal, and Quebec City in Canada (Table 7). Five of the patients were living in Canada.^12,45,50 The study design of the MOMENTUM trial is presented in Figure 3.¹²

Patients were randomly assigned in a 2:1 ratio to receive oral momelotinib plus danazol placebo or danazol plus momelotinib placebo, following a baseline period of 7 days.⁴⁵ Danazol was selected as an active comparator as per the National Comprehensive Cancer Network and European Society for Medical Oncology clinical treatment recommendation for the use of danazol in the treatment of patients with anemia and MF.^7,45,57 Patients receiving JAK inhibitor therapy at screening tapered therapy over at least 1 week, with a lesser (or no) tapering period for those receiving a low-dose JAK inhibitor therapy. Patients then completed a nontreatment period of at least 2 weeks beginning at least 7 days before the first day of the baseline period. Patients were stratified based on MFSAF TSS (< 22 or ≥ 22), baseline palpable spleen length below the left costal margin (< 12 cm or ≥ 12 cm), baseline RBC or whole blood units transfused in the 8 weeks before randomization (0 units, 1 to 4 units, or ≥ 5 units), and study site.^12,45

Patients treated with momelotinib or danazol were eligible to receive momelotinib as an open-label treatment for up to 180 weeks (i.e., through week 204) in the open-label extension phase.^12,45 The planned overall study duration, including screening, baseline, double-blind randomized treatment, open-label treatment, safety follow-up, and long-term follow-up periods, was approximately 7 years.¹²

Populations

Inclusion and Exclusion Criteria

The SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials included adult patients (aged ≥ 18 years) with a confirmed diagnosis of PMF per the WHO criteria or of post-PV MF or post-ET MF per the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.^10-12,43-45 Patients with high-risk, intermediate-2–risk, or intermediate-1–risk MF, as defined by the IPSS (the SIMPLIFY-1 trial), the DIPSS (the SIMPLIFY-2 trial), or the DIPSS-plus (the MOMENTUM trial), were included in the studies. Patients had baseline palpable splenomegaly (≥ 5 cm below the left costal margin), an ECOG PS of less than or equal to 2, and a life expectancy of more than 24 weeks. The SIMPLIFY-1 trial comprised patients who had not previously received a JAK inhibitor, and the SIMPLIFY-2 and MOMENTUM trials comprised patients who had previously received treatment with a JAK inhibitor.^10-12,43-45

Patients in the SIMPLIFY-2 study had experienced complications with prior ruxolitinib treatment, such as hematologic toxicity, as characterized by a requirement for RBC transfusion while on ruxolitinib, or a dosage adjustment of ruxolitinib to less than 20 mg twice daily at the start of or during treatment and the occurrence of CTCAE grade 3 or 4 thrombocytopenia, anemia, or hematoma while receiving ruxolitinib.^11,44 While the SIMPLIFY-1 trial included patients with a baseline platelet count of at least 50 × 10⁹/L and the MOMENTUM trial included patients with a baseline platelet count of at least 25 × 10⁹/L, there was no minimum platelet count eligibility criterion for the SIMPLIFY-2 trial.^10-12 The MOMENTUM study also required patients to have a baseline hemoglobin level of less than 10 g/dL.^12,49

Patients were excluded from all the trials if they had prior splenectomy, were unwilling or unable to undergo MRI or CT imaging, had splenic irradiation 3 months or less before the first dose of the study drug, had received prior treatment with momelotinib, and (for the SIMPLIFY-1 trial only) prior treatment with a JAK1 inhibitor or JAK2 inhibitor.^10-12,43-45

Figure 3: Study Design of the MOMENTUM Trial

DAN = danazol; JAKi = Janus kinase inhibitor; MFSAF = Myelofibrosis Symptom Assessment Form; MMB = momelotinib; TSS = treatment symptom score.

^[1] Patients treated with MMB who completed at least 24 weeks of randomized treatment were eligible for open-label MMB (patient remained blinded). Patients treated with MMB who discontinued treatment early and continued assessments through week 24 or experienced splenic progression were ineligible for open-label MMB (patient was unblinded).

^[2] Crossover from randomized DAN to open-label MMB was allowed, as follows: at end of week 24 if the patient completed the randomized treatment period (patient remained blinded); at end of week 24 if the patient discontinued DAN early but continued study assessments and did not receive prohibited medications unless approved by the sponsor (patient was unblinded); or before the end of week 24 if the patient met criteria for confirmed splenic progression (patient was unblinded).

^[3] Patients treated with DAN receiving clinical benefits after 24 weeks of randomized treatment were eligible for open-label DAN (patient was unblinded).

^[4] Transition to an MMB extension study (SRA-MMB-4365, XAP) was allowed for patients who completed at least 24 weeks of open-label treatment with MMB.

^[5] Patients who completed the safety follow-up visit in the MOMENTUM trial were transitioned to extension study for long-term survival follow-up.

Source: GSK Data on File 2023 (MOMENTUM Clinical Study Report).¹²

Interventions

In the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, patients randomized to the momelotinib arm self-administered momelotinib at a dosage of 200 mg once daily, orally, followed by postdose observation period of at least 4 hours.^10-12,53,54 Treatment with momelotinib was continued until disease progression, confirmed splenic progression, leukemic transformation, pregnancy, or toxicity.^10-12 In the SIMPLIFY-1 and MOMENTUM trials, the momelotinib placebo tablets were visually identical to the momelotinib tablets but without any active ingredients.^10-12

In the SIMPLIFY-1 trial, ruxolitinib was self-administered orally (1 to 2 tablets), with the starting dosage ranging from 5 mg to 20 mg twice daily based on platelet count, creatinine clearance, and aspartate aminotransferase or alanine aminotransferase levels.¹⁰ In the SIMPLIFY-2 trial, patients receiving BAT received treatment at doses and schedules as determined by the investigator per standard of care.¹¹ Regimens for BAT included chemotherapy (e.g., hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, immunomodulating agent, androgen, and interferon. No active treatment was also an option for patients randomized to the BAT arm of the SIMPLIFY-2 trial.¹¹ Treatment switching, interruptions, or holds and treatment with ruxolitinib were also permitted in the BAT arm.^11,54 In the MOMENTUM trial, the active comparator, danazol, was self-administered by patients orally, with a starting dosage of 300 mg twice daily (for a total dose of 600 mg per day).¹²

In the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, treatment with momelotinib or comparators (ruxolitinib, BAT, or danazol, respectively) was interrupted if any of the following occurred: thrombocytopenia, an absolute neutrophil count of less than 0.5 × 10⁹/L, grade 3 or 4 nonhematologic toxicity, or a grade 2 or higher bleeding event.^10-12 Dose re-escalation was allowed following the resolution of toxicity or return to baseline grade, at the investigator’s discretion.^10-12

In the event of insufficient splenic response (a < 50% reduction from the pretreatment baseline in palpable spleen length or a < 35% reduction in spleen volume, as measured by CT or MRI) in the SIMPLIFY-1 and SIMPLIFY-2 trials, for patients receiving less than 200 mg per day of momelotinib, the dose was increased in 50 mg increments up to 200 mg per day, provided there were no new or recurrent instances of the following: momelotinib-related grade 3 or 4 nonhematologic toxicities, grade 2 or higher bleeding, a platelet count less than 50 × 10⁹/L, and/or an absolute neutrophil count of less than 0.75 × 10⁹/L.^10,11 In the SIMPLIFY-1 and SIMPLIFY-2 trials, momelotinib was permanently discontinued if grade 3 or 4 treatment-related nonhematologic toxicity led to treatment interruption at the 100 mg once daily dosage and recurred after restarting momelotinib at the same dosage.^10,11

In the MOMENTUM trial, dose reduction with re-escalation following resolution of symptoms was recommended for patients who experienced mild dizziness or light headedness, hypotension, flushing, nausea, or headache that persisted or recurred beyond the first day of dosing.¹² During randomized treatment, doses of the study treatment (i.e., momelotinib plus danazol placebo or danazol plus momelotinib placebo) were reduced by sequential decrements as presented in Table 8.

In the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, anti-hypertensive therapy was withheld for at least 4 hours after study drug administration on the first day of dosing.^10-12 Patients requiring anti-hypertensive therapy were observed, and anti-hypertensive medication could be administered if considered clinically necessary. Potent CYP3A4 inducers in the MOMENTUM trial and dual CYP3A4 and CYP2C9 inducers were permitted with prior sponsor approval.^10-12

In the MOMENTUM trial, alternatives to breast cancer resistance protein transporter or modified breast cancer resistance protein transporter substrates were permitted, as clinically indicated during the study treatment. Steroids were permitted for the treatment non-MF conditions as supportive care if initiated before screening and continuing at a stable dosage equivalent to no more than 10 mg prednisone daily. If clinically indicated, the steroids could be temporarily increased for up to 10 days (cumulative) in any 28-day period or, if clinically indicated, could be initiated for up to 10 days (cumulative) in any 28-day period. Temporary use of restricted anti-MF medications was permitted for severe splenic progression that required immediate action for patients continuing in the study, until confirmed splenic progression.¹²

Concomitant use of the following agents was prohibited:^10-12

• SIMPLIFY-1 trial: Experimental therapy other than momelotinib, anti-MF therapy, chemotherapy, immunomodulators, systemic corticosteroids, androgens for the treatment of MF, ESAs, interferons, JAK inhibitors other than ruxolitinib, and granulocyte colony-stimulating factor (unless administered for the treatment of neutropenic fever).

• SIMPLIFY-2 trial: Experimental therapy other than momelotinib and anti-MF therapy, including hematopoietic growth factor.

• MOMENTUM trial: Concomitant use of anti-MF therapy, including JAK inhibitors, alkylating agents, hypomethylating agents, interferons, ESAs, immunomodulating agents, corticosteroids, androgens, growth factors, splenic irradiation, and splenectomy, as well as the use of investigational agents within 3 months before randomization. Steroids for the treatment of MF were prohibited within 1 week before the day 1 baseline until study drug discontinuation.

Table 8: Treatment Dose Reduction in the MOMENTUM Trial

Source: GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹²

In the double-blind treatment phase of the SIMPLIFY-1 and MOMENTUM trials, the identity of the study drug was concealed by central blinding of study drug assignments and randomization was achieved via the Interactive Response System. Treatment assignment remained blinded unless unblinding was required for emergency medical care.^10,12 In the SIMPLIFY-1 trial, treatment assignments in the randomized treatment phase remained blinded until all patients had completed week 24 and the study was unblinded for the final efficacy analysis.¹⁰ In the MOMENTUM study, patients in the momelotinib plus danazol placebo arm who received momelotinib in the open-label treatment period remained blinded to their randomized treatment, whereas patients who received danazol in the open-label treatment period as well as those with confirmed symptomatic splenic progression before week 24 were unblinded to their treatment assignment after completing week 24 to confirm their treatment in the randomized treatment period.¹²

Outcomes

A list of efficacy end points assessed in this clinical review report is provided in Table 9, followed by descriptions of the outcome measures. The summarized end points are based on the outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical experts consulted by CDA-AMC and input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected the end points that were considered to be most relevant to inform the expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing the expert committee deliberations were also assessed using GRADE. End points are associated with time points that would allow the information to be clinically relevant. Given the design of the trials (with crossovers to momelotinib after week 24), end points reported after the double-blind period would have significant limitations in interpretations and generalizability. Thus, any clinically relevant end points with a clinically relevant time point beyond 24 weeks were not included as part of the main outcomes of this report.

Table 9: Outcomes Summarized From the Studies Included in the Systematic Review

JAK = Janus kinase; MFSAF = Myelofibrosis Symptom Assessment Form; MPN-SAF = Myeloproliferative Neoplasm Symptom Assessment Form; NR = not reported; RBC = red blood cell.

^aStatistical testing for these end points was adjusted for multiple comparisons through hierarchal testing.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.

Transfusion Independence Response Rate at Week 24

Across all 3 trials, transfusion independence was defined as the absence of RBC transfusions and no hemoglobin levels less than 8 g/dL in the prior 12 weeks, except in the case of clinically overt bleeding.^53-55

SRR at Week 24

Across all 3 trials, SRR was defined as the proportion of patients with at least a 35% reduction from baseline in spleen volume as measured by MRI or CT at week 24.^53-55 The clinical experts consulted by CDA-AMC identified this threshold as clinically meaningful.

Rate of RBC Transfusion at Week 24

In the SIMPLIFY-1 and SIMPLIFY-2 trials, the rate of RBC transfusion was defined as the average number of RBC units per patient-month during the randomized treatment phase (through week 24).^35,36 The rate of RBC transfusion was not reported in the MOMENTUM trial; instead, the total number of transferred units was used to inform this outcome.

MFSAF TSS Response Rate at Week 24

The MFSAF is a validated MF-specific quality-of-life and symptom assessment form that evaluates the severity of 7 key symptoms experienced by patients with MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain.⁵⁸ The 7 symptom domains are assessed on an 11-point numeric rating scale, ranging from 0 to 10, with the TSS representing the sum of the scores across these 7 domains, ranging from 0 to 70. Higher symptom scores correspond to more severe symptoms.³⁷ In the MOMENTUM trial, MFSAF version 4.0 was used.¹² Validation was conducted in the MOMENTUM trial as outline in Table 10.

