Reimbursement Review

Danicopan (Voydeya)

Sponsor: Alexion Pharma GmbH

Therapeutic area: Paroxysmal nocturnal hemoglobinuria

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

EVH = extravascular hemolysis; NOC = Notice of Compliance; PNH = paroxysmal nocturnal hemoglobinuria; t.i.d. = 3 times a day.

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, and potentially life-threatening blood condition caused by an acquired genetic defect in hematopoietic stem cells.^1,2 This defect leads to the production of blood cells that lack 2 glycosylphosphatidylinositol-anchored complement regulatory proteins, CD55 and CD59, at their surface, causing the complement system to recognize red blood cells (RBCs) as damaged. The uncontrolled activation of the complement cascade prematurely attacks these cells resulting in hemolysis. Symptoms of PNH can vary significantly among individuals, and the disease can affect any race, ethnicity, or sex. It may manifest at any age,^3,4 although it typically emerges in young adults, with the median age of diagnosis being around 30 years.^1,2

Intravascular hemolysis (IVH) occurs in both terminal and proximal pathways when RBCs are directly lyzed because of the activation of the alternative complement pathway.⁵ Patients with PNH are susceptible to an increased risk of thrombosis, pain, organ damage (e.g., impaired renal function), underlying bone marrow dysfunction,^1,3,6-8 and increased risk of morbidity and mortality.^1,9 They also have an increased need for transfusions, which can impair health-related quality of life (HRQoL).^1,3,6,10-14

In Canada, ravulizumab and eculizumab are complement component 5 inhibitors (C5is) used as first-line therapy to treat hemolytic PNH. This treatment regimen addresses uncontrolled complement activation through a complete complement component 5 (C5) inhibition in the terminal complement cascade and helps reduce symptoms and complications, resulting in improved survival for patients with PNH.^15,16 However, some patients receiving C5i treatment remain anemic and transfusion-dependent. Possible causes of this include breakthrough hemolysis (BTH), extravascular hemolysis (EVH), nutritional deficiencies, and bone marrow failure.¹⁷

EVH is a mechanistic consequence believed to be caused by ongoing complement component 3 (C3) deposition on surviving yet defective RBCs, which makes them vulnerable to phagocytosis in the liver or spleen.^18-20 While symptoms of EVH are not life-threatening, its manifestation is heterogeneous. For some patients, EVH may consist of having normal hemoglobin (Hb) levels²¹ and being asymptomatic,^22,23 while others may develop severe clinical symptoms and may require blood transfusions to manage ongoing anemia.^22,24,25 Clinical trial and real-world data show that approximately 20% of patients with PNH who were clinically stable on C5i treatment develop clinically significant EVH.²⁶

The historical approach to managing anemia due to EVH in patients in Canada with PNH has been supportive care (e.g., RBC transfusions, corticosteroids, splenectomy, danazol, and epoetin alfa) and continuing C5i treatment to prevent the life-threatening consequences of IVH.²⁰ Pegcetacoplan, a subcutaneous (SC) proximal C3 inhibitor (C3i) is an approved therapy indicated for patients with inadequate response to, or intolerant of, a C5i.²⁷ Per the clinical experts consulted by Canada’s Drug Agency (CDA-AMC), this option would currently be offered as a second-line pharmacologic option to patients diagnosed with EVH.

Because of the rarity of the disease, the prevalence and incidence of PNH have been poorly reported, and published prevalence and incidence estimates of PNH and EVH are not available for the population of people living in Canada. A study in the US estimated the prevalence of PNH at 1.2 to 1.3 per 100,000 persons between 2016 and 2017. The incidence rate over the study period was 0.57 per 100,000 person-years.²⁸

Danicopan selectively inhibits complement alternative pathway factor D,²⁹ which plays a key role in amplifying complement system response. Danicopan is thought to mediate the deposition of C3 fragments on PNH blood cells, which is a key cause of EVH in patients receiving ravulizumab or eculizumab for PNH. Inhibition of factor D activity specifically targets the control point of the complement cascade amplification loop, blocking C3 convertase formation and thereby reducing the production of C3 fragments and downstream membrane attack complex (MAC) formation.³⁰ Although danicopan blocks the alternative pathway–mediated amplification of the complement classical pathway and lectin pathway, these 2 pathways remain active to provide residual complement-dependent protection against infectious pathogens.³¹ When co-administered with ravulizumab or eculizumab, danicopan is anticipated to maintain control over C5 and MAC-mediated IVH.

Danicopan has a Health Canada indication as an add-on to ravulizumab or eculizumab for the treatment of adult patients with PNH who have residual hemolytic anemia due to EVH.²⁹ The sponsor reimbursement request is as per the indication. The recommended starting dose of danicopan is 150 mg 3 times a day administered orally, approximately 8 hours apart (± 2 hours). The dose can be increased to 200 mg 3 times a day if a patient’s Hb level has not increased by at least 2 g/dL after 4 weeks of therapy, if a patient required transfusion within the previous 4 weeks, or to achieve an appropriate Hb response based on clinical judgment.²⁹ Danicopan should not be administered as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab.²⁹

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of danicopan 50 mg and 100 mg film-coated oral tablets as an add-on to ravulizumab or eculizumab, to treat adult patients with PNH who are experiencing signs and symptoms of EVH.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

The Canadian Association of PNH Patients and the Aplastic Anemia & Myelodysplasia Association of Canada submitted a joint input for this review. A clinical summary of PNH was provided and information was gathered through the personal experiences of 1 patient living in Canada who received danicopan.

The patient group input expressed that PNH significantly impacts the quality of life for both patients and their caregivers. Beyond the persistent fatigue and weakness caused by chronic anemia from hemolysis, patients deal with other symptoms such as abdominal pain and dysphagia which influence their dietary habits and social interactions. Managing symptoms requires ongoing medical interventions, medication adjustments, and lifestyle changes. The input noted that even though currently available treatments for PNH, such as C5is (ravulizumab and eculizumab) and a C3i (pegcetacoplan), effectively inhibit IVH, thrombosis, and EVH, approximately 20% of patients continue to experience EVH and persistent anemia and require frequent blood transfusions. The financial costs associated with treatment exacerbate stress, creating a significant economic strain on patients and families. This wide-ranging impact underscores the importance of holistic management approaches to effectively support both patients and their caregivers in managing PNH.

The input stated that patients, caregivers, and families affected by PNH desire tolerable treatment options that reduce treatment burden, decrease hemolysis symptoms, decrease dependency on blood transfusions, slow disease progression, and improve long-term outcomes and quality of life. The input indicated that the 1 patient with experience with danicopan noticed a remarkable improvement in her symptoms.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

CDA-AMC consulted 2 clinical experts with experience treating PNH for this review. Per the clinical experts, PNH is a complicated disease. The initial goals of therapy are to reduce mortality, reduce complications and morbidities associated with IVH, as well as reduce transfusion needs, improve HRQoL with better Hb support and avoidance of iron overload, and help patients attain better functional status and return to prediagnosis activities and employment. The initial treatment of choice for PNH is a C5i, which controls IVH and thus the major mortality and morbidity of the disease, as most deaths in patients with PNH are because of thrombotic complications.

C5is can provide incomplete control of PNH in some circumstances. Possible causes include rare genetic mutations (in people of Japanese ethnicity), inadequate dosing of the C5i, response to vaccination, or infections leading to BTH or symptomatic EVH related to C5 inhibition. The experts estimated that approximately 40% of patients with PNH will continue to have low Hb despite therapy, approximately 30% will require transfusions, and EVH will contribute to poor HRQoL in 20% to 30% of patients.

Per the experts, there is no standard definition for EVH and a diagnosis of EVH generally requires ruling out other possible causes of anemia, which may be challenging as patients often have other comorbidities and it may not be evident that anemia is due to 1 cause. Clinical diagnosis for EVH typically requires anemia along with normal or minimally elevated lactate dehydrogenase (LDH), as well as elevated bilirubin and reticulocyte counts. Alternative explanations for anemia which the experts noted would have to be ruled out include bone marrow failure, hematinic deficiencies (such as vitamin B12 or ferritin), renal insufficiency, or blood loss.

Treatment goals for patients with PNH and EVH remain to reduce mortality, inhibit IVH, and improve HRQoL by providing better Hb support that does not require transfusion, avoids iron overload, and leads to better functional status for patients. The main nonpharmacologic treatment for EVH and persistent anemia in PNH while on C5i treatment is transfusion support, which is associated with several drawbacks such as lengthy hospital visits and risks with transfusion including infection, antibody development, or iron overload. In addition, most patients receiving transfusions will have significantly reduced HRQoL and be unable to maintain regular employment.

Pegcetacoplan is the primary pharmacologic option offered to patients with clinically significant EVH. Pegcetacoplan is a subcutaneous (SC) infusion with twice-weekly dosing and specific transportation requirements. If BTH occurs, the experts noted that the frequency of pegcetacoplan will usually be increased to 3 times weekly.

The experts noted that danicopan would be an alternative to pegcetacoplan as a second-line drug and would be used as an add-on therapy for patients already on a C5i. Some patients already on pegcetacoplan may wish to switch to danicopan plus C5i if they were having ongoing BTH or issues with SC infusions.

Response to therapy would typically be an improvement in Hb and a reduction in transfusion requirements relative to the baseline for a given patient. The experts noted that ongoing anemia and transfusion needs may or may not be a treatment failure, as it is possible that other concurrent diseases such as bone marrow failure, aplastic anemia, other cancers, or comorbidities could be contributing factors. Intolerance or allergy to danicopan would be reason to discontinue therapy, as would a lack of improvement in Hb levels and transfusion needs. The experts noted that an episode of BTH or transfusion requirement in another setting would not be considered a treatment failure, nor would a required stoppage of therapy because of pregnancy or breastfeeding. Stopping danicopan therapy should be considered independent of the C5i as that treatment controls IVH.

Clinician Group Input

One clinician group, the Canadian PNH Network, submitted input for this review based on contributions from 9 clinicians. Information was gathered through publicly available documents, congress abstracts, and published literature.

The clinician group agreed with the clinical experts that the current standard of care for PNH is a C5i (i.e., eculizumab and ravulizumab), which acts via terminal complement blockade, and that there are still some unmet therapeutic needs within the available PNH treatment regimen. The clinician group input agreed with the clinical experts that some patients remain anemic due to EVH, and some remain transfusion-dependent with C5i.

The clinician group agreed with the experts that a subset of patients would benefit from proximal complement inhibition given the development of clinically significant EVH, but for whom pegcetacoplan is less than ideal. Dual complement blockade (i.e., C5i plus danicopan) would provide these patients with the same benefits of improved Hb but with a lower risk of complications.

The clinician group and the clinical experts were also aligned on the patients most likely to benefit from danicopan — those who have persistent anemia despite stable-dose C5i, in whom EVH is suspected. Patients who may receive proximal inhibition monotherapy (e.g., pegcetacoplan), who may not tolerate it, or have repeated BTH or other concerns could also benefit from the therapy. The input further noted that treatment is least suitable for those who are not anemic, or who meet exclusion criteria in clinical trials such as pregnancy.

The clinician input noted that clinically meaningful response to treatment would be sustained control of LDH but with further Hb increases and improvement in anemia-related symptoms. A lack of improvement in the first few months of therapy would be a prompt to increase the dose. Danicopan discontinuation should be considered in patients who develop adverse events (AEs) that preclude ongoing therapy, including poor treatment compliance and intolerable side effects. The most important feature to monitor for would be evidence of BTH.

The clinical experts and clinician group input agreed that patients with PNH should be followed by clinicians who specialize in the condition.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CDA-AMC recommendation for danicopan:

• considerations for relevant comparators

• considerations for initiation or renewal of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• generalizability

• care provision issues.

The clinical expert consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

The ALPHA trial is an ongoing phase III, double-blind, randomized, placebo-controlled trial which enrolled a total of 86 patients with PNH who had clinically significant EVH and were receiving treatment with ravulizumab or eculizumab. The study used a 45-day screening period and randomization was stratified by transfusion history (> 2 transfusions or ≤ 2 transfusions in the 6 months before screening), Hb at screening (< 8.5 g/dL or ≥ 8.5 g/dL), and Japanese patient (yes or no). Stochastic dynamic allocation rules were used to randomize patients 2:1 through an interactive response technology to either receive danicopan 3 times a day added onto their C5i or a placebo 3 times a day added onto their C5i monotherapy, respectively. The study design consisted of a 12-week treatment period 1 (TP1) which was randomized, double-blind, and placebo-controlled, followed by a 12-week treatment period 2 (TP2) where patients initially randomized to placebo switched to receive danicopan and patients initially randomized to danicopan continued to receive danicopan. Patients completing TP2 were eligible to continue onto a total of 2 long-term extensions (LTE1 or LTE2); results from patients who have completed LTE1 to date were included in the submission.

The prespecified interim analysis (IA) submitted for this reimbursement review was planned for when approximately 75% (N = 63 patients) of the total planned sample had been randomized and completed the TP1; the purpose of this analysis, per the submission, was to assess stopping early for efficacy. The data cut-off for the TP1 IA was conducted on June 28, 2022, and a second interim data analysis for TP2 results was conducted with a data cut-off of September 20, 2022. A total of 63 patients formed the interim efficacy analysis set (IEAS) and a total of 86 patients (the entire randomized study sample) formed the interim safety analysis set.

Patients eligible to participate in the study were required to be aged 18 years or older, have a diagnosis of PNH, and have clinically significant EVH defined as patients presenting with anemia (Hb ≤ 9.5 g/dL) and increased reticulocyte count (≥ 120 × 10⁹/L), with or without the need for transfusion, had to be receiving an approved C5i (ravulizumab or eculizumab) with no change in dose or interval for at least 6 months, as well as meet a platelet count threshold of 30,000 or more per µL and a neutrophil count of 500 or more per µL. Patients were eligible regardless of transfusion status. Patients were excluded if they had a history or presence of any clinically significant medical condition or comorbidity, including any conditions leading to anemia that are not primarily because of PNH; if they had any procedures and/or laboratory anomalies which would put them at undue risk to receive danicopan; or patients who were, or who had partners who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study intervention.

All patients received either danicopan or placebo in the form of 50 mg or 100 mg film-coated oral tablets. To assess adherence, adherence was calculated as a percentage of danicopan doses taken divided by the doses scheduled to be taken. The dosage administered started at 150 mg 3 times a day; dosing could be escalated up to a maximum of 200 mg at specific time points and specific clinical circumstances in the study.