The MFSAF TSS response rate was the primary end point in the MOMENTUM trial.¹² It was defined as the proportion of patients with at least a 50% reduction from baseline in mean MFSAF TSS over the 28 days immediately before the end of week 24. No clear rationale was given for this threshold being chosen. However, the clinical experts consulted by CDA-AMC suggested that this threshold is clinically meaningful. The baseline MFSAF TSS was calculated as the mean of the daily TSS values collected over the baseline period of the 7 consecutive days before randomization.^12,37

MPN-SAF TSS Response Rate at Week 24

The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a validated HRQoL measure that evaluates symptom burden and symptom status during the treatment of patients with MPN.^10,11 The modified MPN-SAF version 2.0 is an 8-item questionnaire that consists of 9 symptom domains assessed on an 11-point numeric rating scale, ranging from 0 to 10, with the TSS representing the sum of the scores across these 9 domains, with a range from 0 to 80. The items assess the worst daily occurrences of tiredness, early satiety, abdominal discomfort, night sweats, itching, bone pain, pain under the left ribs, and inactivity. Higher symptom scores correspond to more severe symptoms.^10,11 No information was available on the validity of the questionnaire, as indicated in Table 10.

In the SIMPLIFY-1 and SIMPLIFY-2 trials, the MPN-SAF TSS response rate was a secondary efficacy end point. It was defined as the proportion of patients who have experienced at least a 50% reduction from baseline in mean MFSAF TSS over the 28 days immediately before the end of week 24. No clear rationale was given for this threshold being chosen. However, the clinical experts consulted by CDA-AMC suggested that this threshold is clinically meaningful. The baseline MPN-SAF TSS was calculated as the mean of the daily TSS values collected over the baseline period of the 7 consecutive days before randomization.^53,54

Overall Survival

OS was defined as the interval from the first study drug dosing date in the randomized treatment phase (or randomization in patients who did not receive treatment) to death from any cause.^35-37

Comparative data are only available up to week 24 and are not considered to be clinically relevant according to the feedback received from the clinical experts consulted by CDA-AMC. In the 3 included studies, patients switched to momelotinib after the randomized period (week 24). Results from the extension phase are outlined in Appendix 1.

Leukemia-Free Survival

Across all 3 trials, leukemia-free survival was defined as the interval from the first study drug dosing date (or randomization date for patients who did not receive treatment) to the date of any evidence of leukemic transformation or death from any cause. Leukemic transformation was defined according to IWG-MRT and European Leukemia Net criteria as a bone marrow blast count of at least 20% or a peripheral blood blast content of at least 20% associated with an absolute blast count of at least 1 × 10⁹/L that lasts for 2 weeks or longer.^10-12

Comparative data are only available up to week 24 and are not considered to be clinically relevant according to the feedback received from the clinical experts consulted by CDA-AMC. In the 3 included studies, patients switched to momelotinib after the randomized period (week 24). Results from the extension phase are outlined in Appendix 1.

Safety

The safety of momelotinib in patients with untreated PMF, post-ET MF, or post-PV MF was assessed in the safety analysis set of the SIMPLIFY-1 and SIMPLIFY-2 trials and the in safety population of the MOMENTUM trial using descriptive analyses.^10-12 The Medical Dictionary for Regulatory Activities version 22.0 was used to classify AEs by system organ class and preferred term in the SIMPLIFY-1 and SIMPLIFY-2 trials, and the Medical Dictionary for Regulatory Activities version 24.0 was used in the MOMENTUM trial. AEs were graded using CTCAE version 4.03 in the SIMPLIFY-1 and SIMPLIFY-2 trials and using CTCAE version 5.0 in the MOMENTUM trial.^10-12

Safety data reported in this submission are based on the respective Clinical Study Reports for the most recent database locks in each trial — July 1, 2019, for the SIMPLIFY-1 trial; June 25, 2019, for the SIMPLIFY-2 trial; and December 3, 2021, for the MOMENTUM trial — unless otherwise specified.^10-12

Table 10: Summary of Outcome Measures and Their Measurement Properties

BPI = Brief Pain Inventory; HRQoL = health-related quality of life; ITT = intention to treat; MID = minimal important difference; MF = myelofibrosis; MFSAF = Myelofibrosis Symptom Assessment Form; MPN = myeloproliferative neoplasm; MPN-SAF = Myeloproliferative Neoplasm Symptom Assessment Form; MSAS = Memorial Symptom Assessment Scale; PGI-C = Patient Global Impressions — Change; PGI-S = Patient Global Impressions — Severity; TSS = total symptom score.

Statistical Analysis

Clinical Trial End Points

Transfusion Independence Status at Week 24

In the SIMPLIFY-1 and SIMPLIFY-2 trials, transfusion-independent status at week 24 was a secondary end point; it was a key secondary end point in the MOMENTUM trial.^35-37

In the SIMPLIFY-1 and SIMPLIFY-2 trials, the 95% exact CI was calculated using the Clopper-Pearson method without stratification.^35,36 The 12-week period at week 24 for the absence of transfusion was the consecutive 84-day period with the last day as the earliest date of day 176, or the last randomized treatment phase participation date if the last date is after or on day 162. For the primary analysis of transfusion-independent status at week 24, a patient whose last randomized treatment phase participation was before day 162 was considered not transfusion independent. The noninferiority of momelotinib over ruxolitinib or BAT was evaluated in a similar way as for SRR at week 24 using the Cochran-Mantel-Haenszel (CMH) approach (refer to the SRR at Week 24 section). Three sensitivity analyses were conducted (Table 11).^35,36

In the MOMENTUM trial, a synthesis approach was used to determine the noninferiority of momelotinib versus danazol, wherein the treatment effect of the active control (danazol) was not prespecified, but the proportion of the active control effect to be preserved was specified (i.e., 80% of the response rate in the danazol arm should be preserved in the momelotinib arm). A stratum-adjusted 2-sided 95% CI was calculated to determine the noninferiority treatment difference (lower bound of CI > 0 demonstrates noninferiority of momelotinib versus danazol).³⁷

Rate of RBC Transfusion

In the SIMPLIFY-1 and SIMPLIFY-2 trials, the rate of RBC transfusion was a secondary end point. A negative binomial regression method with an offset parameter was used to analyze the rate of RBC transfusion.^35,36 A time-to-event analysis employing the proportional means model was used as a supportive analysis. To accommodate the presence of multiple units in a transfusion, the recurrence times were perturbed, ensuring they did not appear identical. When calculating RBC transfusion-related end points, transfusions due to clinically overt bleeding were excluded from the calculation. Missing transfusion units were imputed by 2 units.^35,36

In the MOMENTUM trial, a proportional rate or mean model was performed as an exploratory analysis, treating each transfusion unit as a recurrent event, including follow-up time after the last transfusion, and censoring patients at their last follow-up date. A weighting based on the number of units transfused was applied to the transfusion event to calculate the number of units used in a transfusion.³⁷

TSS Response Rate at Week 24

The TSS response rate at week 24, as measured using the modified MPN-SAF, was the first key secondary end point in the SIMPLIFY-1 and SIMPLIFY-2 trials.^35,36 The TSS at week 24 was calculated as the average of daily TSS from a 28-day consecutive period before week 24. The response rate in TSS at week 24 was analyzed for patients who had a baseline TSS greater than or equal to 0 but a nonzero or missing TSS at week 24. Patients with a missing week 24 TSS but a nonmissing baseline TSS were considered not to experience a response. The noninferiority of momelotinib over ruxolitinib or BAT was evaluated in a similar way as for SRR at week 24 using the CMH approach (refer to the SRR at Week 24 section). In the SIMPLIFY-1 trial, the noninferiority of momelotinib was assessed by comparing the difference in TSS response rates at week 24, aiming for a 67% preservation of the ruxolitinib effect, using the CMH approach to adjust for stratification factors at a 2-sided 0.05 level. If noninferiority was established, the 2-sided 95% CI for the difference was then used to evaluate superiority. No clinical rationale was given for the decision to preserve 67% of the treatment effect. The percentage change in TSS from baseline to week 24 was calculated as:^35,36

percentage change = 100 × (week 24 TSS – baseline TSS)/baseline TSS

To evaluate the robustness of the primary results, 5 sensitivity analyses were performed in the SIMPLIFY-1 trial and 4 in the SIMPLIFY-2 trial (Table 11).^35,36

The TSS response rate at week 24, as measured by the MFSAF, was the primary end point in the MOMENTUM trial.³⁷ The TSS at week 24 was calculated as the average of the daily TSS from a 28-day consecutive period before week 24. Patients with a missing week 24 TSS, as well as those with daily TSS measurements for fewer than 20 days during the consecutive 28-day period, were classified as not experiencing a response. The primary analysis of MFSAF TSS response was performed on the intention-to-treat (ITT) analysis set using a stratified CMH test. Primary inference was based on the asymptotic P value, in turn based on the Wald statistic from this CMH test. To evaluate the robustness of the primary results, 3 sensitivity analyses were performed. Further, a sensitivity analysis was conducted on data collected before the treatment switch (danazol to momelotinib), in case more than 10% of patients crossed over from danazol to momelotinib treatment before the end of week 24.³⁷

SRR at Week 24

In the statistical hierarchy of primary and secondary end points in the SIMPLIFY-1 and SIMPLIFY-2 trials, the primary analysis was for SRR at week 24.^35,36 In the MOMENTUM trial, SRR at week 24 was a key secondary end point.³⁷

In the SIMPLIFY-1 and SIMPLIFY-2 trials, the noninferiority of momelotinib over ruxolitinib or BAT was determined using a conventional 2-sided 95% CI greater than 0, based on a stratum-adjusted CMH proportion.^35,36 Additionally, a 2-sided 95% exact CI was provided for each treatment arm based on the Clopper-Pearson method. The noninferiority test aimed to preserve 60% of the treatment effect size of ruxolitinib in the SIMPLIFY-1 trial. No clinical rationale was provided to support the preservation threshold. To evaluate the robustness of the primary results, 4 sensitivity analyses were performed.^35,36

In the MOMENTUM trial, the primary analysis of splenic response was performed on the ITT analysis set, as well as on the per-protocol analysis set for sensitivity purposes, using a CMH test after adjusting for stratification factors.³⁷

Across the 3 trials, patients with a missing baseline spleen volume, a missing scan, or unavailable week 24 spleen volume due to early discontinuation of the randomized treatment phase were considered not to experience a response.^35-37 In addition, patients with splenic assessments (by MRI or CT) taken more than 10 days after the beginning of the open-label treatment phase and patients receiving other anti-MF therapy during the randomized treatment phase were considered not to experience a response in the MOMENTUM trial.³⁷

Safety Outcomes

Safety outcomes were reported by treatment arm and phase using descriptive statistics and graded on the National Cancer Institute CTCAE version 4.03 in the SIMPLIFY-1 and SIMPLIFY-2 trials and CTCAE version 5.0 in the MOMENTUM trial. Safety assessments included AEs, SAEs, AEs leading to premature discontinuation of the study drug, AEs leading to a dose reduction of the study drug, AEs leading to deaths, AESI, and laboratory evaluations.^35-37

Handling of Missing Data

The conventions used for inputting missing data are presented in Table 11. In the SIMPLIFY-1 and SIMPLIFY-2 studies, missing data for the transfusion independence outcome were addressed in the primary analysis by classifying patients with incomplete transfusion independence data as nonresponders; additional imputation methods were applied in the sensitivity analyses to assess the robustness of the results to different assumptions. The MOMENTUM study used a similar approach, categorizing patients with missing transfusion independence data as nonresponders. For the rate of RBC transfusion, both SIMPLIFY studies imputed missing transfusion units as 2 units and applied standard rules for partial date imputation. Assessments up to 10 days after the first momelotinib dose in the extended treatment phase and between days 141 and 197 from the date of randomization were used for week 24 spleen volume if no assessment was available in the randomized phase before or on the date of the first momelotinib dose in the extended treatment phase and between days 141 and 197.^11,36 Patients who discontinued early in the randomized treatment phase before an efficacy assessment visit or with missing assessments at the corresponding visit for MRI spleen response, TSS response, and transfusion independence response were considered to be patients with missing transfusion independence data.³⁶

The MOMENTUM study handled missing data by using a recurrent event model, treating each transfusion as a separate event and censoring patients at their last follow-up. For the SRR and TSS response at week 24 in the primary analysis, all studies classified patients with missing TSS data as nonresponders. Sensitivity analyses, including the last observation carried forward (LOCF) method, were used to assess the impact of the approach for handling missing data.

For safety data, missing data were generally not imputed across the studies. Analyses focused on the observed data, with safety outcomes like AEs reported descriptively.

Sample Size and Power Calculation

SIMPLIFY-1 Trial

The study sample size for the SIMPLIFY-1 trial was based on the primary end point of SRR at week 24.³⁵ The sample size was calculated to compare the SRR at week 24 among participants randomized to receive momelotinib plus ruxolitinib placebo versus ruxolitinib plus momelotinib placebo.³⁵

A sample size of 420 was estimated for randomization to the 2 treatment arms in a 1:1 ratio, based on the assumption of the common treatment effect of momelotinib and ruxolitinib on SRR being 34% (based on the lower bound of the 95% CI of the ruxolitinib effect on SRR observed in Study 351 COMFORT-I).³⁵ This sample size provided more than 90% power for testing the noninferiority hypothesis of SRR at week 24. The sample size calculation also considered the comparison of the TSS response rate at week 24 among participants randomized to receive momelotinib plus ruxolitinib placebo versus ruxolitinib plus momelotinib placebo.³⁵

A sample size of 420 was estimated to provide more than 90% power for testing the noninferiority hypothesis of TSS response rate at week 24, based on the assumption of the common treatment effect of momelotinib and ruxolitinib on TSS response rate at week 24 being 38% (based on the lower bound of the 95% CI of the ruxolitinib effect on TSS response rate observed in Study 351 COMFORT-I).³⁵

With a total sample size of 420, the study was estimated to yield 85% power to detect for testing at least a 15% difference between the 2 treatment arms in the transfusion independence and transfusion dependence rates using a chi-square test.³⁵

SIMPLIFY-2 Trial

The study sample size for the SIMPLIFY-2 trial was based on the primary end point of SRR at week 24.³⁶ The sample size was calculated to compare the SRR at week 24 among participants randomized to receive momelotinib plus BAT-placebo versus BAT plus momelotinib placebo.³⁶

Based on historical data from momelotinib studies and BAT trials, a sample size of 150 was estimated for randomization to the 2 treatment arms in a 2:1 ratio.³⁶ This sample size was based on the common treatment effect on SRR at week 24 in patients previously treated with ruxolitinib being 20% for momelotinib (SRR at week 24 being 23.5% and 33.3% from the CCL09101 and YM387-II-02 studies, respectively) and 1% for BAT (0 out of 73 patients experienced splenic response at week 24 in Study 352 COMFORT-II). With a total sample size of 150, the study was estimated to yield more than 95% power at a 2-sided level of 0.05 using the Fisher exact test.³⁶

MOMENTUM Trial

The study sample size for the MOMENTUM trial was based on the first primary end point of TSS response rate at week 24, the second primary end point of transfusion independence response rate at week 24, and the first key secondary end point of SRR at week 24.³⁷ The sample size was calculated to compare the TSS response rate, the transfusion independence response rate, and SRR at week 24 among participants randomized to receive momelotinib plus danazol placebo versus danazol plus momelotinib placebo.³⁷

A sample size of 180 was estimated for randomization to the 2 treatment arms in a 2:1 ratio.³⁷ With a total sample size of 180, the study was estimated to yield 98.8% power to detect a true difference of 21% (23% with momelotinib versus 2% with danazol) or 90% power to detect a true difference of 15% (17% with momelotinib versus 2% with danazol) in TSS response rate at week 24 using a 2-sided significance of 0.05. Further, with a total sample size of 180, the study was estimated to yield 90% power to detect a true difference of 24% in the proportion of patients with transfusion-independent status (45% with momelotinib versus 21% with danazol) and a true difference of 14% in SRR at week 24 (15% with momelotinib versus 1% with danazol).³⁷

Statistical Testing

SIMPLIFY-1 Trial

A hierarchical testing procedure controlled at 5% (2-sided) was used to control for type I errors for the primary end point and key secondary end points.³⁵

The primary analysis was for SRR at week 24.³⁵ Sequential testing of key secondary end points was conducted only if the primary efficacy analysis was noninferior at the applicable alpha level (0.05). If the SRR at week 24 was statistically significant, then the key secondary end points — TSS response rate at week 24, transfusion independence response rate at week 24, transfusion dependence rate at week 24, and rate of RBC transfusion in the randomized treatment phase — were to be tested (Figure 4). Other end points were not formally tested in a hierarchal testing procedure. The primary analysis of the primary efficacy end point and the secondary end points was conducted when each patient completed the randomized treatment period (July 1, 2019).³⁵

Figure 4: SIMPLIFY-1 Trial Gatekeeping Process for Multiple Hypothesis Tests

RBC = red blood cell; RUX = ruxolitinib; SRR = splenic response rate; TD = transfusion dependence; TI = transfusion independence; TSS = total symptom score.

Note: Statistical significance at P ≤ 0.05.

Source: GSK Data on File, 2016 (SIMPLIFY-1 statistical analysis plan).³⁵

SIMPLIFY-2 Trial

The hierarchical testing procedure in the SIMPLIFY-2 trial was similar to that in the SIMPLIFY-1 trial. A hierarchical testing procedure controlled at 5% (2-sided) was used to control for type I errors for the primary end point and key secondary end points.³⁶

The primary analysis was for SRR at week 24.³⁶ Sequential testing of key secondary end points was conducted only if the primary efficacy analysis was significantly superior at the applicable alpha level (0.05). If the SRR at week 24 was statistically significant, then the key secondary end points — TSS response rate at week 24, rate of RBC transfusion in the randomized treatment phase, transfusion independence response rate at week 24, and transfusion dependence rate at week 24 — were to be tested (Figure 5). Other end points were not formally tested in a hierarchal testing procedure.³⁶ The primary analysis of the primary efficacy end point and the secondary end points was conducted when each patient completed the randomized treatment period (June 25, 2019).^11,36

Figure 5: SIMPLIFY-2 Trial Gatekeeping Process for Multiple Hypothesis Tests

BAT = best available therapy; RBC = red blood cell; RT = randomized treatment; SRR = splenic response rate; TD = transfusion dependence; TI = transfusion independence; TSS = total symptom score.

Note: Statistical significance at P ≤ 0.05.

Source: GSK Data on File, 2016 (SIMPLIFY-2 statistical analysis plan).³⁶

MOMENTUM Trial

A hierarchical testing procedure controlled at 5% (2-sided) was used to control for type I errors for the primary end point and key secondary end points.³⁷

The primary analysis was for MFSAF TSS response rate at week 24.³⁷ Sequential testing of key secondary end points was conducted only if the primary efficacy analysis was significantly superior at the applicable alpha level (0.05). If the MFSAF TSS response rate at week 24 was statistically significant, then the key secondary end points — transfusion independence status at week 24, SRR at week 24 (based on the 25% reduction criterion), MFSAF TSS change from baseline at week 24, SRR at week 24 (based on the 35% reduction criterion), and the rate of no transfusion at week 24 — were to be tested (Figure 6). Other end points were not formally tested in a hierarchal testing procedure.³⁷

The primary analysis of the primary efficacy end point was conducted when each patient completed the randomized treatment period, crossed over early, or dropped out from the randomized treatment (December 3, 2021).^12,37 The study was unblinded at the data cut-off date of December 3, 2021, and all other study end points were analyzed, except for transfusion independence status and SRR at week 24, which were analyzed at the database lock of January 17, 2023.¹² All the data before the data cut-off, including the data from the open-label extended treatment period, were included in the primary analysis.

Figure 6: MOMENTUM Trial Gatekeeping Process for Multiple Hypothesis Tests

DAN = danazol; MFSAF = Myelofibrosis Symptom Assessment Form; SRR = splenic response rate; TI = transfusion independence; TSS = total symptom score.

Notes: If noninferiority is established for TI status, then the P value associated with the test of superiority was estimated. Statistical significance at P ≤ 0.05.

Source: GSK Data on File, 2021 (MOMENTUM statistical analysis plan).³⁷

Subgroup Analyses

SIMPLIFY-1 Trial

Prespecified subgroup analyses were performed by age, sex, race, geographical region, baseline transfusion dependence, baseline spleen volume, TSS at baseline, baseline hemoglobin level (< 8 g/dL or ≥ 8 g/dL), baseline platelet count (< 100, ≥ 100 and ≤ 200, and > 200 × 10⁹/L), IPSS risk category (intermediate risk or high risk), baseline JAK2V617F mutation status (positive or negative), baseline MF disease status (PMF, post-PV MF, or post-ET MF).³⁵

Subgroup analyses were presented as a forest plot of proportion differences (SRR, TSS response rate, rate of RBC transfusion, rate of transfusion independence and transfusion dependence) or treatment arm least squares mean differences by subgroup.³⁵

In addition to the prespecified subgroup analyses, post hoc subgroup analyses were performed for splenic response, TSS, transfusion independence, and transfusion dependence at week 24 as well as for transfusion independence by week 24 and transfusion rate across the following subgroups:¹⁰

• transfusion independence at baseline

• non–transfusion independence at baseline

• baseline TSS (≥ 10)

• baseline hemoglobin (< 10 g/dL, < 12 g/dL, and ≥ 12 g/dL)

• baseline TSS ≥ 10 and hemoglobin < 10 g/dL

• baseline platelet count (≤ 150, > 150 and ≤ 300, > 300 × 10⁹/L).

SIMPLIFY-2 Trial

Prespecified subgroup analyses were performed by age, sex, race, baseline transfusion dependence, baseline spleen volume, TSS at baseline, baseline hemoglobin level (< 8 g/dL or ≥ 8 g/dL), DIPSS risk category (intermediate risk or high risk), baseline JAK2V617F mutation status (positive or negative), baseline MF disease status (PMF, post-PV MF, or post-ET MF), duration of ruxolitinib received before randomization (< 12 weeks or ≥ 12 weeks), and highest dosage of ruxolitinib received since randomization (≥ 20 mg twice daily or < 20 mg twice daily; for BAT treatment arm only).³⁶

Subgroup analyses were presented as a forest plot of proportion differences (SRR, TSS response rate, rate of RBC transfusion, rate of transfusion independence and transfusion dependence) or treatment arm least squares mean differences by subgroup.³⁶

In addition to the prespecified subgroup analyses, post hoc subgroup analyses were performed for splenic response, TSS, transfusion independence, and transfusion dependence at week 24 as well as for transfusion independence by week 24 and transfusion rate across the following subgroups:¹¹

• transfusion independence at baseline

• non–transfusion independence at baseline

• baseline TSS (< 10 or ≥ 10)

• baseline hemoglobin (< 10 g/dL or ≥ 10 g/dL)

• baseline TSS ≥ 10 and hemoglobin < 10 g/dL

• baseline platelet count (< 100, < 150, ≥ 100 and ≤ 200, > 200 × 10⁹/L).

MOMENTUM Trial

Prespecified subgroup analyses were performed by age, sex, race, geographical region, baseline platelet count (< 50, 50 to 150, 150 to 300, or > 300 × 10⁹/L; ≤ 150 or > 150 × 10⁹/L; ≤ 200 or > 200 × 10⁹/L), baseline transfusion dependence and transfusion independence, baseline MFSAF TSS (< 22 or ≥ 22), baseline spleen volume, baseline hemoglobin level (< 8 g/dL or ≥ 8 g/dL), RBC or whole blood units transfused in the 8-week period before randomization (0, 1 to 4, or ≥ 5 units), baseline DIPSS risk category (low risk, intermediate-1 risk, intermediate-2 risk, or high risk), baseline JAK2V617F mutation status (positive, negative, or unknown), baseline MF disease status (PMF, post-PV MF, or post-ET MF), JAK1 inhibitor treatment received before randomization (< 12 weeks or ≥ 12 weeks), ongoing JAK1 inhibitor at screening, prior JAK1 inhibitor total daily dosage received before enrolment (none, < 20 mg twice daily, or ≥ 20 mg twice daily of ruxolitinib or ≤ 200 mg or > 200 mg of fedratinib), and baseline glomerular filtration rate (30 mL/min/1.73 m² to 60 mL/min/1.73 m², or ≥ 60 mL/min/1.73 m²).³⁷

Patients with missing subgroup-determining variables were included in a subgroup of their own.³⁷ Subgroups with too few patients were combined as necessary. Subgroup analyses were presented as a forest plot of proportion differences (TSS response, transfusion independence status, splenic response) or treatment arm least squares mean differences (TSS change from baseline) by subgroup. Analyses of the duration of response or improvement were restricted to those patients whose data qualified for the response or improvement of interest. Unstratified exact 95% CIs were produced for differences in treatment proportions across subgroups.³⁷

Analysis Populations

The main analysis populations in the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies are summarized in Table 12. In all 3 studies, the primary end point was analyzed using the ITT analysis set, which included all randomized patients. Safety analysis populations were defined as all patients who received at least 1 dose of the study drug.

Results

Patient Disposition

A total of 432, 156, and 195 patients were included in the randomized treatment phase of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, respectively.^30,50,51 This included 180 patients in the SIMPLIFY-1 trial (momelotinib: 86; ruxolitinib: 94) and 105 patients in the SIMPLIFY-2 trial (momelotinib: 66; BAT: 39) who had anemia, with hemoglobin levels less than 10 g/dL.^52,72

In the SIMPLIFY-1 and SIMPLIFY-2 trials, a numerically greater proportion of patients discontinued momelotinib than ruxolitinib or BAT in the randomized treatment phase. In the MOMENTUM trial, a greater proportion of patients in the danazol arm discontinued treatment in the randomized treatment phase than in the momelotinib arm. The most common reasons for treatment discontinuation were AEs in the SIMPLIFY-1 and MOMENTUM trials and patient decision in the SIMPLIFY-2 trial. In the SIMPLIFY-1 trial, more patients in the momelotinib group than the ruxolitinib group discontinued due to AEs (4.7% versus 1.8%) and death (2.3% versus 0.9%). In the SIMPLIFY-2 trial, the most noticeable imbalances were AEs (5.8% versus 0%). In the MOMENTUM trial, more discontinuations due to AEs occurred in the danazol group than in the momelotinib group (16.9% versus 12.3%), with additional imbalances seen in discontinuations due to insufficient efficacy, which were slightly higher in the danazol group.^30,50,51

Table 11: Statistical Analysis of Efficacy End Points

AESI = adverse event of special interest; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DAN = danazol; KM = Kaplan-Meier; LCM = left costal margin; LOCF = last observation carried forward; MFSAF = Myelofibrosis Symptom Assessment Form; MMB = momelotinib; MPN-SAF = Myeloproliferative Neoplasm Symptom Assessment Form; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NR = not reported; RBC = red blood cell; SRR = splenic response rate; TD = transfusion dependence; TI = transfusion independence; TSS = total symptom score; vs. = versus.