The primary outcome was change in Hb levels from baseline to week 12. Key secondary outcomes were the proportion of patients with Hb increase of 2 g/dL or greater in the absence of transfusion at week 12, transfusion avoidance (transfusion-free and not requiring transfusion) at week 12, change in absolute reticulocyte count from baseline to week 12, and change in Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) scores from baseline to week 12. The primary and key secondary outcomes were controlled for multiple comparisons and an alpha-spending procedure was applied to account for the fact that a smaller sample size than was required by the power calculations was used for this analysis. The alpha-spending procedure and hierarchical testing structure controlled the family-wise type I error rate for these end points. Secondary outcomes were the proportion of patients with Hb normalization (defined as patients with Hb values > lower limit of the normal reference range [110 g/L for female patients and 125 g/L for male patients]);³² transfusion burden, defined as the number of RBC units transfused and the number of transfusion instances; and change in LDH from baseline. Exploratory outcomes were change from baseline in the EQ visual analogue scale (EQ VAS) scores and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status/quality of life score. All primary, key secondary, secondary, and exploratory outcomes were measured at weeks 12 and 24; Hb, absolute reticulocyte count, LDH, FACIT-F, EQ-5D-3L, and EORTC QLQ-C30 were also measured at week 72 among patients with data at that time point, and reported as LTE1 results.

Most baseline characteristics were broadly similar between study arms. There was a numeric difference in the proportion of patients (66.7% female in the placebo plus C5i arm, 54.8% female in the danicopan plus C5i arm; 33.3% male in the placebo plus C5i arm, 45.2% male in the danicopan plus C5i arm), and the proportion of patients of Asian descent (33.3% in the placebo plus C5i arm, 42.9% in the danicopan plus C5i arm). There were also numeric differences in the proportion of patients treated with each C5i (64.3% of patients in the danicopan plus C5i arm and 47.6% of patients in the placebo plus C5i arm were treated with ravulizumab). There was a numerically higher LDH in the danicopan plus C5i arm (298.73 U/L) relative to the placebo plus C5i arm (278.25 U/L), and a numerically higher proportion of patients in the danicopan plus C5i arm had received a transfusion within 24 weeks of receiving the study drug (90.5% in the danicopan plus C5i arm, 81.0% in the placebo plus C5i arm).

Efficacy Results

Change in Hb Levels

The least squares (LS) mean change from baseline in Hb level to 12 weeks was the primary outcome. At TP1, the LS mean difference for the change in Hb from baseline between the danicopan plus C5i and the placebo plus C5i arms was 24.44 g/L (98.2% confidence interval [CI], 15.25 g/L to 33.63 g/L; P ≤ 0.0001). At TP2, the LS mean change from baseline to week 24 in the danicopan-emergent arm (patients who received danicopan plus C5i from weeks 0 to 12 and continued to receive danicopan plus C5i from weeks 12 to 24) was 31.67 g/L (95% CI, 25.61 g/L to 27.74 g/L). In the placebo-emergent arm (patients who received placebo plus C5i from weeks 0 to 12 and who subsequently switched to receive danicopan plus C5i from weeks 12 to 24), the LS mean change from baseline to week 24 was 22.58 g/L (95% CI, 15.72 g/L to 29.44 g/L). At LTE1, the observed mean change from baseline in Hb levels was 32.00 g/L (standard deviation [SD] = 11.81 g/L) in the danicopan-emergent arm and 31.50 g/L (SD = 10.61 g/L) in the placebo-emergent arm.

Proportion of Patients With Hb Level Increase of 2 g/dL or Greater in the Absence of Transfusion

The proportion of patients with Hb level increases of 2 g/dL or greater was a key secondary outcome in the analysis. At TP1, the LS mean difference for the proportion of patients with Hb level increase of 2 g/dL or greater between the danicopan plus C5i and the placebo plus C5i arms was 45.90% (95.8% CI, 27.40% to 64.42%; P ≤ 0.0001). At TP2, the proportion of patients with this outcome in the danicopan-emergent arm was 46.3% (95% CI, 30.66% to 62.58%); results were not reported for the placebo-emergent arm. This outcome was not reported at LTE1 in either arm.

Proportion of Patients With Hb Normalization

The proportion of patients with Hb normalization was a secondary outcome. At TP1, the LS mean difference for the change in the proportion of patients with Hb normalization between the danicopan plus C5i and the placebo plus C5i arms was 18.40% (95% CI, –0.84% to 37.71%; P = 0.0080). At TP2, the proportion of patients with this outcome in the danicopan-emergent arm was 19.50% (95% CI, 8.82% to 34.87%). This outcome was not reported for the placebo-emergent arm at TP2 and was not reported at LTE1 for either arm.

Transfusion Avoidance

Transfusion avoidance at TP1 was a key secondary outcome in the analysis. At TP1, the LS mean treatment difference (TD) for the proportion of patients with transfusion avoidance between the danicopan plus C5i and the placebo plus C5i arms was 40.80% (95.8% CI, 21.08% to 60.58%; P = 0.0004). At TP2, the proportion of patients with this outcome in the danicopan-emergent arm was 78.00% (95% CI, 62.39% to 89.44%), and was 90.00% (95% CI, 68.30% to 98.77%) in the placebo-emergent arm. This outcome was not reported at LTE1 in either arm.

Transfusion Burden

Transfusion burden was measured by the number of RBC units transfused and the number of transfusion instances; both were secondary outcomes. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in the number of RBC units transfused between the 12 weeks before study drug initiation and the 12 weeks after study drug initiation was –1.31 (95.8% CI, –2.24 to –0.37; P = 0.0072). At TP2, the change in the number of RBC units transfused in the 24 weeks after treatment initiation relative to the 24 weeks before treatment initiation in the danicopan-emergent arm was –2.80 (95% CI, –4.55 to –1.11). This outcome was not reported in the placebo-emergent arm or at LTE1 in either arm.

At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in the number of transfusion instances between the 12 weeks before study drug initiation and the 12 weeks after study drug initiation was –0.72 (95% CI, –1.32 to –0.11; P = 0.0207). At TP2, the change in the number of transfusion instances between the 24 weeks before study drug initiation and the 24 weeks after study drug initiation in the danicopan-emergent arm was –1.50 (95% CI, –2.36 to –0.67). This outcome was not reported in the placebo-emergent arm or at LTE1 in either arm.

Absolute Reticulocyte Count

Change in absolute reticulocyte count from baseline to week 12 was a key secondary outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in absolute reticulocyte count from baseline was –0.087 × 10¹²/L (95.8% CI, –0.119 × 10¹²/L to –0.056 × 10¹²/L; P ≤ 0.0001). At TP2, the change from baseline in absolute reticulocyte counts in the danicopan-emergent arm was –0.080 × 10¹²/L (SD = 0.073 × 10¹²/L), and in the placebo-emergent arm was –0.084 × 10¹²/L (SD = 0.110 × 10¹²/L). At LTE1, the observed mean change from baseline in absolute reticulocyte counts in the danicopan-emergent arm was –0.041 × 10¹²/L (SD = 0.029 × 10¹²/L), and in the placebo-emergent arm was –0.106 × 10¹²/L (SD = not applicable; n = 1 patient).

Lactate Dehydrogenase

Change in LDH from baseline was a secondary outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in LDH from baseline was –20.57 U/L (95% CI, –49.28 U/L to 8.15 U/L; P = 0.1569). At TP2, the mean change from baseline in LDH in the danicopan-emergent arm was –23.46 U/L (SD = 105.40 U/L), and in the placebo-emergent arm was 0.21 U/L (SD = 84.89 U/L). At LTE1, the mean change from baseline in LDH in the danicopan-emergent arm was –20.83 U/L (SD = 67.00 U/L), and in the placebo-emergent arm was 5.00 U/L (SD = 111.89 U/L).

Functional Assessment of Chronic Illness Therapy–Fatigue

The change in FACIT-F (ranging from 0 [extreme fatigue] to 52 [no fatigue] with higher scores indicating less fatigue)³³ scores from baseline was a key secondary outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in FACIT-F scores from baseline was 6.12 (95.8% CI, 2.18 to 10.06; P = 0.0021). At TP2, the LS mean change from baseline in FACIT-F scores in the danicopan-emergent arm was 6.12 (95% CI, 3.41 to 8.82), and in the placebo-emergent arm was 6.44 (95% CI, 1.23 to 11.64). At LTE1, the mean change from baseline in the danicopan-emergent arm was 3.86 (SD = 7.15) and –4.33 (SD = 9.07) in the placebo-emergent arm.

EQ Visual Analogue Scale

The change in EQ VAS (health rating on a scale from 0 to 100, with 0 representing the worst imaginable health state and 100 the best)^34,35 scores from baseline was an exploratory outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change from baseline in EQ VAS scores was 6.27 (95% CI, –2.85 to 15.40; P = 0.1738). At TP2, the mean change from baseline in EQ VAS scores was 13.70 (SD = 20.12) in the danicopan-emergent arm and 9.70 (SD = 21.93) in the placebo-emergent arm. At LTE1, the mean change from baseline in the danicopan-emergent arm was 12.30 (SD = 18.70) and –11.00 (SD = 12.73) in the placebo-emergent arm.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

The change in EORTC QLQ-C30 global health (standardized score ranging from 0 to 100, higher score represents higher HRQoL)³⁶ scores from baseline was an exploratory outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change from baseline in EORTC QLQ-C30 global health scores was 6.62 (95% CI, –1.17 to 14.41; P = 0.0941). At TP2, the mean change from baseline in EORTC QLQ-C30 global health scores was 8.56 (SD = 16.96) in the danicopan-emergent arm and 10.53 (SD = 14.92) in the placebo-emergent arm. At LTE1, the mean change from baseline in the danicopan-emergent arm was 1.19 (SD = 26.97) and 8.33 (SD = 22.05) in the placebo-emergent arm.

Harms Results

Harms were reported separately for TP1, TP2, and LTE1 cut-offs, as well as overall during the entire time patients were exposed to danicopan (total danicopan treatment). Overall, a total of 93.0% of patients in the danicopan-emergent arm and 82.6% of patients in the placebo-emergent arm experienced treatment-emergent AEs (TEAEs) during treatment with danicopan.

During TP1, there were numeric differences in the proportion of patients experiencing TEAEs for anemia (1.8% danicopan plus C5i, 13.8% placebo plus C5i), vomiting (5.3% danicopan plus C5i, 0% placebo plus C5i), upper abdominal pain (1.8% danicopan plus C5i, 6.9% placebo plus C5i), pyrexia (5.3% danicopan plus C5i, 0% placebo plus C5i), asthenia (0% danicopan plus C5i, 13.8% placebo plus C5i), ear infection (0% danicopan plus C5i, 6.9% placebo plus C5i), contusion (1.8% danicopan plus C5i, 10.3% placebo plus C5i), increased aspartate aminotransferase (3.5% danicopan plus C5i, 10.3% placebo plus C5i), pain in extremity (5.3% danicopan plus C5i, 0% placebo plus C5i), dizziness (1.8% danicopan plus C5i, 6.9% placebo plus C5i), and insomnia (1.8% danicopan plus C5i, 10.3% placebo plus C5i). A total of 57 patients in the danicopan plus C5i arm and 29 patients in the placebo plus C5i arm contributed data. There were numeric differences in the proportion of patients experiencing TEAEs for nausea (2.1% danicopan-emergent, 13.0% placebo-emergent), and pyrexia (10.4% danicopan-emergent, 0% placebo-emergent). A total of 48 patients in the danicopan-emergent arm and 23 patients in the placebo-emergent arm contributed data. During the LTE there were numeric differences in the proportion of patients experiencing TEAEs for diarrhea (2.5% danicopan-emergent, 10.0% placebo-emergent), asthenia (2.5% danicopan-emergent, 15.0% placebo-emergent), and back pain (2.5% danicopan-emergent, 10.0% placebo-emergent). A total of 40 patients in the danicopan-emergent arm and 20 patients in the placebo-emergent arm contributed data.

Overall, a total of 12.3% of patients in the danicopan-emergent arm and 26.1% of patients in the placebo-emergent arm experienced any serious AE (SAE) while being treated with danicopan. During TP1, 5.3% of patients in the danicopan plus C5i arm experienced any SAE; the SAEs were pancreatitis, cholecystitis, COVID-19, and blood bilirubin increase (1 report of each). A total of 6.9% of patients in the placebo plus C5i arm experienced any SAE; the SAEs were anemia, abdominal pain, and headache (1 report of each). During TP2, 6.3% of patients in the danicopan-emergent arm experienced any SAE; the SAEs were Dieulafoy vascular malformation, pyrexia, COVID-19 pneumonia, and staphylococcus sepsis (1 report of each). In the placebo-emergent arm, 13.0% of patients experienced any SAE; the SAEs were hemolysis, vertigo, and headache (1 report of each). During LTE, 7.5% of patients in the danicopan-emergent arm experienced any SAE; the SAEs were stent-grant endoleak, decreased Hb, invasive ductal breast carcinoma, pulmonary embolism, and pulmonary hemorrhage (1 report of each). In the placebo-emergent arm, 20.0% of patients experienced any SAE; the SAEs were pericardial effusion, diarrhea, disease progression, COVID-19, and body temperature increased (1 report of each).

During TP1, TEAEs led to withdrawal of the study drug for 5.3% of patients in the danicopan plus C5i arm and 3.4% of patients in the placebo plus C5i arm. SAEs led to withdrawal of the study drug for 1.8% of patients in the danicopan plus C5i arm, and 0% of patients in the placebo plus C5i arm. During TP2, there were no TEAEs or SAEs leading to withdrawal of the study drug in either treatment arm. During LTE, TEAEs led to withdrawal of the study drug in 5.0% of patients in the placebo-emergent arm; there were no TEAEs leading to withdrawal of the study drug in the danicopan-emergent arm. There were no SAEs leading to withdrawal of the study drug in either treatment arm. There were no deaths reported in either study arm, at any time point during the trial to date.