Sources: GSK Data on File, 2016 (SIMPLIFY-1 statistical analysis plan);³⁵ GSK Data on File, 2016 (SIMPLIFY-2 statistical analysis plan);³⁶ GSK Data on File, 2021 (MOMENTUM statistical analysis plan).³⁷ Details included in the table are from the sponsor’s summary of clinical evidence.

Table 12: Analysis Populations of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM Trials

ITT = intention to treat; MF = myelofibrosis; PK = pharmacokinetic; PP = per protocol; PRO = patient-reported outcome; SAS = safety analysis set; TI = transfusion independence; TSS = total symptom score.

^aPatients were grouped according to randomized treatment.

^bPatients were grouped according to the actual treatment received.

Sources: GSK Data on File, 2016 (SIMPLIFY-1 statistical analysis plan);³⁵ GSK Data on File, 2016 (SIMPLIFY-2 statistical analysis plan);³⁶ GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2021 (MOMENTUM statistical analysis plan).³⁷ Details included in the table are from the sponsor’s summary of clinical evidence.

Patient disposition in the randomized phase of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials is summarized in Table 13.

Table 13: Summary of Patient Disposition From Studies Included in the Systematic Review

AE = adverse event; BAT = best available therapy; DAN = danazol; MMB = momelotinib; NR = not reported; RUX = ruxolitinib.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Baseline Characteristics

In the SIMPLIFY-1 trial, the baseline characteristics between the momelotinib and ruxolitinib treatment groups were generally well balanced. Both groups had similar mean ages (65.0 years for momelotinib and 64.4 years for ruxolitinib) and a comparable proportion of male participants (57.7% for momelotinib versus 55.3% for ruxolitinib). The distribution of MF subtypes was also similar, with PMF being the most common subtype in both groups (59.5% for momelotinib and 53.5% for ruxolitinib). The risk categories, based on the IPSS, showed a slightly higher proportion of patients considered to be at high risk in the ruxolitinib group (49.3%, versus 43.3% for momelotinib). Other characteristics, such as mean TSS, ECOG PS, and JAK2V617F mutation status, were also comparable between the groups, indicating minimal baseline imbalances.

In the SIMPLIFY-2 trial, the momelotinib and BAT treatment groups were generally similar in baseline characteristics, though some differences were observed. The mean age was slightly higher in the BAT group (69.4 years) than in the momelotinib group (66.4 years). The momelotinib group had a higher proportion of males (66.3%, versus 46.2% for BAT). The distribution of MF subtypes and DIPSS risk categories was similar, though there was a higher proportion of patients considered to be at intermediate-2 risk in the momelotinib group (59.6%, versus 53.8% for BAT). The ECOG PS showed a slightly higher percentage of patients having an ECOG PS of 1 in the momelotinib group (58.7%, versus 50% for ruxolitinib) and a similar proportion of patients with an ECOG PS of 0. However, more patients in the BAT group had an ECOG PS of 2 (13.5%, versus 6.7% for momelotinib). JAK2V617F mutation status was similar across the groups, with the majority of patients being positive. However, patients in the BAT group had slightly lower mean hemoglobin levels and platelet counts.

In the MOMENTUM study, differences in baseline characteristics were noted between the momelotinib and danazol groups. The danazol group had a slightly older population on average (71.46 years, versus 69.85 years for momelotinib). The proportion of males was higher in the danazol group (67.7%, versus 60.8% in momelotinib). The distribution of DIPSS risk categories showed more patients considered to be at high risk in the momelotinib group (38.5%, versus 29.2% for danazol). Both groups had a majority of patients with an ECOG PS of 1 (63.8% for momelotinib versus 52.3% for danazol). The danazol group had a slightly higher proportion of patients with an ECOG PS of 2 (24.6%, versus 23.8% for momelotinib). A smaller proportion of patients in both groups had an ECOG PS of 0: 12.3% in the momelotinib group and 23.1% in the danazol group. Both groups had very low mean hemoglobin levels (8.06 g/dL for momelotinib and 7.86 g/dL for danazol), reflective of the patient population targeted in the MOMENTUM trial, with all participants having hemoglobin levels less than 10 g/dL (contrasted with mean hemoglobin levels of 10.6 g/dL and 10.7 g/dL [momelotinib versus ruxolitinib] in the SIMPLIFY-1 trial and 9.4 g/dL and 9.5 g/dL [momelotinib versus BAT] in the SIMPLIFY-2 trial). There were also some differences in prior treatment exposure, with a higher proportion of patients in the momelotinib group having received JAK inhibitor treatment for 12 weeks or more before randomization.

The baseline characteristics outlined in Table 14 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results by the CDA-AMC team in consultation with the clinical experts.

Exposure to Study Treatments

A summary of patient exposure to study treatments is provided in Table 15.

Across all 3 trials, the duration of exposure to the study drug was similar, irrespective of the treatment received.^10-12 In the ITT population, the mean momelotinib treatment adherence rate was approximately 99% in the SIMPLIFY-1 trial and 80% in the SIMPLIFY-2 trial.^10,11

In the ITT population, patients randomized to the BAT arm of the SIMPLIFY-2 trial, received ruxolitinib (88.5%), hydroxyurea (23.1%), prednisone or prednisolone (11.5%), danazol (5.8%), no therapy (3.8%), ESA (3.8%), anagrelide (1.9%), darbepoetin alfa (1.9%), acetylsalicylic acid (1.9%), and thalidomide (1.9%). The mean treatment duration of ruxolitinib in the BAT arm of the SIMPLIFY-2 trial among this patient population was 19.6 weeks (standard deviation [SD] = 7.69).¹¹

In patients with hemoglobin levels less than 10 g/dL in the SIMPLIFY-2 trial, those randomized to the BAT arm received ruxolitinib (89.7%), hydroxyurea (15.4%), prednisone or prednisolone (10.3%), danazol (7.7%), no therapy (5.1%), anagrelide (2.6%), darbepoetin alfa (2.6%), ESA (2.6%), and thalidomide (2.6%). The mean treatment duration of ruxolitinib in the BAT arm of the SIMPLIFY-2 trial among this patient population was 20.2 weeks (SD = 7.37).¹¹

Concomitant medication use was reported by more than 95% of patients across the 3 trials.^12,60,61 No information on subsequent therapy was provided.

Efficacy

Transfusion Independence Response Rate at Week 24

In the SIMPLIFY-1 trial, 66.5% of patients in the momelotinib group experienced transfusion independence at week 24 compared to 49.3% in the ruxolitinib group. The proportion difference was 0.18 (95% CI, 0.09 to 0.26). In the subpopulation with hemoglobin levels less than 10 g/dL, the response rates were 46.5% for momelotinib and 26.6% for ruxolitinib, with a treatment difference of 0.20 (95% CI, 0.05 to 0.34). For patients with hemoglobin levels less than 12 g/dL, response rates were 62.3% for momelotinib and 37.2% for ruxolitinib. In the SIMPLIFY-2 trial, 43.3% of patients in the momelotinib group experienced transfusion independence, compared to 21.2% in the BAT group, with a proportion difference of 0.23 (95% CI, 0.09 to 0.37). In the subpopulation with hemoglobin levels less than 10 g/dL, the rates were 33.3% for momelotinib and 12.8% for BAT, with a treatment difference of 0.21 (95% CI, 0.01 to 0.39). For patients with hemoglobin levels less than 12 g/dL, response rates were 40.9% for momelotinib and 15.2% for BAT. In the MOMENTUM study, 30.8% of patients in the momelotinib group experienced transfusion independence at week 24, compared to 20.0% in the danazol group, with a proportion difference of 10.99% (95% CI, –0.80% to 22.77%), with an adjusted proportion difference noninferiority test, which targeted 80% retention of the effect of danazol, at 14.77% (95% CI, 3.13% to 26.41%; P = 0.0064). The results of the sensitivity analyses in the SIMPLIFY-1 and SIMPLIFY-2 trials using the per-protocol analysis set and the LOCF method were in line with those of the ITT analysis. The results of the sensitivity analyses in the MOMENTUM trial were not available.

Table 14: Summary of Baseline Characteristics From Studies Included in the Systematic Review (ITT Analysis Set)

ANC = absolute neutrophil count; BAT = best available therapy; BMI = body mass index; DAN = danazol; DIPSS = Dynamic International Prognostic Scoring System; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ET = essential thrombocythemia; IPSS = International Prognostic Scoring System; ITT = intention to treat; JAK = Janus kinase; MF = myelofibrosis; MMB = momelotinib; NA = not applicable; NR = not reported; PV = polycythemia vera; RUX = ruxolitinib; SD = standard deviation; TSS = total symptom score.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Table 15: Summary of Patient Exposure From Studies Included in the Systematic Review (Safety Analysis Set)

BAT = best available therapy; DAN = danazol; MMB = momelotinib; NR = not reported; Q1 = quarter 1; Q3 = quarter 3; RUX = ruxolitinib; SD = standard deviation.

Notes: The safety analysis set includes all patients in the intention-to-treat population who received at least 1 dose of the study drug. Patients were evaluated based on actual treatment received. In the pooled data from all trials, the relative dose intensity was 100 (range, 0 to 114) for patients randomized to MMB during the treatment phase and was 97.2 (range, 0 to 387) for those who received MMB during the open-label phase.⁴⁷

^aDose intensity = actual cumulative dose / actual duration of the treatment (days).

^bn = 102.

^cRelative dose intensity = actual dose intensity / planned dose intensity.

^dAdherence rate (%) = [total study drug administered / total study drug prescribed per protocol] × 100. Only patients who returned at least 1 bottle of study drug were included in the analysis.

^eDuration of exposure to study drug = ([treatment end date – treatment start date] + 1) / 7.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Rate of RBC Transfusion at Week 24

In the SIMPLIFY-1 trial, the mean rate of RBC transfusion at week 24 was 0.5 units per patient-month (SD = 1.27) in the momelotinib group, compared to 1.0 unit (SD = 1.62) in the ruxolitinib group, with a transfusion rate ratio of 0.28 (95% CI, 0.19 to 0.43). Among the subpopulation with hemoglobin levels less than 10 g/dL, the mean rates were 1.2 units (SD = 1.75) for momelotinib and 1.8 units (SD = 2.01) for ruxolitinib, with a rate ratio of 0.46 (95% CI, 0.30 to 0.70). For patients with hemoglobin levels less than 12 g/dL, the rates were 0.7 units for momelotinib and 1.3 units for ruxolitinib. In the SIMPLIFY-2 trial, the mean transfusion rate was 1.6 units (SD = 2.09) in the momelotinib group compared to 1.8 units (SD = 1.91) in the BAT group, with a transfusion rate ratio of 0.80 (95% CI, 0.49 to 1.31). Among the subpopulation with hemoglobin levels less than 10 g/dL, the mean rates were 2.1 units (SD = 2.12) for momelotinib and 2.0 units (SD = 1.97) for BAT, with a rate ratio of 1.10 (95% CI, 0.71 to 1.70). In the MOMENTUM trial, the total transfusions were 6.6 units (SD = 8.41) in the momelotinib group compared to 10.9 units (SD = 13.20) in the danazol group, with a treatment difference of –5.66 units (95% CI, –10.65 to –0.68 units). The results of the sensitivity analyses in the SIMPLIFY-1 and SIMPLIFY-2 trials using the per-protocol analysis set were in line with those of the ITT analysis. The results of the sensitivity analyses in the MOMENTUM trial were not available.

SRR at Week 24

In the SIMPLIFY-1 trial, 26.5% of patients in the momelotinib group experienced a splenic response at week 24, compared to 29.5% in the ruxolitinib group. Momelotinib achieved the definition of noninferiority, with a proportion difference for noninferiority of 0.09 (95% CI, 0.02 to 0.16; P = 0.014), while the proportion difference for superiority was –0.03 (95% CI, –0.12 to 0.05; P = 0.45). In the subpopulation with hemoglobin levels less than 10 g/dL, the response rates were 31.4% for momelotinib and 33.0% for ruxolitinib, with a treatment difference of –0.02 (95% CI, –0.16 to 0.13). For patients with hemoglobin levels less than 12 g/dL, the response rates were 28.9% for momelotinib and 29.3% for ruxolitinib. In the SIMPLIFY-2 trial, a splenic response was observed in 6.7% of patients in the momelotinib group versus 5.8% in the BAT group, with a proportion difference of 0.01 (95% CI, –0.09 to 0.10; P = 0.90). In the subpopulation with hemoglobin levels less than 10 g/dL, the response rates were 9.1% for momelotinib and 5.1% for BAT. The MOMENTUM study reported an SRR of 23.1% in the momelotinib group compared to 3.1% in the danazol group, with a proportion difference of 19.37% (95% CI, 10.96% to 27.77%; P = 0.001). The sensitivity analyses in the SIMPLIFY-1 and SIMPLIFY-2 trials using the per-protocol analysis set and the LOCF method were in line with those of the ITT analysis. The results of the sensitivity analyses in the MOMENTUM trial were not available.