Meningococcal infections and liver enzyme elevations were prespecified AEs of special interest during the ALPHA study. Throughout TP1, TP2, and LTE, there were no reported AEs of meningococcal infections in either study arm. During TP1, liver enzyme elevations occurred in 14.0% of patients in the danicopan plus C5i arm and 10.3% of patients in the placebo plus C5i arm. During TP2, liver enzyme elevations occurred in 6.3% of patients in the danicopan-emergent arm and 13.0% of patients in the placebo-emergent arm. During LTE, liver enzyme elevations occurred in 2.5% of patients in the danicopan-emergent arm and 5.0% of patients in the placebo-emergent arm. There was a total of 8 TEAEs of hemolysis reported in 7 patients during the study to date, 4 which were hemolysis and 4 of which were BTH based on investigator judgment. All patients were stable on their C5i. No case-specific details were provided in the submission on the management of the hemolysis or BTH events. Per the submission, no events led to treatment discontinuation, and none were associated with an LDH level greater than 2.2 × upper limit of normal (ULN).

Critical Appraisal

There are some limitations pertaining to patient disposition and patient characteristics to note. A total of 18.9% of patients failed to meet the inclusion or exclusion criteria, but it is not specified which inclusion or exclusion criteria were not met during screening; therefore, it is not known whether excluded patients were systematically different from included ones. In addition, while baseline characteristics were broadly balanced between study arms, the differences in the proportion of patients treated with each C5i (64.3% of patients in the danicopan plus C5i arm and 47.6% of patients in the placebo plus C5i arm were treated with ravulizumab) may bias the harms results as according to the clinical experts and literature, ravulizumab is the preferred C5i drug.³⁷ In addition, TP1 and TP2 time points had numerically low patient dropout; however, the small number of patients who have completed LTE1 to date make long-term results for efficacy and safety highly uncertain. There are also some potential limitations associated with the study design. The ALPHA trial IA used a prespecified interim stopping criteria at 75% of patients, as well as an alpha-spending procedure for the primary and key secondary end points. However, given the IA was conducted based on 75% of the originally targeted sample size, there is an increased risk that the true effect of danicopan on these end points is overestimated by the IA. In addition, while the primary and key secondary end points were controlled for multiple comparisons, the secondary and exploratory outcomes were not controlled for this or for the smaller sample size, and there is a risk of inflated type I error when interpreting results from these comparisons. Furthermore, there are possible limitations pertaining to the numbers of complete cases in the danicopan plus C5i and subsequent danicopan-emergent arm; without further information on the patients who were missing, the degree to which the missingness may be informative to the results is not known. In addition, there was no placebo comparator after the end of TP1, therefore, observed results in TP2 and LTE may not all be attributable to treatment. Lastly, there are some potential limitations associated with outcome ascertainment. While laboratory outcomes such as Hb or LDH are likely at low risk of bias because of being centrally measured, the open-label design of TP2 and the LTE mean that knowledge of the treatment being received may impact reporting of subjective quality of life outcomes at those time points (impacting FACIT-F, EORTC QLQ-C30, and EQ-5D-3L outcomes). Similarly, while a measure of treatment adherence was reported in the study, this was based on tablet counts and there is a possibility of reporting bias.

There are some limitations regarding the study population to note. Per the clinical experts, most of the inclusion criteria were reasonable for patients with PNH in a Canadian context; however, the minimum thresholds for platelet and neutrophil counts, as well as the exclusion criteria ruling out patients with other causes of anemia or other clinical comorbidities may exclude patients who could be candidates for treatment in a real-world setting. The clinical experts also noted that while there are certain clinical characteristics alongside persistent anemia whose presence indicate that EVH is the likely cause, there is no standard diagnostic definition of the condition. The cut-off used in the ALPHA study to define anemia was a level at which the clinical experts speculated patients would likely feel symptoms and could require intervention, but was not based on a known standard. In addition, the clinical experts noted that transfusion practices vary greatly and are partially dependent on patient factors such as lifestyle or comorbidities. Therefore, the study population included in the ALPHA study may not represent all patients with PNH with EVH. There are also some limitations regarding the generalizability of the results to clinical situations. The frequency of visits used in the trial setting may not exactly reflect daily clinical practice in Canada and therefore the efficacy and safety profile during the trial may not be extrapolatable to the general patient population. During the trial, the approved C5i dose was not permitted to be increased, nor the interval shortened, which also may not reflect clinical practice. FACIT-F and EORTC QLQ-C30 are validated tools in patients with PNH, but the EQ-5D-3L is not validated in PNH specifically; therefore, changes in health status reflected in that score may not translate perfectly to changes in health status in PNH. Furthermore, there were no minimal important differences (MIDs) provided by the sponsor or the clinical experts for all but 1 of the outcomes in patients with PNH; therefore, information on clinically meaningful change for the majority of outcomes remains lacking.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform the CDA-AMC expert committee’s deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^38,39

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), inconsistency across studies, 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). The target of the certainty of evidence assessment was based on thresholds informed by the sponsor submission, input from the clinical experts, and/or thresholds identified in the literature. 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.

The selection of outcomes for GRADE assessment 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.

• Clinical outcomes — change from baseline to week 12 in the following:

  • Hb levels

  • proportion of patients with Hb increase of 2 g/dL or more in the absence of transfusion

  • transfusion avoidance

  • absolute reticulocyte count

  • transfusion burden (number of RBC units transfused; number of transfusion instances)

  • LDH

  • proportion of patients with Hb normalization.

• Fatigue and HRQoL outcomes — change from baseline to week 12 in the following:

  • FACIT-F

  • EQ-5D-3L

  • EORTC QLQ-C30.

• Mortality — proportion of patients who died

• Harms — proportion of patients with meningococcal infections, proportion of patients with liver enzyme elevation

Table 2: Summary of Findings for Danicopan Plus C5i Versus Placebo Plus C5i for Patients With PNH Experiencing EVH^a

C5i = complement component 5 inhibitor; CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; EVH = extravascular hemolysis; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; HRQoL = health-related quality of life; LDH = lactate dehydrogenase; LLN = lower limit of normal; LS = least squares; MID = minimal important difference; NR = not reported; PNH = paroxysmal nocturnal hemoglobinuria; QoL = quality of life; RBC = red blood cell; RCT = randomized controlled trial.

Note: 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.

^aClinically significant EVH was defined in ALPHA as anemia (Hb ≤ 9.5 g/dL) and absolute reticulocyte count ≥ 120 × 10⁹/L.

^bResults are from the interim efficacy analysis of ALPHA (N = 63 patients; 42 patients randomized to receive danicopan add-on therapy and 21 patients randomized to receive placebo add-on therapy).

^cCIs for the primary outcome (change in Hb from baseline) are 98.2% and for the key secondary outcomes (proportion of patients with Hb increase of ≥ 2 g/dL in the absence of transfusion, proportion of patients achieving transfusion avoidance, change from baseline in absolute reticulocyte counts, change from baseline in FACIT-F scores) CIs are 95.8%, per the interim analysis alpha-spending procedure. For all other outcomes, CIs are 95%.

^dRated down 1 level for serious indirectness. Per the clinical experts, there is no standard definition for EVH, the exclusion criteria do not provide a specific list of comorbidities or laboratory values used in screening, and the minimum requirements for platelet and neutrophil counts may exclude patients with comorbidities who could be considered for treatment with danicopan.

^eStatistical testing for this outcome was not adjusted for multiple comparisons in the trial.

^fRated down 1 level for serious imprecision. The clinical experts specified that the target for the certainty of evidence would be the presence of a non-null effect. The CI includes the possibility of a decrease in the outcome, no effect on the outcome, and an increase in the outcome.

^gRated down 1 level for serious imprecision. The target of the certainty assessment is the presence of a non-null effect. The CI includes the possibility of potential benefit as well as potential harm.

^hRated down 1 level for serious imprecision. The MID provided in the submission was a change in scores from baseline of 5 points. The CI includes the possibility of clinically meaningful benefit as well as the possibility of benefit that is not clinically meaningful.

ⁱRated down 1 level for serious study limitations. The evidence submitted for the ALPHA study was an interim analysis, and as the study is still ongoing the reporting of harms information is incomplete and may bias the reported results.

^jRated down 2 levels for very serious imprecision. There are a very small number of events captured.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence, the ALPHA Clinical Study Report,⁴⁰ and additional information provided by the sponsor.^41,42

LTE Studies

Results of the LTE of the ALPHA study are summarized in the systematic review section.

Indirect Comparisons

Description of Studies

Indirect evidence was required to be considered as part of the submission because the ALPHA trial compared danicopan plus C5i therapy with placebo plus C5i therapy; however, comparative data against pegcetacoplan, the other second-line therapeutic option for PNH, remains lacking. The submission included a systematic literature review (SLR) and feasibility assessment to undertake a matching-adjusted indirect comparison (MAIC) with the PEGASUS trial, which compared pegcetacoplan with eculizumab in adult patients with PNH. A naive comparison of these 2 trials was also submitted but was not appraised because of considerable methodological limitations with this method.

The feasibility assessment consisted of a comparison of the between-trial heterogeneity in trial design, trial end points, patient eligibility criteria, and baseline patient characteristics.

The MAIC analysis compared a subset of the ALPHA study population which was trimmed to meet the additional inclusion criteria which were a part of the PEGASUS study but not the ALPHA study:

• body mass index less than 40 kg/m²

• platelet count greater than 50,000/µL

The MAIC used a weighting approach per the methodology reported by Signorovitch et al.⁴³ and qualitatively reported on the 2 methods in terms of balancing characteristics. The weight model included baseline Hb and baseline reticulocyte count. Efficacy results were reported in the anchored MAICs as differences of TDs for each trial (danicopan plus C5i minus placebo plus C5i; or pegcetacoplan minus eculizumab). The unanchored MAICs reported efficacy results as TDs between the danicopan plus C5i arm and the pegcetacoplan arm.

The distribution of calculated weights from both methods was reported, as well as the baseline characteristics after adjustment by both methods. After weighting, anchored and unanchored MAICs were undertaken for the following efficacy outcomes: change in Hb from baseline, change in absolute reticulocyte count from baseline, change in LDH from baseline, change in FACIT-F scores from baseline, and transfusion avoidance. The following safety outcomes were also reported from the MAICs: time-to-hemolysis AE and probability of BTH during extended follow-up (48 weeks for pegcetacoplan and 34.5 weeks for the ALPHA study). Time to discontinuation because of BTH was also reported, but in an unweighted population and therefore was not appraised. All analyses compared results from the ALPHA study at 12 weeks to results from the PEGASUS study at 20 weeks (the study design consisted of a 4-week run-in with C5i monotherapy coadministration, followed by a 16-week randomized period).

Efficacy Results

In the feasibility assessment, the sponsor detailed differences in trial design, inclusion criteria, baseline characteristics, and treatment duration between the ALPHA trial and the PEGASUS trial. Differences in the mean baseline Hb were also highlighted by the sponsor in the baseline characteristics between the trimmed ALPHA study population (7.7 g/dL in the danicopan plus C5i arm, 7.8 g/dL in the placebo plus C5i arm) and the PEGASUS study population (8.69 g/dL in the pegcetacoplan arm, 8.68 g/dL in the eculizumab arm). In addition, there were numeric differences between the trimmed ALPHA study population and the PEGASUS study population in the proportion of patients of Asian descent (47.4% danicopan plus C5i arm, 31.6% placebo plus C5i arm of the ALPHA study, versus 12% in the pegcetacoplan arm, 18% in the eculizumab arm of the PEGASUS study), proportion of white patients (42.1% danicopan plus C5i and 47.4% placebo plus C5i in the ALPHA study, versus 59% pegcetacoplan and 64% eculizumab in the PEGASUS study), absolute reticulocyte count (238.8 × 10⁹ danicopan plus C5i and 242.9 × 10⁹ placebo plus C5i in the ALPHA study, versus 217.5 × 10⁹ pegcetacoplan and 216.2 × 10⁹ eculizumab in the PEGASUS study), and total bilirubin (33.2 µmol/L danicopan plus C5i and 34.8 µmol/L placebo plus C5i in the ALPHA study, versus 42.5 µmol/L pegcetacoplan and 40.5 µmol/L eculizumab in the PEGASUS study). There was no information on the potential clinical importance of these differences in the submission.

The conclusions for the anchored and unanchored MAICs were numerically similar for most efficacy outcomes, with 2 exceptions: transfusion avoidance, where the unanchored MAIC showed that danicopan was favoured for transfusion avoidance, but the anchored MAIC did not (anchored TD = –0.32; 95% CI, –2.70 to 2.06; unanchored TD = 1.64; 95% CI, 0.06 to 3.22), and absolute reticulocyte count, where the reduction reported favoured pegcetacoplan with a greater reduction than danicopan plus C5i (anchored TD = 53.70; 95% CI, 16.90 to 90.50; unanchored TD = 32.80; 95% CI, 13.60 to 51.90). Neither danicopan plus C5i nor pegcetacoplan were favoured for the outcomes of Hb change from baseline, LDH change from baseline, change in FACIT-F scores from baseline, or transfusion avoidance (anchored MAIC only).

Harms Results

Based on a time-to-event analysis of BTH, there was no significant difference between the time to BTH AE for patients in the trimmed ALPHA study sample or in the PEGASUS study. Based on the extended follow-up from the PEGASUS study (48 weeks) and a median follow-up of 34.6 weeks from patients in the danicopan-emergent arm of the ALPHA study, the results from the weighted, unanchored MAIC found that there was no difference in the probability of BTH between the 2 trials.

Critical Appraisal

The indirect evidence assessment is subject to several major limitations that make drawing firm conclusions about the comparative results challenging. With regards to the SLR and feasibility assessment, the submission did not provide a preregistered protocol for the SLR and so it is not known whether the search criteria, study selection, or subgroups of interest were prespecified before the search. It is also not known whether statistical testing was undertaken during the feasibility assessment to determine differences in study population or whether there was a prespecified threshold to determine the meaningfulness of differences between populations. Per the clinical experts consulted by CDA-AMC, the differences highlighted in the feasibility assessment for inclusion criteria and baseline characteristics did not represent clinically meaningful differences. They noted that the anemia and platelet cut-offs being different was not hugely meaningful from a clinical perspective as the mean values for both in the baseline characteristics were similar; they also noted that patient-specific factors such as lifestyle and important symptoms are often a driver of treatment choices. As this information was not included in the submission, the impact of these factors on patient differences is unknown. Ravulizumab is the suggested C5i therapy over eculizumab when both are available; however, the 2 therapies have similar efficacy results.³⁷ Therefore, there is enough overlap between the study populations to suggest that the reported characteristics do not represent enough of a source of heterogeneity to rule out a MAIC.