TSS Response Rate at Week 24

In the SIMPLIFY-1 trial, 28.4% of patients in the momelotinib group experienced a TSS response at week 24, compared to 42.2% in the ruxolitinib group (using the MPN-SAF score). The proportion difference was –14.0% (95% CI, –23.0% to –5.0%; P = 0.9985). A noninferiority test that targeted 67% retention of ruxolitinib failed to the predefined noninferiority margin, where the lower bound of the 2-sided 95% CI should be greater than 0. Specifically, the adjusted proportion difference noninferiority testing was 0.00 (95% CI, –0.08 to 0.08; P = 0.98). Among the subpopulation with hemoglobin levels less than 10 g/dL, the response rates were 25% for momelotinib and 35.5% for ruxolitinib, with a treatment difference of –0.10 (95% CI, –0.25 to 0.04). For patients with hemoglobin levels less than 12 g/dL, response rates were 29.7% for momelotinib and 39.9% for ruxolitinib. In the SIMPLIFY-2 trial, TSS response was observed in 26.2% of patients in the momelotinib group versus 5.9% in the BAT group (using the MPN-SAF score), with a proportion difference of 0.20 (95% CI, 0.09 to 0.32; P < 0.001). In the subpopulation with hemoglobin levels less than 10 g/dL, the response rates were 32.3% for momelotinib and 2.6% for BAT. The MOMENTUM study reported a TSS response rate of 24.6% in the momelotinib group compared to 9.2% in the danazol group (using the MFSAF score), with a proportion difference of 15.67% (95% CI, 5.54% to 25.81%; P = 0.0095). The results of the sensitivity analyses in all 3 trials were in line with ITT analysis.

Table 16: Summary of Key Efficacy Results From Studies Included in the Systematic Review (ITT Analysis Set)

BAT = best available therapy; CI = confidence interval; DAN = danazol; ITT = intent to treat; MMB = momelotinib; NR = not reported; RBC = red blood cell; RUX = ruxolitinib; SD = standard deviation.

^aDelta for noninferiority (defined as p[MMB] – 0.8 × p[DAN]) of 14.77% (95% CI, 3.13 to 26.41) ruling out 0% (i.e., noninferiority was to be declared if 80% of the response rate in the DAN group was preserved in the MMB group).

^bP values lie outside of a statistical testing hierarchy and are thus not adjusted for multiple testing.

^cDelta for noninferiority (defined as p[MMB] – 0.6 × p[RUX]) of 9.0% (95% CI, 2.0% to 16.0%) ruling out 0% (i.e., noninferiority was to be declared if 60% of the response rate in the RUX group was preserved in the MMB group).

^dDelta for noninferiority (defined as p[MMB] – 0.67 × p[RUX]) of 0.0% (95% CI, –8.0% to 8.0%) including 0% (i.e., noninferiority was not achieved).

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Table 17: Summary of Key Efficacy Results in the SIMPLIFY-1 Trial in ITT Analysis Subsets — Hemoglobin < 10 g/dL and Hemoglobin < 12 g/dL

CI = confidence interval; ITT = intention to treat; MMB = momelotinib; RBC = red blood cell; RUX = ruxolitinib; SD = standard deviation.

^aN = 163.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report).¹⁰ Details included in the table are from the sponsor’s summary of clinical evidence.

Table 18: Summary of Key Efficacy Results in the SIMPLIFY-2 Trial in ITT Analysis Subsets — Hemoglobin < 10 g/dL and Hemoglobin < 12 g/dL

BAT = best available therapy; CI = confidence interval; ITT = intention to treat; MMB = momelotinib; RBC = red blood cell; SD = standard deviation.

Sources: GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report).¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Harms

Refer to Table 19 for harms data.^10-12

Adverse Events

The majority of patients experienced at least 1 AE across all studies. Thrombocytopenia was a commonly reported AE across all studies, with higher incidence in the ruxolitinib group of the SIMPLIFY-1 trial (29.2%) and the momelotinib group of the MOMENTUM trial (22.3%) than in the momelotinib groups in the SIMPLIFY-1 trial (18.7%) and the SIMPLIFY-2 trial (10.6%). Anemia was frequently observed, particularly in the ruxolitinib group of the SIMPLIFY-1 trial, where it occurred in 37.5% of patients. In comparison, anemia was reported in 14.5% of patients in the momelotinib group of the SIMPLIFY-1 trial and in 13.5% of the momelotinib group in the SIMPLIFY-2 trial (compared with 17.3% in the BAT group). Diarrhea was notably common in the momelotinib groups, with 32.7% in the SIMPLIFY-2 trial and 22.3% in the MOMENTUM trial; it was less frequent in the comparator groups (15.4% in the BAT group in the SIMPLIFY- 2 trial and 9.2% in the danazol group in the MOMENTUM trial). Asthenia (weakness) was observed in the SIMPLIFY-2 trial, occurring in 19.2% of patients in the momelotinib group patients and 21.2% of patients in the BAT group.

Serious AEs

In the SIMPLIFY-1 trial, 74 patients (34.6%) in the momelotinib group and 94 patients (43.5%) in the ruxolitinib group experienced at least 1 grade 3 or 4 AE. In the SIMPLIFY-2 trial, 57 patients (54.8%) in the momelotinib group and 22 patients (42.3%) in the BAT group experienced such AEs. In the MOMENTUM study, 63 patients (48.5%) in the momelotinib group and 41 patients (63.1%) in the danazol group experienced at least 1 grade 3 or 4 AE.

The most common grade 3 or 4 AEs across the studies were thrombocytopenia and anemia. Thrombocytopenia was reported in 15 patients (7.0%) in the momelotinib group of the SIMPLIFY-1 trial, 11 patients (10.6%) in the momelotinib group of the SIMPLIFY-2 trial, and 22 patients (16.9%) in the momelotinib group of the MOMENTUM trial. It was less frequent in the comparator groups but still notable, affecting 10 patients (4.6%) in the ruxolitinib group of the SIMPLIFY-1 trial, 3 patients (5.8%) in the BAT group of the SIMPLIFY-2 trial, and 5 patients (7.7%) in the danazol group of the MOMENTUM trial. Anemia was another frequent grade 3 or 4 AE, occurring in 13 patients (6.1%) in the momelotinib group of the SIMPLIFY-1 trial, 14 patients (13.5%) in the momelotinib group of the SIMPLIFY-2 trial, and 10 patients (7.7%) in the momelotinib group of the MOMENTUM trial, with the highest incidence observed in the ruxolitinib group of the SIMPLIFY-1 trial: 49 patients (22.7%). Grade 3 to 4 anemia occurred among 17.3% of patients in the BAT group of the SIMPLIFY-2 trial and 6.2% of patients in the danazol group of the MOMENTUM trial.

At least 1 SAE was reported in 49 patients (22.9%) in the momelotinib group and 39 patients (18.1%) in the ruxolitinib group in the SIMPLIFY-1 trial. In the SIMPLIFY-2 trial, 37 patients (35.6%) in the momelotinib group and 12 patients (23.1%) in the BAT group experienced at least 1 SAE. The MOMENTUM study reported that 45 patients (34.6%) in the momelotinib group and 26 patients (40.0%) in the danazol group experienced at least 1 SAE.

Common SAEs included anemia, which was reported in 4 patients (1.9%) in the momelotinib group of the SIMPLIFY-1 trial, 4 patients (3.8%) in the momelotinib group of the SIMPLIFY-2 trial, and 5 patients (3.8%) in the momelotinib group of the MOMENTUM trial. In comparison, 8 patients (3.7%) in the ruxolitinib group of the SIMPLIFY-1 trial and 3 patients (4.6%) in the danazol group of the MOMENTUM trial experienced anemia. No cases of anemia were reported as SAEs in the BAT group in the SIMPLIFY-2 trial. Pneumonia was another significant SAE, occurring in 4 patients (1.9%) in the momelotinib group of the SIMPLIFY-1 trial and 6 patients (9.2%) in the danazol group of the MOMENTUM trial. In contrast, it was reported in 3 patients (1.4%) in the ruxolitinib group of the SIMPLIFY-1 trial, while no cases were reported in the SIMPLIFY-2 trial. Additionally, sepsis was reported as an SAE in 3 patients (2.9%) in the momelotinib group of the SIMPLIFY-2 trial, 2 (1.5%) in the momelotinib group of MOMENTUM, and 3 patients (4.6%) in the danazol group of the MOMENTUM trial. There were no reported cases of sepsis as a SAE in the momelotinib group of the SIMPLIFY-1 trial, the ruxolitinib group of the SIMPLIFY-1 trial, or the BAT group of the SIMPLIFY-2 trial.

Withdrawals due to AEs

Across the 3 studies, a number of patients discontinued treatment due to AEs. In the SIMPLIFY-1 trial, 27 patients (12.6%) in the momelotinib group and 12 patients (5.6%) in the ruxolitinib group discontinued treatment due to AEs. In the SIMPLIFY-2 trial, 22 patients (21.2%) in the momelotinib group and 1 patient (1.9%) in the BAT group discontinued treatment due to AEs. In the MOMENTUM study, 23 patients (17.7%) in the momelotinib group and 15 patients (23.1%) in the danazol group discontinued treatment due to AEs.

Among the specific AEs leading to treatment discontinuation, thrombocytopenia was a common cause, reported in 3 patients (1.4%) in the momelotinib group of the SIMPLIFY-1 trial, 5 patients (4.8%) in the momelotinib group of the SIMPLIFY-2 trial, and 1 patient (0.8%) in the momelotinib group of the MOMENTUM trial. In the comparator groups, thrombocytopenia led to discontinuation in 4 patients (1.9%) in the ruxolitinib group of the SIMPLIFY-1 trial, with no cases reported in the BAT group of the SIMPLIFY-2 trial, and 2 cases (3.1%) in the danazol group of the MOMENTUM trial.

Thrombocytopenia was the most common AE leading to treatment interruption or dose reduction, affecting 13 patients (6.1%) in the momelotinib group of the SIMPLIFY-1 trial, 5 patients (4.8%) in the momelotinib group of the SIMPLIFY-2 trial, and 13 patients (10.0%) in the momelotinib group of the MOMENTUM trial. In the comparator groups, thrombocytopenia led to these events in 53 patients (24.5%) in the ruxolitinib group of the SIMPLIFY-1 trial, 3 patients (5.8%) in the BAT group of the SIMPLIFY-2 trial, and 2 patients (3.1%) in the danazol group of the MOMENTUM trial. Other notable AEs leading to treatment interruption or dose reduction included anemia, experienced by 3 patients (1.4%) in the momelotinib group and 12 patients (5.6%) in the ruxolitinib group of the SIMPLIFY-1 trial, as well as diarrhea, experienced by 3 patients (1.4%) in the momelotinib group and 4 patients (1.9%) in the ruxolitinib group of the SIMPLIFY-1 trial, and 3 patients (2.3%) in the momelotinib group of the MOMENTUM trial; no cases were reported in the danazol group of the MOMENTUM trial.

Mortality

In the SIMPLIFY-1 trial, 8 patients (3.7%) in the momelotinib group and 6 patients (2.8%) in the ruxolitinib group died. In the SIMPLIFY-2 trial, there were 8 deaths (7.7% of patients) in the momelotinib group and 5 deaths (9.6% of patients) in the BAT group. The MOMENTUM study reported a higher number of deaths: 38 patients (29.2%) in the momelotinib group and 20 patients (30.8%) in the danazol group.

The causes of death varied across the studies. In the SIMPLIFY-1 trial, 7 deaths (3.3% of patients) in the momelotinib group and 6 deaths (2.8% of patients) in the ruxolitinib group were attributed to TEAEs not related to disease progression, while 1 death (0.5% of patients) in the momelotinib group was due to disease progression. In the SIMPLIFY-2 trial, 5 deaths (4.8% of patients) in the momelotinib group and 3 deaths (5.8% of patients) in the BAT group were due to TEAEs not related to disease progression. Additionally, 2 deaths in both the momelotinib group (1.9% of patients) and BAT group (3.8% of patients) were related to disease progression.

In the MOMENTUM study, 16 deaths (12.3% of patients) in the momelotinib group and 11 deaths (16.9% of patients) in the danazol group were due to TEAEs not related to disease progression. Notably, 1 patient (0.8%) in the momelotinib group died due to progression to AML.

Notable Harms

Peripheral Neuropathy

In the SIMPLIFY-1 trial, 22 patients (10.3%) in the momelotinib group and 12 patients (5.6%) in the ruxolitinib group experienced peripheral neuropathy. In the SIMPLIFY-2 trial, this event was reported in 12 patients (11.5%) in the momelotinib group, with no cases reported in the BAT group. In the MOMENTUM study, peripheral neuropathy occurred in 5 patients (3.8%) in the momelotinib group and 1 patient (1.5%) in the danazol group.

Infections

In the MOMENTUM study, 44 patients (33.8%) in the momelotinib group and 23 patients (35.4%) in the danazol group experienced infections. A matching category was not included in the SIMPLIFY-1 trial or the SIMPLIFY-2 trial.