The MAICs themselves are also subject to considerable limitations. The anchored MAICs provided control on 2 treatment effect modifiers and the sponsor noted that these were the only effect modifiers able to be adjusted on; however, the clinical experts noted that the modifiers used in weighting were not a comprehensive list of possible modifiers or prognostic factors. Therefore, the anchored MAICs would not be able to account for all possible sources of heterogeneity between the study populations. In addition, key differences in the comparator arms for the ALPHA and PEGASUS trials were noted including which C5i therapies were used in the placebo arm and the duration of follow-up, which suggests that the comparators in these 2 trials may not be an appropriate anchor for the MAIC. This increases the uncertainty in the results, and thus, drawing firm conclusions based on these results about the comparative effectiveness of danicopan add-on and pegcetacoplan is not recommended. Unanchored MAICs were also undertaken for all efficacy and safety outcomes. This method requires the assumption that all prognostic factors and treatment effect modifiers are accounted for, which is a strong assumption largely considered impossible to meet — failure of this assumption leads to an unknown amount of bias in the effect estimate.

In addition, the ALPHA and PEGASUS trials differ in other ways which may impact the risk of bias in the results and the generalizability of the results. Patients in the PEGASUS study were exposed to pegcetacoplan monotherapy for 4 weeks longer than patients were exposed to danicopan in the ALPHA study, which may bias the efficacy results to favour pegcetacoplan. Furthermore, the trial design for pegcetacoplan was an open-label trial, which may bias the reporting of FACIT-F, a subjective outcome. The results from the MAICs are subject to the same concerns about generalizability to the PNH population as the ALPHA study, and without detailed information from the PEGASUS study, the generalizability of that study population to the wider PNH population is not known. In addition, results were only reported for efficacy outcomes at week 20 for the PEGASUS study and week 12 for the ALPHA study, and so any information on efficacy past this time is not known. For BTH events, these were reported only up to 48 weeks in the PEGASUS study and 34.6 weeks for the ALPHA study; therefore, longer-term data on safety and information on other harms is unknown.

Studies Addressing Gaps in the Evidence From the Systematic Review

A phase II dose-finding study was submitted providing information on lower doses of danicopan add-on therapy; as these doses either overlapped with the dosing from the ALPHA study or were outside of the approved indication, the study was not appraised.

Conclusions

PNH is a rare disease with significant morbidity and mortality — mortality is predominantly because of thrombosis related to IVH and is treated by C5i therapies (ravulizumab or eculizumab). Approximately 20% of patients with PNH who were clinically stable on C5i treatment develop clinically significant EVH.²⁶ Evidence from the IA of the ALPHA study, a phase III RCT with a 12-week placebo-controlled, double-blind portion plus a 12-week single-arm, open-label extension and a LTE for an additional 52 weeks was appraised to assess the impact of danicopan added on to C5i therapy versus placebo plus C5i therapy. The results demonstrated that over 12 weeks, when compared with placebo plus C5i therapy, danicopan plus C5i therapy likely increased Hb levels, the proportion of patients with Hb increase of 2 g/dL or more in the absence of transfusion, and the proportion of patients with transfusion avoidance. In addition, danicopan plus C5i therapy likely decreased markers of transfusion burden and absolute reticulocyte counts, and may increase the proportion of patients attaining Hb normalization. Results from week 24, the open-label, single-arm treatment period of the ALPHA study where all patients were receiving danicopan therapy, suggested this trend was maintained for most hematologic outcomes. Danicopan plus C5i therapy may result in an increase in FACIT-F scores; however, danicopan plus C5i therapy may result in little to no difference in EQ VAS scores or EORTC QLQ-C30 global health status/quality of life scores at week 12 when compared to placebo plus C5i therapy. Results from week 24 suggest that score increases were maintained for FACIT-F in both treatment arms and suggest a trend toward increased scores in both treatment arms for EQ-5D-3L and EORTC QLQ-C30 scores. Results from the LTE portion were only available from a fraction of patients for all outcomes and therefore remain highly uncertain. With regards to safety, the majority of patients in both trial arms experienced any TEAE, and there was a numerically higher proportion of patients in the placebo-emergent arm who experienced SAEs while being treated with danicopan; there were also imbalances between the treatment arms in the proportion of patients with some TEAEs. However, a numerically low proportion of SAEs led to withdrawal of the study drug across treatment arms. Study limitations include that the ALPHA study is an IA and some missing data were reported for efficacy outcomes; it is unknown whether the missing data are informative or not. There is also no standard clinical definition for danicopan’s indication of EVH, and the study definition as well as the inclusion and exclusion criteria may leave out patients who would be treatment candidates in a clinical context. The safety results are particularly limited by the fact that the ALPHA study is an ongoing trial, therefore potential additional safety signals are possible which would not be captured by this review, particularly since the data from the full sample of patients are not available for the TP2 and LTE phases of the trial. The limitations associated with the indirect evidence submitted did not allow for firm conclusions on the effectiveness of danicopan plus C5i therapy relative to pegcetacoplan, and therefore conclusive information on the comparative effectiveness between danicopan and pegcetacoplan remains lacking.

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 danicopan 50 mg and 100 mg film-coated oral tablets as an add-on to ravulizumab or eculizumab, to treat signs and symptoms of EVH in adult patients with PNH.

Disease Background

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

The complement system is a powerful mechanism of the innate immune response, responsible for immune surveillance and host defence. There are 3 distinct pathways through which the complement cascade can be activated on different molecules for their initiation: classical, lectin, and alternative.^44,45 The first classical and lectin pathways are activated when specific triggers are recognized by host pattern-recognition receptors, while the alternative pathway is continuously active. When activated after a trigger, the 3 pathways involve a series of reactions that form a C3 convertase, leading to the activation of and a cascade down through C5 to generate a host immune defensive effect.^44,45

PNH is a rare, chronic, and potentially life-threatening blood condition caused by an acquired genetic defect in hematopoietic stem cells.^1,2 This defect leads to the production of blood cells that lack 2 glycosylphosphatidylinositol-anchored complement regulatory proteins, CD55 and CD59, at their surface, causing the complement system to recognize RBCs as damaged. The uncontrolled activation of the complement cascade prematurely attacks these cells resulting in hemolysis.²

Hemolysis occurs through 2 mechanisms in PNH. IVH occurs in both terminal and proximal pathways when RBCs are directly lyzed because of the activation of the alternative complement pathway⁵ involving the formation of complexed complement proteins such as C3 convertase, C5 convertase, and the formation of the MAC. EVH occurs in the proximal pathway when RBCs are opsonized by fragments of the complement protein C3, which targets RBCs by macrophages in the spleen and liver.^3,18,46 Constant IVH results in hemoglobinuria, mainly characterized by dark-coloured urine, particularly noticeable in the morning because of overnight urine concentration.^1,2 In addition to hemolytic anemia and its related symptoms (e.g., fatigue, dyspnea), patients with PNH are susceptible to an increased risk of thrombosis, pain, organ damage (e.g., impaired renal function), and underlying bone marrow dysfunction.^1,3,6-8 These symptoms and the IVH association with an increased need for transfusions have a significant effect on patients’ daily living, impair their HRQoL,^1,3,6,10-14 and increase the risk of morbidity and mortality with 10-year mortality rates of 29%.^1,9 Symptoms of PNH can vary significantly among individuals, and the disease can affect any race, ethnicity, or sex. It may manifest at any age,^3,4 although it typically emerges in young adults, with the median age of diagnosis being around 30 years.^1,2

In Canada, ravulizumab or eculizumab are C5is used as first-line therapy to treat hemolytic PNH. This treatment regimen addresses uncontrolled complement activation through a complete C5 inhibition in the terminal complement cascade and helps reduce symptoms and complications, resulting in improved survival for patients with PNH.^15,16

However, some patients receiving C5i treatment remain anemic and transfusion-dependent. Possible causes of Hb less than 10 g/dL include BTH, EVH, nutritional deficiencies, and bone marrow failure.¹⁷ Approximately 11% to 27% of patients may experience BTH on approved doses of eculizumab, and fewer patients experience BTH with ravulizumab. BTH is characterized by the return of IVH and the reappearance of PNH symptoms, and it may occur because of suboptimal C5 inhibition.^18,47 EVH is a mechanistic consequence believed to be caused by ongoing C3 deposition on surviving yet defective RBCs, which makes them vulnerable to phagocytosis in the liver or spleen.^18-20 While symptoms of EVH are not life-threatening, its manifestation is heterogeneous. For some patients EVH may consist of having normal Hb levels²¹ and being asymptomatic,^22,23 while others may develop severe clinical symptoms and may require blood transfusions to manage ongoing anemia.^22,24,25

Because of the rarity of the disease, the prevalence and incidence of PNH have been poorly reported, and published prevalence and incidence estimates of PNH and EVH are not available for the population of people living in Canada. A study in the UK estimated the 15-year prevalence of PNH at 1.59 per 100,000 and the annual incidence of approximately 0.13 per 100,000 persons.⁴⁸ Another study in the UK reported an overall prevalence of 3.81 per 100,000 and an overall annual incidence rate of 0.35 per 100,000 persons.⁴⁹ A study in the US estimated the prevalence of PNH at 1.2 to 1.3 per 100,000 persons between 2016 and 2017. The incidence rate over the study period was 0.57 per 100,000 person-years.²⁸ Clinical trial and real-world data showed that approximately 20% of patients with PNH who were clinically stable on C5i treatment develop clinically significant EVH.²⁶

Once suspected by clinical and laboratory data (e.g., low Hb levels, abdominal pain, persistent fatigue dyspnea, cytopenias, iron deficiency, hemolysis), the diagnosis of PNH is established in an appropriate clinical setting by flow cytometry, which demonstrates a deficiency of glycosylphosphatidylinositol-anchored proteins (e.g., CD55, CD59) on RBCs.^1,2 Regular clinical workups to identify clinically significant EVH (e.g., lowered Hb levels and elevated reticulocyte counts) are available and conducted as part of the routine monitoring for patients receiving treatment for PNH.

Standards of Therapy

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

The clinical course of PNH is unpredictable, and symptoms can arise at any age.^3,4 As the primary cause of mortality and morbidity in PNH is IVH and complications of thrombosis, in Canada patients receive ravulizumab or eculizumab as standard first-line therapy, which reduces the uncontrolled complement activation and its complications through C5 inhibition in the terminal complement cascade.^16,50 The 2 agents have comparable efficacy and toxicity but ravulizumab is dosed less frequently, is dosed by weight, and is associated with fewer episodes of BTH.³ The main C5i are both IV infusions; ravulizumab is administered every 8 weeks and eculizumab is administered every 2 weeks.

EVH is an iatrogenic effect of C5 blockade and is not life-threatening. Per the clinical experts consulted by CDA-AMC, the diagnosis of EVH is complex as it is important to rule out other possible underlying causes of anemia. Once diagnosed, treatment focuses on addressing residual anemia^22,24,25 and continued terminal complement blockade remains important to prevent the life-threatening consequences of IVH.^2,16,51 EVH can become clinically relevant for patients with persistent symptoms of anemia and patients who become dependent on transfusions.^18,22

According to the Canadian PNH Network and clinical experts, the historical approach to managing anemia due to EVH in patients living in Canada with PNH has been supportive care (e.g., RBC transfusions, corticosteroids, splenectomy, danazol, and epoetin alfa) and continuing C5i treatment.²⁰ Per the clinical experts consulted by CDA-AMC, the main nonpharmacologic treatment for EVH and persistent anemia in PNH while on C5i treatment is transfusion support. Folic acid and vitamin B12 support are also supportive options. Hematopoetic stem cell transplant is considered curative, but transplant-related mortality and morbidity are significant and it is reserved for patients with PNH with specific additional comorbidities.⁵²

Pegcetacoplan, a proximal C3i, is an approved therapy indicated for patients with inadequate response to, or intolerant of, a C5i.²⁷ The product monograph recommends pegcetacoplan 1,080 mg SC infusion be given twice weekly with a syringe system infusion pump either by a health care professional, the patient, or caregiver.²⁷ Dosage increase to 1,080 mg every third day may be considered if the LDH level is at least 2 times greater than the ULN on twice-weekly dosing.²⁷ Per the clinical experts consulted by CDA-AMC, this option would currently be offered as a second-line pharmacologic option to patients diagnosed with EVH. Pegcetacoplan is intended to be used as a monotherapy which patients will switch to after an initial period of co-treatment with the C5i and pegcetacoplan. Pegcetacoplan has been previously reviewed by CDA-AMC with the recommendation to reimburse with conditions.¹⁶

Drug Under Review

Danicopan selectively inhibits complement alternative pathway factor D,²⁹ which plays a key role in amplifying complement system response. Danicopan is thought to mediate the deposition of C3 fragments on PNH blood cells, which is a key cause of EVH in patients receiving ravulizumab or eculizumab for PNH. Inhibition of factor D activity specifically targets the control point of the complement cascade amplification loop, blocking C3 convertase formation and thereby reducing the production of C3 fragments and downstream MAC formation.³⁰ Although danicopan blocks the alternative pathway-mediated amplification of the complement classical pathway and lectin pathway, these 2 pathways remain active to provide residual complement-dependent protection against infectious pathogens.³¹ When coadministered with ravulizumab or eculizumab, danicopan is anticipated to maintain control over C5 and MAC-mediated IVH.

Danicopan has a Health Canada indication as an add-on to ravulizumab or eculizumab for the treatment of adult patients with PNH who have residual hemolytic anemia due to EVH.²⁹ The sponsor reimbursement request is as per the indication.

The recommended starting dose of danicopan is 150 mg 3 times a day, administered orally, approximately 8 hours apart (± 2 hours). The dose can be increased to 200 mg 3 times a day if a patient’s Hb level has not increased by at least 2 g/dL after 4 weeks of therapy, if a patient required transfusion within the previous 4 weeks, or to achieve an appropriate Hb response based on clinical judgment.²⁹ Danicopan should not be administered as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab.²⁹

If danicopan is discontinued, the dose should be tapered over a 6-day period until complete cessation as follows:²⁹

• 150 mg regimen — 100 mg 3 times a day for 3 days, followed by 50 mg 3 times a day for 3 days

• 200 mg regimen — 100 mg 3 times a day for 3 days, followed by 100 mg twice a day for 3 days

Key characteristics of danicopan are summarized in Table 3 with other treatments available for PNH.

Table 3: Key Characteristics of Danicopan, Pegcetacoplan, Eculizumab, and Ravulizumab

C3 = complement component 3; C5 = complement component 5; EVH = extravascular hemolysis; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; SC = subcutaneous; ULN = upper limit of normal.

^aHealth Canada–approved indication.

^bDose escalation of eculizumab to 1,200 mg every 14 weeks or reduction of dosing interval to 900 mg every 12 days is considered in patients with PNH experiencing breakthrough hemolysis in clinical practice, as per the Canadian PNH Network.⁵³

Source: Details included in the table are from the product monographs of danicopan,²⁹ pegcetacoplan,²⁷ eculizumab,⁵³ and ravulizumab.⁵⁴

Perspectives of Patients, Clinicians, and Drug Plans

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website for danicopan.

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups.

The Canadian Association of PNH Patients and the Aplastic Anemia and Myelodysplasia Association of Canada submitted a joint input for this review. A clinical summary of PNH was provided and information was gathered through the personal experiences of 1 patient living in Canada who received danicopan.

The patient group input expressed that PNH significantly impacts the quality of life for both patients and their caregivers. Beyond the persistent fatigue and weakness caused by chronic anemia from hemolysis, patients deal with other symptoms that demand continuous management, such as abdominal pain and dysphagia, influencing their dietary habits and social interactions. Managing symptoms requires ongoing medical interventions, medication adjustments, and lifestyle changes. The disease's nature often leads to social isolation as fatigue and frequent medical appointments hinder participation in social activities, exacerbating feelings of loneliness. Additionally, these symptoms can severely impact work productivity and cause significant emotional and psychological strain not only for patients but also for their caregivers.

According to the input, even though currently available treatments for PNH, such as C5is (e.g., eculizumab, ravulizumab) and a C3i (e.g., pegcetacoplan) effectively inhibit IVH, thrombosis, and EVH, approximately 20% of patients continue to experience EVH and persistent anemia and require frequent blood transfusions. Also, these therapies can introduce side effects, disrupt daily routines, and demand substantial time and resources. The financial costs associated with treatment exacerbate stress, creating a significant economic strain on patients and families. This wide-ranging impact underscores the importance of holistic management approaches to effectively support both patients and their caregivers in managing PNH. Danicopan, an oral factor D inhibitor, has shown promise as an add-on treatment to C5is, targeting residual hemolysis and improving overall disease control in patients with PNH with EVH.

The input stated that patients, caregivers, and families affected by PNH desire tolerable treatment options that reduce treatment burden, decrease hemolysis symptoms, decrease dependency on blood transfusions, slow disease progression, and improve long-term outcomes and quality of life. These improvements could lead to reduced symptom burden, increased independence, and enhanced emotional well-being, significantly impacting daily life and overall well-being for those affected by PNH.

The input indicated that the 1 patient with experience with danicopan noticed a remarkable improvement in her symptoms.

Clinician Input

Input was received from 2 clinical experts and 1 clinician group for this review.

Input From Clinical Experts Consulted by CDA-AMC

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding 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 PNH.

Unmet Needs

Per the clinical experts, PNH is a complicated disease and the initial goals of therapy are to reduce mortality, reduce complications and morbidities associated with IVH, as well as reduce transfusion needs and improve HRQoL with better Hb support and avoidance of iron overload, helping patients to attain better functional status and returning to prediagnosis activities and employment.

The clinical experts noted that C5is can provide incomplete control of PNH in some circumstances: rare genetic mutations (in people of Japanese ethnicity), inadequate dosing, response to vaccination, or infections leading to BTH or symptomatic EVH related to C5 inhibition. Per the experts, approximately one-third of patients require higher doses of C5i, although this may be less likely with ravulizumab since it is dosed by weight. Patients may also develop BTH toward the end of their treatment cycles if they would benefit from more frequent perfusion; per the clinical experts, this last situation is not generally considered a treatment failure. The experts estimated that approximately 40% of patients with PNH will continue to have low Hb despite therapy, approximately 30% will require transfusions, and, in 20% to 30% of patients, EVH will contribute to their poor HRQoL. Treatment goals for patients with PNH and EVH remain to reduce mortality, inhibit IVH, and improve HRQoL with better Hb support that does not require transfusion and avoids iron overload, leading to better functional status for patients.

Treatment strategies for clinically relevant EVH include splenectomy, erythropoietin administration, and steroids which, per the experts, have questionable efficacy; the main nonpharmacologic treatment for EVH and persistent anemia in PNH while on C5i treatment is transfusion support. Transfusion is associated with several drawbacks, according to the clinical experts: hospital visits of 2 to 4 hours are required and may be longer if blood typing is not done in advance, and there are risks with transfusion including infection, antibody development, or iron overload which can lead to heart and liver failure or endocrine disorders including diabetes, as well as liver cancer if untreated. In addition, most patients on transfusion will have significantly reduced HRQoL and be unable to maintain regular employment.

Pegcetacoplan, a C3i, is a second-line SC therapy which, per the clinical experts, would be the primary pharmacologic option offered for patients with clinically significant EVH. They noted that pegcetacoplan is a SC infusion with twice-weekly dosing and specific transportation requirements. If BTH occurs, the experts noted that the frequency of pegcetacoplan will usually be increased to 3 times weekly. If BTH is severe, doses of ravulizumab or eculizumab would also be added and the experts noted that these may not be on formulary in all hospitals.

Place in Therapy

If approved, the experts noted that danicopan would be an alternative drug to pegcetacoplan, as a second-line drug, and would be used as an add-on therapy for patients already on C5i.

Patient Population

Per the experts, most patients with clinically significant EVH as the cause of their persistent anemia, with optimized control of other causes of anemia, would be suitable candidates for danicopan. They estimated this to be approximately 30% of patients with PNH. They also highlighted that patients who are potentially undertreated because of not wanting transfusions, whose anemia is not severe enough for transfusion, or for whom SC therapy is unacceptable or unfeasible would likely benefit from danicopan as an oral therapeutic option. The experts noted that some patients already on pegcetacoplan may wish to switch to danicopan plus C5i if they were having ongoing BTH or issues with SC infusions.

The indication and reimbursement criteria for danicopan would require a diagnosis of EVH. Per the experts, a diagnosis of EVH generally required ruling out other possible causes of anemia, including incomplete C5 inhibition. This may be challenging as patients often have other comorbidities and it may not be evident that anemia is because of 1 cause, though they noted that EVH remains an important iatrogenic effect of C5 inhibition. Per the clinical experts, clinical diagnosis for EVH typically requires anemia along with normal or minimally elevated LDH, as well as elevated bilirubin and reticulocyte counts. Alternative explanations for anemia which the experts noted would have to be ruled out include bone marrow failure, hematinic deficiencies (such as vitamin B12 or ferritin), renal insufficiency, or blood loss.

The experts noted that in certain circumstances, a trial with add-on danicopan therapy may be needed to assess for efficacy in certain complicated patients or to avoid the potential confounding effect of recent transfusion as the cause of improvement.

Assessing the Response to Treatment

The clinical experts noted that response to therapy is typically an improvement in Hb and a reduction in transfusion requirements relative to the baseline for a given patient. They noted that ongoing anemia and transfusion needs may or may not be a treatment failure, as it is possible that other concurrent diseases such as bone marrow failure, aplastic anemia, other cancers, or comorbidities could be contributing factors. The experts note that failures or suboptimal responses emphasize the need for full evaluation of the cause of anemia.

Discontinuing Treatment

Per the clinical experts, intolerance or allergy to danicopan would be reason to discontinue therapy, as would a lack of improvement in Hb levels and transfusion needs. The experts noted that an episode of BTH or transfusion requirement in another setting would not be considered a treatment failure, nor would a required stoppage of therapy because of pregnancy or breastfeeding. The experts highlighted that stopping danicopan therapy should be considered independent of the C5i as the purpose of that medication is to manage IVH.

Prescribing Considerations

Per the clinical experts, treatment with danicopan would need to be initiated by a hematologist, preferably with expertise in PNH, and that at the least a consultation with a PNH expert would be warranted if a patient with PNH was being followed in a shared-care model (i.e., a hematologist with expertise in PNH along with a local hematologist).

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups.

One clinician group, the Canadian PNH Network, submitted input for this review based on contributions from 9 clinicians. Information was gathered through publicly available documents, congress abstracts, and published literature.

The group noted that the current standard of care for PNH is C5is (i.e., eculizumab and ravulizumab), which act via terminal complement blockade. Although not curative, these treatments have been shown to be effective in controlling IVH, leading to significant improvement in fatigue, HRQoL, transfusion dependence, thrombosis, and overall survival. In addition, pegcetacoplan (proximal complement inhibitor) has been recently approved for patients with persistent anemia despite C5i therapy or those who are intolerant to C5is. The only curative treatment for PNH is allogeneic hematopoietic stem cell transplant, reserved for patients with predominant or progressive bone marrow failure that can coincide with a diagnosis of PNH.

According to the clinician group, there are still some unmet therapeutic needs within the available PNH treatment regimen. Some patients remain anemic due to EVH, and some remain transfusion-dependent with C5i therapy. Moreover, the delivery mechanism of pegcetacoplan could be unfeasible and time-consuming and can be challenging for some patients with needle phobia, vision problems, poor skin integrity, and/or issues with manual dexterity.

The clinician group indicated that a subset of patients would benefit from proximal complement inhibition given the development of clinically significant EVH but for whom pegcetacoplan is less than ideal. Dual complement blockade (i.e., anti-C5 plus a proximal inhibitor) would provide these patients with the same benefits of improved Hb but with a lower risk of complications.

The group stated that danicopan, an oral factor D (proximal complement) inhibitor taken 3 times a day, could potentially improve Hb in patients with suboptimal response to C5is alone when used as an add-on to C5is for patients with PNH and EVH.

According to the clinician group, the patients most likely to benefit from danicopan are those who have persistent anemia despite stable-dose C5i, in whom EVH is suspected. Patients who may receive proximal inhibition monotherapy (e.g., pegcetacoplan) who may not tolerate it or have repeated BTH or other concerns could also benefit from the therapy. This treatment is least suitable for those who are not anemic or who meet exclusion criteria in clinical trials, such as pregnancy.

The input stated that outcomes used in clinical practice to determine treatment response include an increase in Hb and a reduction in LDH (LDH ratio < 1.5 × ULN), which should be accompanied by decreased fatigue, transfusion requirements, improved HRQoL, and improved overall survival. A clinically meaningful response to treatment would be sustained control of LDH but with further Hb increases and improvement in anemia-related symptoms. Efficacy outcomes would typically be followed every 2 to 4 weeks initially, but follow-up would be required less often (e.g., every 3 to 6 months) as a patient becomes established on the drug and does not show evidence of side effects or other concerns. A lack of improvement in the first few months of therapy would be a prompt to dose increase.

Danicopan discontinuation should be considered in patients who develop AEs that preclude ongoing therapy, including poor treatment compliance and intolerable side effects. The most important feature to monitor for is evidence of BTH. Treatment is contraindicated during pregnancy or breastfeeding.

Patients with PNH should be followed by clinicians who specialize in the area. However, treatment with danicopan plus C5 inhibition could be done entirely at the patient’s home (or the C5i infusions could be given at an infusion clinic or hospital based on local or provincial practices).

Drug Program Input

The drug programs provide input on each drug being reviewed through the CDA-AMC 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 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

C5i = complement component 5 inhibitor; CDA-AMC = Canada's Drug Agency; EVH = extravascular hemolysis; IVH = intravascular hemolysis; Hb = hemoglobin; PNH = paroxysmal nocturnal hemoglobinuria.

Clinical Evidence

The objective of the CDA-AMC Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of danicopan (Voydeya) 50 mg and 100 mg film-coated oral tablets in the treatment of signs and symptoms of EVH in adults with PNH. The focus will be placed on comparing danicopan to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of danicopan is presented in 4 sections with the CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were 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 LTE studies. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

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

• One RCT identified in systematic review

• One LTE study (extension of the RCT and therefore presented in the systematic review section)

• One indirect treatment comparison.

Systematic Review

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

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

C5 = complement component 5; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EVH = extravascular hemolysis; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; LDH = lactate dehydrogenase; LTE = long-term extension; PNH = paroxysmal nocturnal hemoglobinuria; RBC = red blood cell; t.i.d. = 3 times a day.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The ALPHA trial is an ongoing phase III, double-blind, randomized placebo-controlled trial which enrolled a total of 86 patients with PNH who had clinically significant EVH, on treatment with ravulizumab or eculizumab. The study is ongoing; data presented in the current submission come from a prespecified IA consisting of 75% of the total sample (N = 63 patients) and was based on data from enrolment until database lock on September 20, 2022. The study design consisted of a 12-week TP1 which was randomized, double-blind, and placebo-controlled, followed by a 12-week TP2 where patients initially randomized to placebo switched to receive danicopan and patients initially randomized to danicopan continued to receive danicopan. Patients completing TP2 were eligible to continue onto to a total of 2 LTEs (LTE1 or LTE2); results from LTE1 to date are presented in the submission. Treatment assignment in TP1 was not unblinded until after the first interim database lock occurred in August 2022.

The study sites were located in 18 countries in Europe, Asia, South America, and North America, including Canada. The study used a 45-day screening period and randomization was stratified by transfusion history (> 2 transfusions or ≤ 2 transfusions in the 6 months before screening), Hb at screening (< 8.5 g/dL or ≥ 8.5 g/dL), and Japanese patient (yes or no). Stochastic dynamic allocation rules were used to randomize patients 2:1 through an interactive response technology to either receive danicopan 3 times a day added onto their C5i or a placebo 3 times a day added onto their C5i, respectively. Full study design is in Figure 1.

Figure 1: ALPHA Study Design

D = day; DAN = danicopan; ecu = eculizumab; EVH = extravascular hemolysis; F/U = follow-up; LTE1 = long-term extension year 1; LTE2 = long-term extension year 2; PBO = placebo; PNH = paroxysmal nocturnal hemoglobinuria; rav = ravulizumab; tid = 3 times a day; TP1 = treatment period 1; TP2 = treatment period 2; W = week.

^aAfter TP1, all placebo participants were switched to DAN and remained on DAN throughout the study.

^bAs of the interim analysis cut-off date (September 20, 2022), 86 participants were randomized, and 63 participants were included for interim efficacy analysis.