Nonhematological AEs

In the SIMPLIFY-1 trial, nonhematological AEs occurred in 193 patients (90.2%) in the momelotinib group and 200 patients (92.6%) in the ruxolitinib group. In the SIMPLIFY-2 trial, they occurred in 100 patients (96.2%) in the momelotinib group and 45 patients (86.5%) in the BAT group. A matching category was not included in the MOMENTUM trial.

Hemorrhage

In the MOMENTUM study, 28 patients (21.5%) in the momelotinib group and 12 patients (18.5%) in the danazol group experienced hemorrhage. A matching category was not included in the SIMPLIFY-1 trial or the SIMPLIFY-2 trial.

Malignancies

In the MOMENTUM study, 7 patients (5.4%) in the momelotinib group and 6 patients (9.2%) in the danazol group developed malignancies. A matching category was not included in the SIMPLIFY-1 trial or the SIMPLIFY-2 trial.

Thromboembolism

In the MOMENTUM study, 5 patients (3.8%) in the momelotinib group and 6 patients (9.2%) in the danazol group experienced thromboembolism. A matching category was not included in the SIMPLIFY-1 trial or the SIMPLIFY-2 trial.

AML or Transformation to AML

In the MOMENTUM trial, AML or transformation to AML occurred in 4 patients (3.1%) in the momelotinib group and 3 patients (4.6%) in the danazol group. A matching category was not included in the SIMPLIFY-1 trial or the SIMPLIFY-2 trial.

Table 19: Summary of Harms Results From Studies Included in the Systematic Review

AE = adverse event; AML = acute myeloid leukemia; BAT = best available therapy; DAN = danazol; MMB = momelotinib; NR = not reported; RUX = ruxolitinib; TEAE = treatment-emergent adverse event.

Notes: AEs mapped according to Medical Dictionary for Regulatory Activities version 22.0. Severity grades were defined by Common Terminology Criteria for Adverse Events version 4.03. Multiple AEs were counted only once per patient.

^aThe term disease progression included the following: disease progression, myelofibrosis, and AML.

^bIncluded disease progression more than 30 days after the last dose of the study drug, unknown, and other reported causes of death.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Critical Appraisal

Internal Validity

All studies are randomized with an active control arm. Two of the studies — the SIMPLIFY-1 and MOMENTUM trials — are double masked (or double blind); the SIMPLIFY-2 trial was an open-label study. The randomization and allocation concealment procedures (where applicable) were described in detail and likely to have been effective in balancing out baseline characteristics (with the exception of some imbalance in ECOG PS across trials and anemia in the MOMENTUM trial). Two of the studies aimed to assess noninferiority as a primary outcome (SIMPLIFY-1 and MOMENTUM trials). The lower margin to achieve noninferiority (0 at the lower end of the 95% CI) was considered acceptable by the clinical experts consulted by CDA-AMC. However, despite using previous evidence to gauge the power needed to achieve noninferiority, the clinical rationale of preserving 60% of the ruxolitinib effect is not explicitly clear. The studies provided a comprehensive and appropriate approach to assessing various efficacy outcomes with a predefined statistical hierarchy to control type I error. Data imputation methods were implemented, with an overall approach of imputing missing data as a ‘nonresponse’ and several sensitivity analyses were implemented to assess the robustness of data imputation. All results from the subgroup analyses have considerable limitations due to the potential lack of power and type I error control.

Primary limitations to the internal validity of the included studies lie in the open-label design of the SIMPLIFY-2 trial, large and imbalanced treatment discontinuation, and lack of control for type I error (i.e., no adjustment for multiple testing). Furthermore, the lack of a washout period may prove a potential confounder.

In the SIMPLIFY-1 trial, more patients discontinued momelotinib (27; 12.6%) than ruxolitinib (9; 4.1%). Within the SIMPLIFY-1 trial, the primary analysis of the rate of transfusion independence at week 24 does not include an approach to handle missing data. The sponsor conducted a sensitivity analysis where missing data were classified as nonresponders with a result similar to the ITT analysis. The outcomes of splenic response and TSS response used a conservative approach of imputing missing data as nonresponders. However, additional sensitivity analysis using other methods (e.g., LOCF) suggest similar results to the ITT analysis, despite the assumption of LOCF being unlikely true. As such, the effect of the disproportional treatment discontinuation on the internal validity of the SIMPLIFY-1 trial remains unclear but is unlikely to be a major limitation. However, a larger limitation affecting the reported outcomes is the lack of adjustment for type I error (multiple testing) for the outcomes of transfusion independence, SRR, and TSS. This is due to the failure of the testing hierarchy at the point of the secondary outcome of noninferiority of momelotinib versus ruxolitinib in TSS response rate. As such, there is an increased risk that statistically significant results among these end points (i.e., transfusion independence response rate) are false-positives. Thus, in the context of causal inference, results for these end points should only be considered as supportive evidence.

The SIMPLIFY-2 trial was of an open-label design which would increase the risk of bias, potentially in favour of momelotinib for subjective outcomes. This risk of bias is likely to apply mostly to the TSS response rate as it is a patient-reported outcome covering symptoms related to the disease. There was a large, but similar, proportion of treatment discontinuation in both treatment groups. This may affect both internal and external validity, where the comparative end point could have looked different had the missing data existed. Finally, the SIMPLIFY-2 trial failed to achieve its primary objective (i.e., the superiority of momelotinib versus BAT for SRR), rendering all comparative testing nominal in nature and not adjusted for type I error. As such, there is an increased risk that statistically significant results for subsequently tested end points (i.e., transfusion independence response rate and TSS response rate) are false-positives. Thus, in the context of causal inference, results for these end points should only be considered as supportive evidence. Adding a limitation to the SIMPLIFY-2 trial is the lack of a washout period at screening combined with a relatively large proportion of patients who were on ruxolitinib or fedratinib within 12 weeks of randomization. Specifically, 15.4% of patients in the momelotinib treatment group were on a JAK inhibitor within 12 weeks of randomization as opposed to 19.2% in the BAT treatment group. The implications are that the observed results may not have been solely driven by the intervention or control and may have been influenced, to an unknown extent, by the prior JAK inhibitor therapy.

The MOMENTUM trial had a large proportion of treatment discontinuation in both treatment groups as well as a large imbalance of treatment discontinuation between the 2 groups (27.7% in momelotinib and 41.5% in danazol). For the primary efficacy end point of TSS, missing data were imputed as patients not experiencing a response. This could possibly bias the result in favour of momelotinib. The sponsor conducted a number of sensitivity analyses (no imputation, no stratification, LOCF, and controlled-based multiple imputation). The control-based multiple imputation delivered a P value of 0.062, while all other sensitivity analyses supported the primary ITT analysis with a similar direction of effect. While these analyses may increase the overall robustness of the primary analysis results, the large number of missing data and the imbalance between treatment groups is still a major limitation with an unknown directional effect on the results. This limitation applies to the rest of the efficacy end points presented here, including transfusion independence response rate, rate of RBC transfusion, and SRR. Within the reported efficacy end points of the MOMENTUM trial, the transfusion independence response rate superiority testing and the rate of RBC transfusion are outside of the statistical hierarchy and are thus not adjusted for type I error (multiple testing). As such, there is an increased risk that the result for the rate of RBC transfusion is a false-positive; in the context of causal inference, this end point should only be interpreted as supportive evidence. The superiority test for transfusion independence response rate yielded a result that was not statistically significant.

External Validity

The 3 studies reviewed in this submission attempted to capture various representations of the patient population with MF. The SIMPLIFY-1 trial enrolled patients who had not previously been treated with a JAK inhibitor, regardless of anemia status; the SIMPLIFY-2 trial enrolled patients who had previously been treated with a JAK inhibitor, regardless of anemia status; and the MOMENTUM trial enrolled patients who had previously been treated with a JAK inhibitor and who had anemia. All the studies included patients who were considered at high risk or intermediate risk. According to the clinical experts consulted by CDA-AMC, more than one-half the patients seen in their clinics would be eligible to participate in 1 of these trials. This is further reinforced by the clinical expert opinion that the baseline characteristics of the patients in these studies are generally representative of the majority of the patient population in Canada.

Overall, limitations to external validity in the studies include lack of comparison against relevant comparators, a large number of treatment discontinuations, the short duration of assessment for survival and progression outcomes, and the lack of established minimal important differences for the outcomes of interest.

The momelotinib intervention is in accordance with the Health Canada indication. The comparator in the SIMPLIFY-1 trial (ruxolitinib) is an appropriate representation of clinical practice in Canada. According to the clinical experts, currently patients who experience intolerance or anemia can be given the option of switching to fedratinib. However, clinical practice in Canada tends to attempt to maintain patients on ruxolitinib for as long as possible, even in cases where there is disease progression. In the SIMPLIFY-2 trial, the comparison was BAT, where the majority of patients (89.7%) ended up receiving ruxolitinib but none received fedratinib. Due to the large proportion of patients receiving ruxolitinib in the SIMPLIFY-2 trial, it is likely that the results observed would mostly apply to the comparative efficacy and safety of momelotinib versus ruxolitinib but not versus other modalities of treatment. The use of danazol in the MOMENTUM trial does not reflect Canadian clinical practice. According to the clinical experts consulted by CDA-AMC, patients who experience anemia are usually treated with hydroxyurea with the possible add-on of ESAs, and danazol is uncommonly used. Both hydroxyurea and ESAs were prohibited in the MOMENTUM trial.

All the included studies exhibited either a notable imbalance in treatment discontinuation between the treatment groups, a high proportion of treatment discontinuation, or both. This reduces the overall generalizability of the results to only those who are likely to finish the trial (commonly the ones who are responding well to treatment and can tolerate it). This is especially true in the SIMPLIFY-2 and MOMENTUM trials.

A limitation of the 24-week study design is the lack of information on clinical outcomes related to survival and disease progression, as 24 weeks is considered too short to be informative and patients cross over to momelotinib after 24 weeks. According to the clinical experts, a time point of 2 years for a comparative clinical end point would provide clinically meaningful results.

The lack of established minimal important difference of the outcomes of interests reduces the ability to better understand the clinical meaningfulness of the difference between the intervention and the comparators. The clinical experts consulted on this review suggested that the definition of “patients experiencing a response” across the outcomes of interest is clinically meaningful. However, they were unable to determine a magnitude of difference in the rate of patients experiencing a response that would be clinically meaningful in determining which treatment is better. Moreover, there was no clear clinical justification behind the thresholds of the definitions of “patients experiencing a response.”

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform the expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^62,63

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

• Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. In the case of the outcomes presented in this report, the target of certainty was assessed based on the location of the point estimate relative to the null.

For the GRADE assessments, the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials were assessed individually because of the differences in the patient population and comparators included in these trials.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for momelotinib versus ruxolitinib. Table 3 presents the GRADE summary of findings for momelotinib versus BAT. Table 4 presents the GRADE summary of findings for momelotinib versus danazol.

Long-Term Extension Studies

The contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CDA-AMC review team.

Description of Studies

SIMPLIFY-1 Trial

The open-label extension of the SIMPLIFY-1 trial evaluated open-label treatment with momelotinib for up to 216 weeks (i.e., through week 240) after the randomized, double-blind phase.¹⁰

SIMPLIFY-2 Trial

The open-label extension of the SIMPLIFY-2 trial evaluated open-label treatment with momelotinib for up to 204 weeks (i.e., through week 228) after the randomized treatment phase.¹¹

For the open-label extension of both the SIMPLIFY-1 and SIMPLIFY-2 trials, a posttreatment follow-up visit was scheduled 12 weeks after the discontinuation of the study treatment and patients were followed up with approximately every 6 months for 5 years or until study termination for the long-term assessment for survival. The 12-week and survival follow-up visits were not required for patients who continued treatment with momelotinib following the end of the study.^10,11

MOMENTUM Trial

The open-label extension of the MOMENTUM trial evaluated open-label treatment with momelotinib for up to 180 weeks (i.e., through week 204) and danazol for up to 24 weeks after the randomized, double-blind phase of the MOMENTUM trial.¹²

A safety follow-up visit was scheduled for 30 days after the last dose of the study drug, and long-term follow-up assessments were made for survival and leukemic transformation 7 years after the first dose.¹² Patients who completed at least 24 weeks of open-label treatment with momelotinib had the option to continue treatment in the momelotinib extension study, and those who completed the safety follow-up visit in the MOMENTUM trial were transitioned to the open-label extension study.¹²

Populations

Patients who completed the 24-week randomized treatment phase in the SIMPLIFY-1 and SIMPLIFY-2 trials had the option to participate in the open-label extension phases.^10,11

Patients who completed the 24-week randomized treatment phase in the MOMENTUM trial but discontinued treatment early due to splenic progression or discontinued treatment early for other reasons but completed scheduled assessments through week 24 had the option to continue momelotinib in the open-label extension phase. Patients treated with momelotinib who completed treatment through the end of week 24 had the option to continue momelotinib as open-label treatment for up to 180 weeks (i.e., through week 204) for a total of approximately 4 years.¹² Patients treated with danazol had the option to cross over to open-label momelotinib treatment in the following situations: if they had completed the 24-week randomized treatment period; if they had discontinued treatment with danazol but continued study assessments through week 24 without receiving any prohibited medications; or if they had met the criteria for confirmed splenic progression before the end of week 24.¹² Patients treated with danazol who continued to receive clinical benefit at the end of week 24 of the double-blind randomized treatment phase had the option to continue danazol as open-label treatment through week 48.¹²