Source: Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Populations

Inclusion and Exclusion Criteria

Patients eligible to participate in the study were required to be aged 18 years or older, have a diagnosis of PNH, and have clinically significant EVH defined as patients presenting with anemia (Hb ≤ 9.5 g/dL) and increased reticulocyte count (≥ 120 × 10⁹/L), with or without the need for transfusion, had to be receiving an approved C5i (ravulizumab or eculizumab) with no change in dose or interval for at least 6 months, as well as meet a platelet count threshold of 30,000 or more per µL and a neutrophil count of 500 or more per µL. Patients were eligible regardless of transfusion status. Patients were excluded if they had a history or presence of any clinically significant medical condition or comorbidity, including any conditions leading to anemia that are not primarily because of PNH; if they had any procedures and/or laboratory anomalies which would put them at undue risk to receive danicopan; or patients who were, or who had partners who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study intervention. The submission provided some specifics on the medical conditions, laboratory values, or procedures which would meet the criteria for study exclusion in the study protocol.⁵⁷

Interventions

C5i Therapy

All participants were to be treated with danicopan or placebo in combination with a C5i therapy (i.e., ravulizumab or eculizumab) at stable doses. In countries where ravulizumab was not approved, local amendments were issued to provide it as an investigational medical product. Participants could not switch between ravulizumab or eculizumab during the first 24 weeks but were permitted to do so during the LTE period. The only C5i switch permitted was from eculizumab to ravulizumab. With the exception of ravulizumab’s weight-based dosing changes in response to changes in weight, the approved C5i dose was not permitted to be increased, nor the interval shortened, during the study. The dose was permitted to be decreased if indicated, with a dose re-escalation to the prior dose if the reduction was not tolerated. Changes in C5i administration frequency because of patient convenience or logistical reasons but which did not result in a change of prescribed dose or frequency, were considered stable and were to be discussed with the medical monitor before randomization.

Danicopan or Placebo Add-On

All patients received either danicopan or placebo in the form of 50 mg or 100 mg film-coated oral tablets in white high-density polyethylene bottles with white child-resistant polypropylene screw caps, fitted with induction-sealed aluminum faced liners. The majority of doses were taken at home, with patients supplied enough study drug to last until their next study visit. To assess adherence, adherence was calculated as a percentage of danicopan doses taken divided by the doses scheduled to be taken.

The dosage administered started at 150 mg 3 times a day; an option to start dosing at 100 mg 3 times a day for patients with alanine transferase or direct bilirubin screening values greater than 1.5 × ULN was initially specified and then removed in a protocol amendment; any patients on 100 mg 3 times a day at the time were escalated to 150 mg 3 times a day. Dosing could be escalated up to a maximum of 200 mg. During TP1, dosing could be escalated at week 6 under the following circumstances:

• if the participant’s Hb level at week 4 had not increased by 2 g/dL (20 g/L) or more from their baseline value, or

• if the participant received a transfusion in the past 4 weeks.

Dose escalation could be performed in a similar manner for both treatment arms to maintain blinding. In TP2, dosing could be escalated at weeks 12 or 18 if, at weeks 10 or 16, respectively, 1 of the following circumstances occurred:

• the participant’s Hb had not been normalized to at least the midpoint of the normal range for their sex relative to the baseline value, or

• the participant received a transfusion during the previous 4 weeks.

Dose escalation could be done up to a maximum of 200 mg 3 times a day during the LTE phases if they had been on their previous dose for at least 4 weeks and if the investigator, after discussion with the sponsor, believed that additional efficacy could be achieved.

Patients discontinuing the study had to undergo a dose tapering over 6 days, with 2 taper visits and a follow-up visit approximately 30 days after the last dose during the tapering period. Participants continued to receive their background C5i therapy at the same dose and interval they were receiving during the taper and follow-up visits.

Concomitant Medications and Procedures

Concomitant treatments with folic acid, erythropoiesis-stimulating agents, steroids, or other immunosuppressants were permitted if patients were on stable doses for a prespecified period before study initiation and remained on stable doses through week 24 of the trial. Patients taking iron, folic acid, and vitamin B12 supplements were eligible if their dose was stable for at least 30 days. Hormonal therapies were permitted for contraception or hormonal replacement therapy. Prophylactic antibodies for treatment with a complement inhibitor were permitted if deemed appropriate by local clinical practice and/or guidelines.

Transfusions were administered to patients with Hb less than 7 g/dL regardless of symptoms; they were also administered to patients who had a Hb less than 9 g/dL in the presence of signs or symptoms to warrant a transfusion (i.e., angina, change in mental status, syncope, light-headedness, confusion, shortness of breath, and fatigue). The study investigator determined the appropriate number of packed RBCs to administer.

Outcomes

A list of efficacy and safety end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on 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 CDA-AMC review team selected end points that were considered to be most relevant to inform the CDA-AMC expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points reported at week 12 of the ALPHA study were assessed using GRADE. Select notable harms outcomes considered important for informing the expert committee deliberations of the CDA-AMC were also assessed using GRADE.

Table 6: Outcomes Summarized From the ALPHA Study

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; HRQoL = health-related quality of life; LDH = lactate dehydrogenase; RBC = red blood cell.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Hb Levels

Change in Hb Levels

Hb is used in the diagnosis and monitoring of disease activity of PNH.⁵⁸ The primary outcome of the ALPHA study was change in Hb levels from baseline to week 12. All blood tests were performed by a central laboratory. A MID has not been established in the PNH population for Hb level.

For the change in Hb at week 12, the submission noted that an increase in Hb of 2 g/dL or greater was considered to be clinically meaningful in anemic patients with cancer.⁵⁹ The clinical experts consulted by CDA-AMC noted that any change in Hb would likely be meaningful in a real-world setting.

Proportion of Patients With Hb Increases of 2 g/dL or Greater in the Absence of Transfusion

The proportion of patients with Hb increase of 2 g/dL or greater in the absence of transfusion at week 12 was a key secondary end point. All blood tests were performed by a central laboratory. An MID for this outcome has not been established in patients with PNH. Patients with an improvement in Hb of at least 2 g/dL have previously been shown to experience significantly greater increases in FACIT-F subscale scores relative to those who did not achieve this level of Hb response.⁵⁹ The submission noted that Canadian clinician feedback received is aligned with this MID.⁴² The clinical experts consulted by CDA-AMC noted that any change in this measure would likely be clinically meaningful in their context.

Proportion of Patients With Hb Normalization

The proportion of patients with Hb normalization, defined as patients with Hb values greater than the lower limit of the normal reference range (110 g/L for females and 125 g/L for males),³² was a secondary outcome. All blood tests were performed by a central laboratory. A MID for this outcome has not been established in patients with PNH. The clinical experts consulted by CDA-AMC noted that any change in this measure would likely be clinically meaningful in their context.

Transfusions

Transfusion Avoidance

Transfusion avoidance was a key secondary outcome of the ALPHA study and was defined as the proportion of patients who were transfusion-free and did not require a transfusion. Patients with severe anemia have high transfusion burden, and there is potential for complications such as iron overload with chronic transfusions.^31,60 Transfusions were administered to patients who had a Hb less than 7 g/dL regardless of symptoms and to those who had a Hb less than 9 g/dL with signs or symptoms to warrant a transfusion. A MID has not been established for transfusion avoidance. Canadian clinician feedback received by the sponsor noted that a 50% reduction in transfusion burden over 6 months would represent a clinically meaningful improvement.⁴² The clinical experts consulted by CDA-AMC noted that the 50% reduction would be an important change, but any change in this measure would likely be clinically meaningful.

Number of RBCs and Number of Transfusion Instances

Transfusion burden, defined as the number of RBC units transfused and the number of transfusion instances, was a secondary outcome. An MID has not been established for transfusion burden. Canadian clinician feedback received by the sponsor noted that a 50% reduction in transfusion burden over 6 months would represent a clinically meaningful improvement.⁴² The clinical experts consulted by CDA-AMC noted that any change in this measure would likely be clinically meaningful in their context.

Absolute Reticulocyte Count

Change in absolute reticulocyte count from baseline to week 12 was a key secondary outcome. Reticulocyte count is an indicator of hemolytic anemia. Elevated reticulocyte count may indicate overcompensation of marrow production in response to hemolysis.⁶¹ For EVH, reticulocyte count correlates better than LDH with increased C3 on PNH erythrocytes, raised bilirubin, and increased transfusion dependence.⁶² All blood tests were performed by a central laboratory.

An MID has not been established for change in absolute reticulocyte count in patients with PNH. Canadian clinician feedback received by the sponsor noted that normalization of absolute reticulocyte count is considered to be less than 100 × 10⁹/L.⁴² The clinical experts consulted by CDA-AMC noted that any change in this measure would likely be clinically meaningful.

Lactate Dehydrogenase

LDH is a marker of IVH⁶¹ and is used in the diagnosis and monitoring of disease activity of PNH.⁵⁸ It was reported that an LDH level of at least 1.5 × greater than the ULN was associated with an increased risk of thromboembolism based on data from a national South Korean PNH registry including patients who were eculizumab-naive.⁶³

An MID has not been established for LDH values. The submission noted that participants in the ALPHA study were on stable C5i therapy before entry, and the mean values for LDH from the trial (mean = 292.12 U/L; SD = 95.19 U/L) were within the reference range (135 U/L to 330 U/L) at baseline.⁴² The clinical experts consulted by CDA-AMC noted that any change in this measure would likely be clinically meaningful in their context; however, LDH measures that are already in normal range should not be expected to change.

Fatigue and HRQoL

Descriptions of the type of outcomes, conclusions about their measurement properties, and relevant information about MIDs in the change in scores are detailed in Table 7, followed by further detail on these outcomes.

Table 7: Summary of Fatigue and HRQoL Measures and Their Measurement Properties

ARC = absolute reticulocyte count; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; ES = effect size; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GHS = global health status; Hb = hemoglobin; HL = Hodgkin lymphoma; HRQoL = health-related quality of life; MID = minimum important difference; PNH = paroxysmal nocturnal hemoglobinuria; QoL = quality of life.

Functional Assessment of Chronic Illness Therapy–Fatigue

FACIT-F is a validated and reliable patient-reported outcome instrument used for evaluation of fatigue associated with anemia in different patient populations, including patients with PNH.⁶⁸ A change in score of 5 points is considered the MID in the PNH population based on distribution-based estimations using real-world data from the International PNH Registry.⁶⁸ The clinical experts consulted by CDA-AMC noted that this tool is not commonly used in clinical practice.

EQ-5D-3L

MID values have not been established for this measurement tool in the PNH population. The clinical experts consulted by CDA-AMC noted that this tool is not commonly used in clinical practice.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

The EORTC QLQ-C30 tool has been validated in patients with PNH; however, MID values have not been established for this measurement tool in the PNH population. However, an increase of 10 or more points in EORTC QLQ-C30 score for patients with cancer is considered moderately large and represents a clinically important improvement.⁷² The clinical experts consulted by CDA-AMC noted that this tool is not commonly used in clinical practice.

Statistical Analysis

Analysis Populations

Planned Interim Analyses

The prespecified IA was planned for when approximately 75% of the total planned sample (N = 63 patients) had been randomized and completed the TP1; the purpose of this analysis, per the submission, was to assess stopping early for efficacy. The data cut-off for the TP1 IA was conducted on June 28, 2022, and a second interim data analysis for TP2 results was conducted with a data cut-off of September 20, 2022. A total of 63 patients formed the IEAS and a total of 86 patients (the entire randomized study sample) formed the interim safety analysis set.

Analyses were based on the intention-to-treat (ITT) principle. Full details of the analysis populations are provided in Table 8.

Table 8: Analysis Populations for the ALPHA Study

CSR = Clinical Study Report; IA = interim analysis; ITT = intention to treat; TP1 = treatment period 1; TP2 = treatment period 2.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Sample Size and Power Calculations

The submission noted that a minimum difference in the primary outcome of 2 g/dL between danicopan and placebo treatments at 12 weeks would be considered clinically meaningful, and also noted that the mean baseline Hb levels of patients included in the study (≤ 9.5 g/dL) is lower than the average Hb values reported in the literature for patients who are receiving an approved C5i but are still anemic (average Hb is 10.5 g/dL). The submission also anticipated that approximately 10% of all patients would discontinue therapy before the primary end point measurement at week 12.

With a full target sample of 84 patients, for the primary end point of change from baseline to week 12 in Hb level, the statistical power using a 2-sample t test was 99% to detect the difference in mean change from baseline of 2 g/dL (alternative hypothesis), assuming the 2-sided statistical significance level of 0.05 and an SD of 1.6 g/dL, which was estimated from results of Study ACH471-101, a dose-finding study included in the submission.⁷³ For the key secondary end point of patients with a Hb increase or 2 g/dL or more at week 12 with the absence of transfusion, the full study had more than 95% power for detecting a significant difference between treatment groups with a 2-sided alpha of 0.05, assuming at least 35% of patients in the danicopan arm and 5% of patients in the placebo arm met the threshold. For the key secondary end point of patients with transfusion avoidance, the study had 70% power for detecting a significant difference between treatment groups, assuming 90% of patients in the danicopan arm and 64% of patients in the placebo arm had transfusion avoidance. For the key secondary end point of change from baseline to week 12 in FACIT-F scores, the study had 91% power with a 2-sample t test to detect a 9-point difference between treatment arms in mean change from baseline, which per the submission was considered clinically meaningful. The submission did not provide any reference for this assumption. The power calculation for FACIT-F was based on the assumption of an SD of 11, which was observed in Study ALXN1210-PNH-301 in patients with PNH (not included in the submission). The power would be 80% based on the SD assumption of 13, which was observed in Study ACH471-101, the dose-finding study included in the submission.⁷³

IA Sample Adjustment

For the current submission sample size of 63 patients, analyses for the primary and key secondary end points were evaluated using an alpha-spending method to control the family-wise error rate. The evaluation of the primary end point used a 2-sided alpha level of 0.018, and the evaluation of the key secondary end points used a 2-sided alpha of 0.042. The overall family-wise error rate was controlled at a 2-sided 0.05 level across the primary and key secondary end points among the interim and full final analyses.

Efficacy Analysis

Full details of the efficacy analysis methods, adjustments, handling of missing data and sensitivity analyses by end point can be found in Table 9, followed by a detailed description of certain methods.

Primary End Point Analysis

The primary end point was based on the ITT population and analyzed using a mixed model for repeated measures method which included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of a baseline Hb value and the randomization stratification factor of transfusion history. The alpha-spending method described previously was applied. As transfusions could impact the primary outcome, Hb values collected within 4 weeks after a transfusion were not included in the mixed model for repeated measures. An unstructured covariance matrix was used to model the within-patient errors. If the analysis model failed to converge, the covariance matrix structures was evaluated in the following order until model convergence was met: Toeplitz, first-order autoregressive, and compound symmetry. The order was specified according to decreasing number of covariance parameters in the structure. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom.