Interventions

In the open-label extension phase in the SIMPLIFY-1 and SIMPLIFY-2 trials, all patients received momelotinib 200 mg once daily.^10,11

In the open-label extension phase of the MOMENTUM trial, patients received momelotinib at a dosage of 200 mg orally once daily, unless the dose of momelotinib was reduced in the randomized treatment phase due to an AE.¹² The dosage of momelotinib was eventually increased to 200 mg once daily after the resolution of events leading to dose reduction at the investigator’s discretion. Patients were followed up with for at least a 4-hour postdose observation period after the first dose.¹²

For those patients who received open-label danazol treatment, danazol was administered orally at a total daily dose of 400 mg.¹² Patients who received a reduced dose of danazol during the randomized treatment phase continued to receive the same dose, which was then progressively reduced to the minimum dose to maintain a response.¹²

Outcomes

For the open-label extension phases, only outcomes relevant to the review were reported. This included splenic response at any time for the SIMPLIFY-1 and SIMPLIFY-2 trials and SRR (≥ 35% reduction from baseline spleen volume at week 24) and transfusion independence response rate at week 48 for the MOMENTUM trial. Rate of RBC transfusion was not reported for the open-label extension phases of the SIMPLIFY-1, SIMPLIFY-2, or MOMENTUM trials.^10-12 For the MOMENTUM trial, the TSS response rate was reported during the open-label extension phase at week 48.¹² The TSS response rate was not reported for the open-label extension phases of the SIMPLIFY-1 and SIMPLIFY-2 trials.^10,11 For the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, the safety outcomes — including AEs, SAEs, treatment-related discontinuations, deaths, and AESIs — were reported for the safety population for the open-label extension phases.^10-12

Statistical Analysis

In the SIMPLIFY-1 and SIMPLIFY-2 trials, baseline assessments were carried out as part of the randomized phase of the pivotal trials. The baseline assessment for patients continuing momelotinib (momelotinib to momelotinib) was done before or on the date of randomization in both the SIMPLIFY-1 and SIMPLIFY-2 trials. For those patients who switched to momelotinib (ruxolitinib to momelotinib in the SIMPLIFY-1 trial or BAT to momelotinib in the SIMPLIFY-2 trial), the baseline assessment was done before or on the date of the first dose of momelotinib in the open-label extended treatment phase.³⁵

In the SIMPLIFY-1 and SIMPLIFY-2 trials, the open-label analysis set included patients who had received at least 1 dose of momelotinib in the open-label extension phase. Patients were grouped based on their treatment group assignment in the pivotal treatment phase.³⁵

For both the SIMPLIFY-1 and SIMPLIFY-2 trials, data pertaining to the open-label extension phases were collected after the date of the first open-label dose of momelotinib, with the exception that MRI or CT spleen volume or IWG-MRT or European Leukemia Net overall response rate assessments collected within 10 days of the first extended open-label dose of momelotinib were included in the analysis of the randomized phase due to the challenge of scheduling MRI and CT scans. It was anticipated that an additional 10 days of treatment with momelotinib would not have a significant impact on the spleen volume.³⁵ Data on concomitant medications in the open-label extension phase were collected with a start date of the date of the first extended open-label dose of momelotinib.³⁵

In the SIMPLIFY-1 and SIMPLIFY-2 trials, exposure to momelotinib was presented for the duration of the extended treatment phase for patients who switched to momelotinib from ruxolitinib or BAT, and the combined duration of the randomized and extended treatment phases was presented for patients who were continuing momelotinib treatment.³⁵

In the SIMPLIFY-1 and SIMPLIFY-2 trials, AEs with an onset date of the day of the first extended open-label dose of momelotinib and reported as occurring in the extended open-label phase or with no information on which phase the event occurred in were classified as occurring in the open-label extension phase.³⁵

In the open-label extension phase of the MOMENTUM trial, all patients who received momelotinib were grouped based on their treatment group assignment in the double-blind randomized treatment phase into continuing (momelotinib to momelotinib), continuing (danazol to danazol), and switch (danazol to momelotinib).³⁵ Data pertaining to the open-label, long-term extension phase were collected following the completion of the randomized week 24 treatment or following the crossover visit for early crossover in cases of confirmed splenic progression.³⁵

During the open-label extension phase of the MOMENTUM study, averages for any TSS data available were calculated. For the calculation of mean TSS during the open-label phase, TSS was only considered missing if all the 7 daily TSS results were missing.³⁵ All statistical tests were 2-sided and performed at the 5% significance level. No control for multiple testing was reported by the sponsors for the open-label extension phase.³⁵ AEs were described using descriptive statistics by the treatment group from the randomized period; data for patients continuing with danazol treatment up to week 48 and for patients switching from danazol to momelotinib were reported separately.³⁵

Results

Patient Disposition

In the SIMPLIFY-1, SIMPLIFY-2 and MOMENTUM trials, the proportions of patients who either reached open-label extension phase week 24 or discontinued the study drug before week 24 in the open-label phase were 83.6% (n = 361), 64.7% (n = 101), and 68.7% (n = 134), respectively.^10-12 Among patients randomized in the SIMPLIFY-1 trial, 78.6% in the momelotinib group and 88.5% in the ruxolitinib group reached the open-label extension phase week 24 or discontinued the study drug before week 24.¹⁰ Among the patients randomized in the SIMPLIFY-2 trial, 60.6% in the momelotinib group and 73.1% in the BAT group reached the open-label extension phase week 24 or discontinued the study drug before week 24.¹¹ Among the patients randomized in the MOMENTUM trial, 71.5% in the momelotinib group and 63.1% in the danazol group reached the open-label extension phase week 24 or discontinued the study drug before week 24.¹²

In the SIMPLIFY-1 trial, the proportion of patients who discontinued treatment before week 24 of open-label treatment was higher among those who switched from ruxolitinib to momelotinib (20.3%) than among those who continued with momelotinib (10.2%). Across both populations, AEs followed by disease progression were the most common reasons for treatment discontinuation, with a greater proportion of patients who had received ruxolitinib in the double-blind phase than those treated with momelotinib discontinuing treatment due to AEs (21 [9.7%] versus 10 [4.7%]) and disease progression (9 [4.1%] versus 2 [1.0%]).¹⁰

In the SIMPLIFY-2 trial, the proportion of patients discontinuing treatment in the open-label extended treatment phase was numerically higher among those in the switch to momelotinib treatment group (34.6%; n = 18) than among those in the continuing momelotinib group (13.5%; n = 14). AEs were the most common reason for treatment discontinuation in both treatment groups, with a numerically larger proportion of patients who had received BAT in the double-blind phase discontinuing treatment due to AEs (25.0%; n = 13) than those treated with momelotinib (5.8%; n = 6).¹¹

In the MOMENTUM trial, the proportion of patients discontinuing treatment was similar between the 2 treatment groups. The most common reasons for treatment discontinuation in both treatment groups were AEs (11 [8.5%] versus 1 [1.5%] in the continuing momelotinib group and switch to momelotinib treatment group, respectively) and death (6 [4.6%] versus 3 [4.6%] in the continuing momelotinib group and switch to momelotinib treatment group, respectively).¹²

The disposition of patients in the open-label extension phase of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials in the ITT population is presented in Table 20.

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Table 20: Summary of Patient Disposition in the Open-Label Extension Phase of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM Trials

BAT = best available therapy; DAN = danazol; MMB = momelotinib; NA = not applicable; NR = not reported; RUX = ruxolitinib.

Note: Results are from the final analysis at the database lock of July 1, 2019, for the SIMPLIFY-1 trial; June 25, 2019, for the SIMPLIFY-2 trial; and January 17, 2023, for the MOMENTUM trial.

^a“Reached week 24 of open-label treatment” refers to patients whose last extended open-label treatment phase participation date was more than 176 days after the first extended open-label treatment dose of MMB for the SIMPLIFY-1 and SIMPLIFY-2 trials.

^b“Discontinued study drug before week 24 of open-label treatment” refers to patients who discontinued the extended open-label treatment phase study drug and had a last extended open-label treatment phase participation date less than 162 days after the first open-label treatment dose of MMB for the SIMPLIFY-1 and SIMPLIFY-2 trials.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Baseline Characteristics

The baseline characteristics of the patients enrolled in the open-label extension phase of the SIMPLIFY-1 and SIMPLIFY-2 trials in the ITT population are presented in Table 21.

In the open-label extension phase of the SIMPLIFY-1 trial, the mean age of the patients in the ITT population was 64.2 years. There were slightly more males in the continuing momelotinib group (59.1%) than in the switch to momelotinib treatment group (54.8%). The majority of patients in the continuing momelotinib group (40.4%) and the switch to momelotinib treatment group (48.7%) had high-risk MF per the IPSS criteria and a positive JAK2V617F mutation status (58.5% and 64.0% in the continuing momelotinib and switch to momelotinib groups, respectively) at baseline. The proportion of patients who were transfusion dependent was similar in both the continuing momelotinib group and the switch to momelotinib treatment group (22.8% versus 21.8%, respectively). Other characteristics, such as mean TSS, ECOG PS, and mean hemoglobin, were also similar in both groups. There were some imbalances between the 2 groups in hemoglobin level at baseline: The proportion of patients with a hemoglobin level less than 10 g/dL was higher in the switch to momelotinib treatment group (56.3%) than in the continuing momelotinib group (37.4%).¹⁰

In the open-label extension phase of the SIMPLIFY-2 trial, the mean age of the patients in the ITT population was 68.1 years. There were more males in the continuing momelotinib group (64.1%) than in the switch to momelotinib treatment group (40.0%). The majority of patients in the continuing momelotinib group (64.1%) and the switch to momelotinib treatment group (55.0%) had intermediate-2–risk MF per the DIPSS criteria, and more than 60% of patients in both treatment groups had a positive JAK2V617F mutation status (60.9% versus 72.5% in the continuing momelotinib group and switch to momelotinib treatment group, respectively). A numerically larger proportion of patients were transfusion dependent in the continuing momelotinib group (57.8%) than in the switch to momelotinib treatment group (50.0%).¹¹ There were some imbalances between the 2 groups in ECOG PS and hemoglobin level at baseline. The proportion of patients with an ECOG PS of 1 was higher in the continuing momelotinib group (64.1%) than in the switch to momelotinib treatment group (47.5%). A numerically smaller proportion of patients had an ECOG PS of 2 in the continuing momelotinib group (4.7%) than in the switch to momelotinib treatment group (15.0%). There were no patients with an ECOG PS of 3 in the continuing momelotinib group, but 5% of patients in the switch to momelotinib treatment group had an ECOG PS of 3. The proportion of patients with a hemoglobin level less than 8 g/dL was higher in the continuing momelotinib group (28.1%) than in the switch to momelotinib treatment group (7.5%).¹¹

The population demographics or baseline disease characteristics were not presented separately for patients who participated in the open-label extension phase of the MOMENTUM trial.¹²

Table 21: Summary of Baseline Characteristics in the Open-Label Extension Phase of the SIMPLIFY-1 and SIMPLIFY-2 Trials (ITT Analysis Set)

ANC = absolute neutrophil count; BAT = best available therapy; BMI = body mass index; DIPSS = Dynamic International Prognostic Scoring System; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ET = essential thrombocythemia; IPSS = International Prognostic Scoring System; ITT = intention to treat; MF = myelofibrosis; MMB = momelotinib; PV = polycythemia vera; RUX = ruxolitinib; SD = standard deviation; TSS = total symptom score.

Notes: For the continuing (MMB to MMB) treatment group, the baseline is the last assessment before or on the date of randomization. For the switch (RUX to MMB in the SIMPLIFY-1 trial or BAT to MMB in the SIMPLIFY-2 trial) treatment group, the baseline is the last assessment before or on the date of the first dose of MMB in the extended treatment phase.

^aAge was calculated in years at the date of randomization.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report).¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Exposure to Study Treatments

A summary of patient exposure in the open-label extension phases of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials is presented in Table 22. In the overall safety population of the SIMPLIFY-1 trial, the mean treatment adherence rates were more than 90% and were approximately similar across the continuing momelotinib group and switch to momelotinib treatment group (94.2% versus 94.8%, respectively). The mean daily dose of momelotinib was slightly higher in the continuing momelotinib treatment group than in the switch to momelotinib treatment group (180.3 mg/day versus 174.6 mg/day, respectively).¹⁰

In the overall safety population in the extended treatment phase of the SIMPLIFY-2 trial, the mean treatment adherence rates were numerically higher in the continuing momelotinib group than in the switch to momelotinib treatment group (39.2% versus 31.6%, respectively). The mean daily dose of momelotinib was numerically higher in the switch to momelotinib treatment group than in the continuing momelotinib group (176.3 mg/day versus 163.9 mg/day, respectively).¹¹

The mean duration of momelotinib treatment in the open-label extension phase of the MOMENTUM trial was similar for patients who continued momelotinib treatment and those who switched to momelotinib after randomized treatment with danazol. The mean relative dose intensity was similar in both groups.¹²

Concomitant Medications and Co-Interventions

Concomitant medication use was reported by approximately 99% of patients in the overall safety population who transitioned to the open-label extension phase of the SIMPLIFY-1 trial.¹⁰ Concomitant medication use was reported by all patients (100%) in the overall safety population who transitioned to the open-label treatment phase of the SIMPLIFY-2 trial.¹¹ Concomitant medications and co-interventions were not reported separately for patients who participated in the open-label extension phase of the MOMENTUM trial.¹²

Details on subsequent treatments were not available for the open-label phase.

Efficacy

The overall median duration of follow-up in the SIMPLIFY-1 trial safety analysis set (combined randomized and open-label extension phases) was 35.3 months (range, 0.4 to 59.3 months; momelotinib: 35.4 months and ruxolitinib: 35.2 months).¹⁰ In the SIMPLIFY-2 trial, the overall median duration of follow-up in the safety analysis set (combined randomized and open-label extension phases, and long-term follow-up) was 28.2 months (range, 0.3 to 50.4 months; momelotinib: 28.2 months and BAT: 27.2 months).¹¹

Table 22: Summary of Patient Exposure in the Open-Label Extension Phase of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM Trials (Safety Analysis Set)

BAT = best available therapy; DAN = danazol; MMB = momelotinib; NR = not reported; Q1 = quarter 1; Q3 = quarter 3; RUX = ruxolitinib; SD = standard deviation.

Note: The Safety population comprises all patients in the intention-to-treat population who received at least 1 dose of the study drug. Patients were evaluated based on actual treatment received.

^aDose intensity = actual cumulative dose / actual duration of the treatment (days).

^bRelative dose intensity = actual dose intensity / planned dose intensity. In the pooled data from all trials, the relative dose intensity was 100 (range, 0 to 114) for patients randomized to MMB during the treatment phase and was 97.2 (range, 0 to 387) for those who received MMB during the open-label phase.⁴⁷

^cAdherence rate (%) = [total study drug administered / total study drug prescribed per protocol] × 100. Only patients who returned at least 1 bottle of the study drug were included in the analysis.

^dDuration of exposure to study drug = ([treatment end date – treatment start date] + 1) / 7.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report);¹¹ GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Transfusion Independence Response Rate, Week 48

The transfusion independence response rate was not reported for the open-label extension phases of the SIMPLIFY-1 and SIMPLIFY-2 trials.^10,11 In the open-label extension phase of the MOMENTUM trial, transfusion independence response was reported as the transfusion independence response rate at week 48 and the transfusion independence response rate by week 48, as described in Table 23. Transfusion independence at week 48 was defined as the absence of RBC transfusion and no hemoglobin level less than 8 g/dL during the 12 weeks immediately before the week 48 visit. Transfusion independence by week 48 was defined as the absence of RBC transfusion and no hemoglobin level less than 8 g/dL in any rolling period of 12 weeks (i.e., 84 consecutive days) before the week 48 visit.¹²

The transfusion independence response rate during the first 24 weeks of the open-label extension phase for the MOMENTUM trial is presented in Table 23. In the MOMENTUM trial, the majority of patients were transfusion independent at week 24 and week 48, including 88.2% of patients (n = 30 of 34) in the continuing momelotinib group and 80.0% of patients (n = 8 of 10) in the switch to momelotinib treatment group. Further, 24.2% of patients (n = 8 of 33) in the continuing momelotinib group and 50.0% of patients (n = 10 of 20) in the switch to momelotinib treatment group without transfusion-independence status at week 24 and met the criteria for transfusion independence response at week 48.¹²

Table 23: Summary of Transfusion Independence Response During the Open-Label Extension Phase in the MOMENTUM Trial (ITT Analysis Set)

DAN = danazol; ITT = intention to treat; MMB = momelotinib; RBC = red blood cell.

^aCompleted the week 48 visit and had no RBC or whole blood transfusion, had no hemoglobin level less than 8 g/dL, and provided hemoglobin assessments during the 12 weeks immediately before the week 48 visit.

^bCompleted the week 48 visit and did not meet the transfusion independence criteria.

^cHad no RBC or whole blood transfusion, had no hemoglobin level less than 8 g/dL, and provided hemoglobin assessments during any rolling 12-week period from the first day of the open-label treatment period up to the week 48 visit.

^dCompleted the week 48 visit and did not meet the transfusion independence criteria.

Source: GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Rate of RBC Transfusion at Week 48

The rate of RBC transfusion was not reported for the SIMPLIFY-1 and SIMPLIFY-2 trials and was not reported for the open-label extension phase of the MOMENTUM trial.^10-12

Splenic Response at Any Time

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The proportion of patients with and without a splenic response at week 24 in the MOMENTUM trial who were classified as having a splenic response at week 48 is shown in Table 25. Most patients (n = 19 of 24; 79.2%) in the continuing momelotinib group and 50.0% of patients (n = 1 of 2) in the switch to momelotinib treatment group who experienced splenic response at week 24 were also classified as experiencing splenic response at week 48. Of those not experiencing splenic response at week 24 in the continuing momelotinib group (n = 43) and the switch to momelotinib treatment group (n = 28), 23.3% and 10.7%, respectively, were classified as experiencing a splenic response at week 48.¹²

Table 24: Splenic Response at Any Time in Combined Double-Blind and Open-Label Extension Phases of the SIMPLIFY-1 and SIMPLIFY-2 Trials (ITT Analysis Set)

BAT = best available therapy; ITT = intention to treat; MMB = momelotinib; RUX = ruxolitinib.

Note: The baseline spleen volume used is from the last assessment before or on the date of randomization.

Sources: GSK Data on File, 2021 (SIMPLIFY-1 Clinical Study Report);¹⁰ GSK Data on File, 2021 (SIMPLIFY-2 Clinical Study Report).¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Table 25: Splenic Response at Week 48 in the Open-Label Extension Phase of the MOMENTUM Trial

DAN = danazol; ITT = intent to treat; MMB = momelotinib.

Notes: Splenic response is defined as having at least a 35% reduction from baseline spleen volume. Splenic response at week 48 was assessed in patients who crossed over to open-label treatment with MMB and had a week 48 spleen scan. The imaging modality was required to match at baseline and week 48. Results are from the final analysis at the database lock on January 17, 2023.

^aPatients with at least a 35% reduction from baseline spleen volume at week 48.

Source: GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

TSS Response Rate, Week 48

TSS response rates were not reported for the SIMPLIFY-1 and SIMPLIFY-2 open-label extension studies.^10,11

Table 26 presents the results for MFSAF TSS response during the first 24 weeks of the open-label extension phase for the MOMENTUM trial, expressed as “at week 48” and “by week 48.” Patients experiencing a TSS response at week 48 were defined as patients with at least a 50% reduction from baseline in mean MFSAF TSS during the 28-day period immediately before the end of week 48. Patients experiencing a TSS response by week 48 were defined as patients with at least a 50% reduction from baseline in mean MFSAF TSS during any rolling 28-day evaluation period from the first day of the open-label extension period up to week 48.¹² A majority of patients with at least a 50% reduction from baseline MFSAF TSS at week 24 were also experiencing a TSS response at week 48, including 72.0% of patients (n = 18 of 25) in the continuing momelotinib group and all patients (n = 5 of 5; 100%) in the switch to momelotinib treatment group. Further, 27.9% (n = 12 of 43) and 40.0% (n = 10 of 25) of nonresponders at week 24 in the continuing momelotinib group and the switch to momelotinib treatment group had a TSS response at week 48.¹² A majority of patients with at least a 50% reduction from baseline MFSAF TSS at week 24 were experiencing a TSS response by week 48, including 96.7% of patients (n = 29 of 30) in the continuing momelotinib group and all patients (n = 5 of 5; 100%) in the switch to momelotinib treatment group. Further, 37.0% (n = 17 of 46) and 51.9% (n = 14 of 27) of nonresponders at week 24 in the continuing momelotinib group and the switch to momelotinib treatment group had a TSS response by week 48.¹²

Table 26: MFSAF TSS Response Rate at Week 48 or by Week 48 in the Open-Label Extension Phase of the MOMENTUM Trial (Weeks 24 to 48)

DAN = danazol; DBL = database lock; MFSAF = Myelofibrosis Symptom Assessment Form; MMB = momelotinib; TSS = total symptom score.

Note: Results are from the final analysis at the database lock on January 17, 2023.

^aHad at least a 50% reduction from baseline in mean MFSAF TSS during the 28-day period immediately before the end of week 48.

^bCompleted the week 48 visit and did not meet response criteria.

^cHad a at least a 50% reduction from baseline in mean MFSAF TSS during any rolling 28-day evaluation period from the first day of the open-label treatment period up to week 48.

^dCompleted the week 48 visit and had MFSAF TSS data but did not meet response criteria.

Source: GSK Data on File, 2023 (MOMENTUM Clinical Study Report).¹² Details included in the table are from the sponsor’s summary of clinical evidence.

Harms

A summary of safety outcomes in the overall safety population of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials in the open-label extension phase is provided in Table 27.

Across the overall safety population in the SIMPLIFY-1 trial, the frequencies of TEAEs were numerically higher in patients who switched from ruxolitinib to momelotinib than those who continued on momelotinib (89.8% versus 78.4%, respectively) after 24 weeks of treatment with momelotinib in the open-label extension phase. Similar trends were observed for the most common grade 3 or 4 AEs (37.6% versus 27.5%), for SAEs (23.4% versus 15.8%), and for TEAEs leading to treatment discontinuation (14.7% versus 8.8%), with numerically higher proportions for patients who switched from ruxolitinib to momelotinib than for those who continued on momelotinib after 24 weeks of treatment with momelotinib in the open-label extension phase.¹⁰ The most commonly reported AEs in both groups, occurring in at least 10% of patients, were diarrhea, thrombocytopenia, anemia, fatigue, nausea, and cough. No SAE occurred in more than 2% of patients in either group.¹⁰ In the overall safety population, the most common AEs leading to treatment discontinuation were thrombocytopenia, fatigue, and peripheral sensory neuropathy (no events in the continuing momelotinib group and relatively few, 2.0% to 2.5%, in the switch to momelotinib group). In the continuing momelotinib and the switch to momelotinib groups, the following AESIs were reported: peripheral neuropathy (5.3% versus 7.6% of patients), nonhematological AEs (77.2% versus 87.3% of patients), cataract (4.7% versus 3.6% of patients), and first dose effect (NR versus 2.0% of patients). In the continuing momelotinib group, 10.5% of patients died from TEAEs not related to disease progression; in the switch to momelotinib group, this percentage was 8.6%.¹⁰

Across the overall safety population in the SIMPLIFY-2 trial, the frequencies of the following were numerically higher in patients who switched from BAT to momelotinib than in those who continued on momelotinib after 24 weeks of treatment with momelotinib in the open-label extension phase: TEAEs (100% versus 93.8%), grade 3 or 4 AEs (55.0% versus 28.1%), SAEs (27.5% versus 20.3%), TEAEs leading to treatment discontinuation (37.5% versus 7.8%), and AEs leading to treatment interruption and/or dose reduction (19.2% versus 16.3%).¹¹ The most commonly reported AEs occurring in at least 15% of patients were, in the continuing momelotinib group, cough and diarrhea and, in the switch to momelotinib treatment group, asthenia, pyrexia, diarrhea, thrombocytopenia, cough, and anemia. The most commonly reported SAEs in patients who switched from BAT to momelotinib, occurring in at least 5% of patients, were anemia, pyrexia, and confusional state.¹¹ The most common AEs leading to treatment discontinuation were thrombocytopenia, diarrhea, and headache (no events in the continuing momelotinib group, and 5.0% to 7.5% of patients experiencing events in the switch to momelotinib group). Among the continuing momelotinib group and the switch to momelotinib treatment group, the following AESIs were reported: peripheral neuropathy (10.9% versus 20.0%), nonhematological AEs (98.4% versus 100%), cataract (1.6% versus 0%), and first dose effect (NR versus 7.5%). Deaths due to TEAEs not related to disease progression in the overall safety population were reported in 21.9% of patients who continued treatment with momelotinib and 7.5% of patients who switched from BAT to momelotinib.¹¹

In the MOMENTUM trial, after 24 weeks of treatment with momelotinib in the open-label treatment phase, the overall frequencies of TEAEs (89.2% versus 85.4%), grade 3 or higher TEAEs (51.6% versus 48.8%), and serious TEAEs (32.3% versus 29.3%) were numerically slightly higher in patients who continued on momelotinib than in those who switched from danazol to momelotinib.¹² The most commonly reported AEs occurring in at least 10% of patients were, among patients who continued on momelotinib, diarrhea, thrombocytopenia, pyrexia, asthenia, and anemia and, among those who switched from danazol to momelotinib, thrombocytopenia and diarrhea. The most commonly reported SAEs occurring in at least 2% of patients were, among patients who continued on momelotinib, urinary tract infection, acute kidney injury, febrile neutropenia, and squamous cell carcinoma of the skin and, among those who switched from danazol to momelotinib, acute kidney injury and urinary tract infection. In the overall safety population, the most common AEs leading to treatment discontinuation were anemia, AML, and transformation to AML (no events in the continuing momelotinib group for AML or transformation to AML and no events in the switch to momelotinib treatment group for anemia). No deaths due to TEAEs not related to disease progression were reported in either of the treatment groups.¹²

Table 27: Summary of Harms in the Open-Label Extension Phase of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM Trials (Safety Analysis Set)