A sensitivity analysis was conducted exploring TDs using a rerandomization test; rerandomized treatment assignments were simulated for all randomized patients for 1,500 iterations using the same randomization algorithm as the original randomization, keeping patient stratification factors and entry.

Table 9: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; LDH = lactate dehydrogenase; MMRM = mixed model for repeated measures; RBC = red blood cell; TA = transfusion avoidance.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Key Secondary End Point Analyses

The key secondary end points were analyzed on the ITT population using a hierarchical fixed sequence test procedure, provided that statistical significance was declared for the primary end point. The prespecified alpha-spending method described previously was applied. In order of importance, the sequential testing process for key secondary outcomes was:

1. difference in proportion of patients with Hb increase of 2 g/dL or greater at week 12 in the absence of transfusions

2. difference in proportion of patients with RBC transfusion avoidance between danicopan and placebo groups during the first 12 weeks of treatment

3. difference in changes from baseline in FACIT-F scores between danicopan and placebo groups at week 12

4. difference in changes from baseline in absolute reticulocyte counts between danicopan and placebo groups at week 12.

Subgroup Analysis

Subgroup analyses were descriptive in nature and did not take multiple comparisons into account. The primary end point was summarized by the following prespecified subgroups (not appraised by CDA-AMC):

• transfusion history (≤ 2 or > 2 transfusions in the last 6 months)

• Hb levels (< 8.5 g/dL or ≥ 8.5 g/dL)

• Japanese ethnicity (yes or no).

The primary and key secondary end points were summarized by subgroups on the basis of the following (not appraised by CDA-AMC):

• sex

• race

• region

• age (aged < 65 years and ≥ 65 years)

• background C5i (ravulizumab or eculizumab)

Results

Patient Disposition

Complete details of patient disposition for the IEAS are available in Table 10. Briefly, 111 patients were screened for inclusion in the trial and 25 (22.5%) failed screening. A total of 21 (18.9%) of patients did so because of not meeting inclusion or exclusion criteria; the submission did not provide additional detail on which criterion was the most common reason for exclusion. A total of 1 patient discontinued from each treatment arm during TP1, and 1 patient from the danicopan plus C5i arm discontinued during TP2. A total of 6 patients from the danicopan plus C5i arm and 3 patients from the placebo plus C5i arm had completed year 1 of the LTE at the time of study submission.

Table 10: Summary of Patient Disposition From the ALPHA Study — Interim Efficacy Analysis

C5i = complement component 5 inhibitor; IEAS = interim efficacy analysis set; ISAS = interim safety analysis set; LTE = long-term extension.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. Briefly, most baseline characteristics were broadly similar between study arms. There was a numeric difference in the proportion of patients (66.7% female in the placebo plus C5i arm, 54.8% female in the danicopan plus C5i arm; 33.3% male in the placebo plus C5i arm, 45.2% male in the danicopan plus C5i arm), and the proportion of patients of Asian descent (33.3% in the placebo plus C5i arm, 42.9% in the danicopan plus C5i arm). There were also numeric differences in the proportion of patients treated with each C5i (64.3% of patients in the danicopan plus C5i arm and 47.6% of patients in the placebo plus C5i arm were treated with ravulizumab). There was a numerically higher LDH in the danicopan plus C5i arm (298.73 U/L) relative to the placebo plus C5i arm (278.25 U/L), and a numerically higher proportion of patients in the danicopan plus C5i arm had received a transfusion within 24 weeks of receiving the study drug (90.5% in the danicopan plus C5i arm, 81.0% in the placebo plus C5i arm).

In addition, a total of 41 (97.6%) patients in the danicopan plus C5i arm and 21 (100%) patients in the placebo plus C5i arm reported experiencing PNH symptoms at any time before consenting to the study. The most commonly reported (> 30% of patients) symptoms in the danicopan plus C5i arm were fatigue or asthenia (90.5%), red or dark urine (71.4%), shortness of breath (59.5%), jaundice (38.1%), or central nervous system symptoms such as headache (31.0%). The most commonly reported (> 30% of patients) in the placebo plus C5i arm were fatigue or asthenia (90.5%), abdominal pain (57.1%), shortness of breath (42.9%), red or dark urine (42.9%), or jaundice (33.3%).

Table 11: Summary of Baseline Characteristics From the ALPHA Study — IEAS

BMI = body mass index; C5i = complement component 5 inhibitor; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; pRBC = packed red blood cells; SD = standard deviation.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Details of patient exposure to danicopan are summarized in Table 12. Briefly, mean and median exposure durations were similar for TP1 and TP2; the median duration of exposure during LTE1 was numerically larger in the placebo plus C5i arm (251 days) than the danicopan plus C5i arm (179.5 days). Patients in the danicopan plus C5i arm had numerically different mean durations of exposure than the placebo plus C5i arm at 150 mg danicopan dosing (63.5 days in the danicopan plus C5i arm, 55.5 days in the placebo plus C5i arm during TP2; 153.2 days in the placebo plus C5i arm, 143.8 days in the danicopan plus C5i arm in LTE1). This was also reported for exposure to 200 mg danicopan dosing (71.9 days in the danicopan plus C5i arm, 40.5 days in the placebo plus C5i arm during TP2; 200.3 days in the danicopan plus C5i arm, 213 days in the placebo plus C5i arm during LTE1). Overall adherence based on pill counts was greater than 95% for all treatment periods and in all treatment arms.

Efficacy

Detailed outcomes from baseline to week 12 (TP1) are presented in Table 13, and results from baseline to week 24 (TP2) and from baseline to week 72 (LTE1) are presented in Table 14.

Hb Levels

Change in Hb Levels

The LS mean change from baseline in Hb level to 12 weeks (at TP1) was the primary outcome. At TP1, the LS mean difference for the change in Hb from baseline between the danicopan plus C5i and the placebo plus C5i arms was 24.44 g/L (98.2% CI, 15.25 g/L to 33.63 g/L; P ≤ 0.0001). At TP2, the LS mean change from baseline to week 24 in the danicopan-emergent arm (patients who received danicopan plus C5i from weeks 0 to 12 and continued to receive danicopan plus C5i from weeks 12 to 24) was 31.67 g/L (95% CI, 25.61 g/L to 27.74 g/L). In the placebo-emergent arm (patients who received placebo plus C5i from weeks 0 to 12 and who subsequently switched to receive danicopan plus C5i from weeks 12 to 24), the LS mean change from baseline to week 24 was 22.58 g/L (95% CI, 15.72 g/L to 29.44 g/L). At LTE1, the observed mean change from baseline in Hb levels was 32.00 g/L (SD = 11.81 g/L) in the danicopan-emergent arm and 31.50 (SD = 10.61) in the placebo-emergent arm.

Proportion of Patients With Hb Level Increase of 2 g/dL or Greater in the Absence of Transfusion

The proportion of patients with Hb level increases of 2 g/dL or greater was a key secondary outcome in the analysis. At TP1, the LS mean difference for the proportion of patients with Hb level increase of 2 g/dL or greater between the danicopan plus C5i and the placebo plus C5i arms was 45.90% (95.8% CI, 27.40% to 64.42%; P ≤ 0.0001). At TP2, the proportion of patients with this outcome in the danicopan-emergent arm was 46.3% (95% CI, 30.66% to 62.58%); results were not reported for the placebo-emergent arm. This outcome was not measured at LTE1.

Proportion of Patients With Hb Normalization

The proportion of patients with Hb normalization, defined as patients with Hb values greater than the lower limit of the normal reference range, was a secondary outcome. At TP1, the LS mean difference for the change in the proportion of patients with Hb normalization between the danicopan plus C5i and the placebo plus C5i arms was 18.40% (95% CI, –0.84% to 37.71%; P = 0.0080). At TP2, the proportion of patients with this outcome in the danicopan-emergent arm was 19.50% (95% CI, 8.82% to 34.87%). This outcome was not reported for the placebo-emergent arm at TP2 and was not reported at LTE1 for either arm.

Transfusions

Transfusion Avoidance

Transfusion avoidance at TP1 was a key secondary outcome in the analysis. At TP1, the LS mean TD for the proportion of patients with transfusion avoidance between the danicopan plus C5i and the placebo plus C5i arms was 40.80% (95.8% CI, 21.08% to 60.58%; P = 0.0004). At TP2, the proportion of patients with this outcome in the danicopan-emergent arm was 78.00% (95% CI, 62.39% to 89.44%), and was 90.00% (95% CI, 68.30% to 98.77%) in the placebo-emergent arm. This outcome was not reported at LTE1.

Table 12: Summary of Patient Exposure During the ALPHA Study — ISAS

C5i = complement component 5 inhibitor; DAN = danicopan; ISAS = interim safety analysis set; LTE = long-term extension; NA = not applicable; SD = standard deviation; TP = treatment period.

^aAdherence based on tablet counts.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Transfusion Burden

Transfusion burden was measured by the number of RBC units transfused and the number of transfusion instances; both were secondary outcomes. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in the number of RBC units transfused between the 12 weeks before study drug initiation and the 12 weeks after study drug initiation was –1.31 (95.8% CI, –2.24 to –0.37; P = 0.0072). At TP2, the change in the number of RBC units transfused in the 24 weeks after treatment initiation relative to the 24 weeks before treatment initiation in the danicopan-emergent arm was –2.80 (95% CI, –4.55 to –1.11). This outcome was not reported in the placebo-emergent arm or at LTE1 in either arm.

Table 13: Summary of Key Efficacy Results From the ALPHA Study During TP1 — IEAS

C5i = complement component 5 inhibitor; CI = confidence interval; CMH = Cochran Mantel-Haenszel; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; IESA = interim efficacy analysis set; LDH = lactate dehydrogenase; LS = least squares; NR = not reported; QoL = quality of life; RBC = red blood cell; SD = standard deviation; TP = treatment period.

^aThe CI level which matches the alpha level specified in the multiple testing structure is reported.

^bP value adjusted for multiple comparisons.

^cBaseline measurement for the full study sample, obtained from the ALPHA Clinical Study Report.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence, additional information provided by the sponsor,⁴¹ and the ALPHA Clinical Study Report.⁴⁰

Table 14: Summary of TP2 and LTE Efficacy Results From the ALPHA Study — IEAS

C5i = complement component 5 inhibitor; CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; IEAS = interim efficacy analysis set; LDH = lactate dehydrogenase; LS = least squares; LTE = long-term extension; NA = not available; NR = not reported; QoL = quality of life; RBC = red blood cell; SD = standard deviation; TP = treatment period.

^aBaseline measurement for the full study sample, obtained from the ALPHA Clinical Study Report.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence and the ALPHA Clinical Study Report.⁴⁰

At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in the number of transfusion instances between the 12 weeks before study drug initiation and the 12 weeks after study drug initiation was –0.72 (95% CI, –1.32 to –0.11; P = 0.0207). At TP2, the change in the number of transfusion instances between the 24 weeks before study drug initiation and the 24 weeks after study drug initiation in the danicopan-emergent arm was –1.50 (95% CI, –2.36 to –0.67). This outcome was not reported in the placebo-emergent arm or at LTE1 in either arm.

Absolute Reticulocyte Count

Change in absolute reticulocyte count from baseline to week 12 was a key secondary outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in absolute reticulocyte count from baseline was –0.087 × 10¹²/L (95.8% CI, –0.119 × 10¹²/L to –0.056 × 10¹²/L; P ≤ 0.0001). At TP2, the change from baseline in absolute reticulocyte counts in the danicopan-emergent arm was –0.080 × 10¹²/L (SD = 0.073 × 10¹²/L), and in the placebo-emergent arm was –0.084 × 10¹²/L (SD = 0.110 × 10¹²/L). At LTE1, the observed mean change from baseline in absolute reticulocyte counts in the danicopan-emergent arm was –0.041 × 10¹²/L (SD = 0.029 × 10¹²/L), and in the placebo-emergent arm was –0.106 × 10¹²/L (SD = not applicable; n = 1 patient).

Lactate Dehydrogenase

Change in LDH from baseline was a secondary outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in LDH from baseline was –20.57 U/L (95% CI, –49.28 U/L to 8.15 U/L; P = 0.1569). At TP2, the mean change from baseline in LDH in the danicopan-emergent arm was –23.46 U/L (SD = 105.40 U/L), and in the placebo-emergent arm was 0.21 U/L (SD = 84.89 U/L). At LTE1, the mean change from baseline in LDH in the danicopan-emergent arm was –20.83 U/L (SD = 67.00 U/L), and in the placebo-emergent arm was 5.00 U/L (SD = 111.89 U/L).

Fatigue and HRQoL

Functional Assessment of Chronic Illness Therapy–Fatigue

The change in FACIT-F scores from baseline was a key secondary outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change in FACIT-F scores from baseline was 6.12 (95.8% CI, 2.18 to 10.06; P = 0.0021). At TP2, the LS mean change from baseline in FACIT-F scores in the danicopan-emergent arm was 6.12 (95% CI, 3.41 to 8.82), and in the placebo-emergent arm was 6.44 (95% CI, 1.23 to 11.64). At LTE1, the mean change from baseline in the danicopan-emergent arm was 3.86 (SD = 7.15) and –4.33 (SD = 9.07) in the placebo-emergent arm.

EQ Visual Analogue Scale

The change in EQ VAS scores from baseline was an exploratory outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change from baseline in EQ VAS scores was 6.27 (95% CI, –2.85 to 15.40; P = 0.1738). At TP2, the mean change from baseline in EQ VAS scores was 13.70 (SD = 20.12) in the danicopan-emergent arm and 9.70 (SD = 21.93) in the placebo-emergent arm. At LTE1, the mean change from baseline in the danicopan-emergent arm was 12.30 (SD = 18.70) and –11.00 (SD = 12.73) in the placebo-emergent arm.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

The change in EORTC QLQ-C30 global health scores from baseline was an exploratory outcome. At TP1, the LS mean TD between the danicopan plus C5i arm and the placebo plus C5i arm for the change from baseline in EORTC QLQ-C30 global health scores was 6.62 (95% CI, –1.17 to 14.41; P = 0.0941). At TP2, the mean change from baseline in EORTC QLQ-C30 global health scores was 8.56 (SD = 16.96) in the danicopan-emergent arm and 10.53 (SD = 14.92) in the placebo-emergent arm. At LTE1, the mean change from baseline in the danicopan-emergent arm was 1.19 (SD = 26.97) and 8.33 (SD = 22.05) in the placebo-emergent arm.

Sensitivity Analyses

For each primary and key secondary outcome from baseline to week 12, per-protocol analysis was done as a sensitivity, all of which had similar results to the ITT analysis. Change from Hb at 12 weeks additionally included an analysis using Hb values collected less than 4 weeks from transfusion, with similar results. Transfusion avoidance had an analysis with alternate handling of patients who withdrew from treatment, wherein those who discontinued the study because of lack of efficacy during TP1 were excluded. This analysis also yielded similar results.

Harms

Harms reporting was done on the interim safety analysis set, using the full sample size recruited and including all patients who had received at least 1 dose of study drug as of the data cut-off. As of the data cut-off date, a total of 4 patients were still receiving placebo in TP1 and 2 patients discontinued before the switch to danicopan in TP2. Harms were reported separately for TP1, TP2, and LTE1 cut-offs, as well as overall during the entire time patients were exposed to danicopan (total danicopan treatment). Table 15 contains reporting of the most common harms data.

During TP1, in the danicopan plus C5i arm, 17.5% patients had TEAEs that were grade 3, and 1.8% had TEAEs that were grade 4 (no grade 5 events). In the placebo plus C5i arm, 13.8% of patients had TEAEs that were grade 3 (no grade 4 or 5 events). During TP2, in the danicopan-emergent arm, 12.5% of patients had TEAEs that were grade 3 (no grade 4 or 5 events); in the placebo-emergent arm, 13.0% of patients had TEAEs that were grade 3 and 4.3% had TEAEs that were grade 4. During LTE, 7.5% of patients in the danicopan-emergent arm and 15.0% of patients in the placebo-emergent arm experienced grade 3 TEAEs, 2.5% of patients in the danicopan-emergent arm and 5.0% of patients in the placebo-emergent arm experienced grade 4 TEAEs, and there were no grade 5 TEAEs reported during the LTE.

Adverse Events

Overall, a total of 93.0% of patients in the danicopan-emergent arm and 82.6% of patients in the placebo-emergent arm experienced TEAEs during treatment with danicopan. The most common TEAEs during treatment with danicopan were COVID-19 (21.1% danicopan-emergent and 21.7% placebo-emergent), diarrhea (14.0% danicopan-emergent and 17.4% placebo-emergent), headache (17.5% danicopan-emergent and 8.7% placebo-emergent), pyrexia (15.8% danicopan-emergent and 8.7% placebo-emergent), nausea (12.3% danicopan-emergent and 13.0% placebo-emergent), and fatigue (10.5% danicopan-emergent and 8.7% placebo-emergent).

During TP1, 73.7% of patients in the danicopan plus C5i arm and 62.1% of patients in the placebo plus C5i arm experienced any TEAEs. There were numeric differences in the proportion of patients experiencing TEAEs for anemia (1.8% danicopan plus C5i, 13.8% placebo plus C5i), vomiting (5.3% danicopan plus C5i, 0% placebo plus C5i), upper abdominal pain (1.8% danicopan plus C5i, 6.9% placebo plus C5i), pyrexia (5.3% danicopan plus C5i, 0% placebo plus C5i), asthenia (0% danicopan plus C5i, 13.8% placebo plus C5i), ear infection (0% danicopan plus C5i, 6.9% placebo plus C5i), contusion (1.8% danicopan plus C5i, 10.3% placebo plus C5i), increased aspartate aminotransferase (3.5% danicopan plus C5i, 10.3% placebo plus C5i), pain in extremity (5.3% danicopan plus C5i, 0% placebo plus C5i), dizziness (1.8% danicopan plus C5i, 6.9% placebo plus C5i), and insomnia (1.8% danicopan plus C5i, 10.3% placebo plus C5i). A total of 57 patients in the danicopan plus C5i arm and 29 patients in the placebo plus C5i arm contributed data.

During TP2, when both arms were receiving danicopan, a total of 64.6% of patients in the danicopan-emergent arm and 56.5% of patients in the placebo-emergent arm reported TEAEs. There were numeric differences in the proportion of patients experiencing TEAEs for nausea (2.1% danicopan-emergent, 13.0% placebo-emergent), and pyrexia (10.4% danicopan-emergent, 0% placebo-emergent). A total of 48 patients in the danicopan-emergent arm and 23 patients in the placebo-emergent arm contributed data.

During LTE (up until the data cut-off of September 20, 2022), a total of 62.5% of patients in the danicopan-emergent arm and 80.0% of patients in the placebo-emergent arm reported TEAEs. There were numeric differences in the proportion of patients experiencing TEAEs for diarrhea (2.5% danicopan-emergent, 10.0% placebo-emergent), asthenia (2.5% danicopan-emergent, 15.0% placebo-emergent), and back pain (2.5% danicopan-emergent, 10.0% placebo-emergent). A total of 40 patients in the danicopan-emergent arm and 20 patients in the placebo-emergent arm contributed data.

Serious AEs

Overall, a total of 12.3% of patients in the danicopan-emergent arm and 26.1% of patients in the placebo-emergent arm experienced any SAE while being treated with danicopan.

During TP1, 5.3% of patients in the danicopan plus C5i arm experienced any SAE; the SAEs were pancreatitis, cholecystitis, COVID-19, and blood bilirubin increase (1 report of each). A total of 6.9% of patients in the placebo plus C5i arm experienced any SAE; the SAEs were anemia, abdominal pain, and headache (1 report of each).

During TP2, 6.3% of patients in the danicopan-emergent arm experienced any SAE; the SAEs were Dieulafoy vascular malformation, pyrexia, COVID-19 pneumonia, and staphylococcus sepsis (1 report of each). In the placebo-emergent arm, 13.0% of patients experienced any SAE; the SAEs were hemolysis, vertigo, and headache (1 report of each).

During LTE (up until the data cut-off on September 20, 2022), 7.5% of patients in the danicopan-emergent arm experienced any SAE; the SAEs were stent-grant endoleak, decreased Hb, invasive ductal breast carcinoma, pulmonary embolism, and pulmonary hemorrhage (1 report of each). In the placebo-emergent arm, 20.0% of patients experienced any SAE; the SAEs were pericardial effusion, diarrhea, disease progression, COVID-19, and body temperature increased (1 report of each).

Withdrawals Due to AEs

During TP1, TEAEs led to withdrawal of the study drug for 5.3% of patients in the danicopan plus C5i arm and 3.4% of patients in the placebo plus C5i arm. SAEs led to withdrawal of the study drug for 1.8% of patients in the danicopan plus C5i arm, and 0% of patients in the placebo plus C5i arm. During TP2, there were no TEAEs or SAEs leading to withdrawal of the study drug in either treatment arm. During LTE, TEAEs led to withdrawal of the study drug in 5.0% of patients in the placebo-emergent arm; there were no TEAEs leading to withdrawal of the study drug in the danicopan-emergent arm. There were no SAEs leading to withdrawal of the study drug in either treatment arm.

The submission did not provide further details on whether the TEAEs or SAEs that led to withdrawal of the study drug also led to patient discontinuation from the study; per the submission, there was 1 patient withdrawal in each arm due to AEs during TP1, 1 patient withdrawal due to AEs in the danicopan-emergent arm during TP2 (0 in the placebo-emergent arm), and 1 patient withdrawal in the placebo-emergent arm due to AEs in the LTE (0 in the danicopan-emergent arm).

Mortality

There were no deaths reported in either study arm, at any time point during the trial to date.

Notable Harms

AEs of Special Interest

Meningococcal infections and liver enzyme elevations were prespecified AEs of special interest during the ALPHA study. Throughout TP1, TP2, and LTE until September 20, 2022, there were no reported AEs of meningococcal infections in either study arm.

Liver enzyme elevations were defined using the MedDRA preferred terms for drug-related hepatic disorders – severe events only [narrow] [20000007] and liver-related investigations, signs and symptoms [narrow] [20000008]. During TP1, liver enzyme elevations occurred in 14.0% of patients in the danicopan plus C5i arm and 10.3% of patients in the placebo plus C5i arm. During TP2, liver enzyme elevations occurred in 6.3% of patients in the danicopan-emergent arm and 13.0% of patients in the placebo-emergent arm. During LTE, liver enzyme elevations occurred in 2.5% of patients in the danicopan-emergent arm and 5.0% of patients in the placebo-emergent arm.

Hemolysis and BTH Events

There was a total of 8 TEAEs of hemolysis reported in 7 patients during the study to date, 4 which were hemolysis and 4 of which were BTH based on investigator judgment. All patients were stable on their C5i. No case-specific details were provided in the submission on the management of the hemolysis or BTH events. Per the submission, no events led to treatment discontinuation, and none were associated with an LDH level greater than 2.2 × ULN.

In TP1, 1 patient in the danicopan plus C5i arm had a TEAE of hemolysis (LDH 1.2 × ULN; reference range 135 to 281 U/L) which was graded as nonserious; this event resolved. Another patient in the danicopan plus C5i arm had a nonserious hemolysis TEAE during TP1 (LDH 1.2 × ULN) and a nonserious BTH TEAE during TP2 (LDH 1.6 × ULN); they received a transfusion around the time of the second event.

In TP2, 1 patient in the danicopan-emergent arm had a nonserious BTH TEAE (LDH 1.9 × ULN), which resolved in 15 days. Another patient in the placebo-emergent arm had a serious hemolysis TEAE (normal LDH); they received a transfusion around the time of the event. It resolved after 1 day.

During LTE, 2 patients in the danicopan-emergent arm had nonserious BTH TEAEs (1 with LDH 2.2 × ULN with pyrexia and COVID-19 concurrently, and 1 with LDH 1.5 × ULN). Another patient in the placebo-emergent group had a nonserious TEAE of hemolysis (LDH 1.3 × ULN), which resolved with sequelae after 32 days.

Table 15: Summary of Harms Results From the ALPHA Study — ISAS

AE = adverse event; C5i = complement component 5 inhibitor; ISAS = interim safety analysis set; LTE = long-term extension; NR = not reported; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aThe cut-off for most common TEAEs was ≥ 5% patients in any treatment arm during treatment period 1, treatment period 2, and LTE, or ≥ 5% in both arms for overall danicopan treatment.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

The IA of the ongoing ALPHA study is a phase III, double-blind RCT with a 12-week placebo-controlled period where patients stable on a C5i were randomized either to danicopan add-on therapy or placebo add-on therapy, with an additional 12-week single-arm portion where both arms received danicopan add-on therapy, and an LTE to 72 weeks and ongoing. There appeared to be a low risk of bias from the treatment blinding process and randomization and treatment allocation processes, as randomization was stratified and done via interactive response technology, and treatment allocation was not unblinded until after a database lock. Per the clinical experts, the criteria for permitted concomitant medications, danicopan or placebo dosing escalations, timing of escalations, and criteria for transfusions were all reasonable in their experience. They also noted that 12 weeks would be a sufficient length of time to note the impacts of treatment, and requiring patients to be stable on C5i therapy for 6 months would also align with clinical practice, as they would usually trial a new therapy for 6 months before considering changes in dose or therapeutic drug.

There are some limitations pertaining to patient disposition and patient characteristics to note. A total of 18.9% of patients failed to meet the inclusion or exclusion criteria, but it is not specified which inclusion/exclusion criteria were not met during screening; therefore, it is not known whether excluded patients were systematically different from included ones. In addition, while baseline characteristics were broadly balanced between study arms, the differences in the proportion of patients treated with each C5i (64.3% of patients in the danicopan plus C5i arm and 47.6% of patients in the placebo plus C5i arm were treated with ravulizumab) may bias the harms results as ravulizumab is suggested as a first-line choice where both agents are available.³⁷ Per the submission, 40 patients in the danicopan-emergent arm and 20 patients in the placebo-emergent arm (95.2% of patients in each arm) completed TP1 and TP2, representing numerically low patient dropout in these phases. However, the LTE phase of this trial is ongoing, and to date, 6 (14.3%) patients in the danicopan-emergent arm and 3 (14.3%) patients in the placebo-emergent arm have completed LTE1; furthermore, 4 (9.5%) patients in the danicopan-emergent arm and 1 (4.8%) patient in the placebo-emergent arm discontinued during the LTE. The small number of patients who have completed the LTE to date make long-term results for efficacy and safety highly uncertain.

There are some potential limitations associated with the study design. The ALPHA trial IA used a prespecified interim stopping criteria of 75% of patients, as well as an alpha-spending procedure for the primary and key secondary end points to account for the fact that a smaller sample size than was required by the power calculations was used for this analysis. The alpha-spending procedure and hierarchical testing structure controlled the family-wise type I error rate for these end points. However, given the IA was conducted based on 75% of the originally targeted sample size, there is an increased risk that the true effect of danicopan on these end points is overestimated by the IA. In addition, while the primary and key secondary outcomes were controlled for multiple comparisons, the secondary and exploratory outcomes were not controlled for this or for the smaller sample size, and there is a risk of inflated type I error when interpreting results from these comparisons. Furthermore, there are possible limitations pertaining to the numbers of complete cases (i.e., patients observed at each time point of the analysis) in the danicopan plus C5i/danicopan-emergent arm. At TP1, in the danicopan plus C5i arm (n = 42), there were 36 complete cases for the change in Hb, 35 cases for absolute reticulocyte count, and the complete cases were missing for the proportion of patients with Hb increase of 2 g/dL (20 g/L) or more in the absence of transfusion and the proportion of patients with transfusion avoidance. The models used in the analysis assumed that missing data are missing-at-random (mixed model for repeated measures) or missing-completely-at-random (analysis of covariance, transfusion burden outcomes only). Without further information on the patients who were missing, the degree to which the missingness may be informative to the results is not known. Lastly, there was no placebo comparator after the end of TP1; therefore, observed results in TP2 and LTE may not all be attributable to treatment.

There are some potential limitations associated with outcome ascertainment. While laboratory outcomes such as Hb or LDH are likely at low risk of bias because of being centrally measured, the open-label design of TP2 and LTE mean that knowledge of the treatment being received may impact reporting of subjective quality of life outcomes at those time points (impacting FACIT-F, EORTC QLQ-C30, and EQ-5D-3L outcomes). Similarly, while a measure of treatment adherence was reported in the study, this was based on tablet counts and there is a possibility of reporting bias.

External Validity

There are some limitations regarding the study population to note. Per the clinical expert, most of the inclusion criteria were reasonable for patients with PNH in a Canadian context; however, the minimum thresholds for platelet and neutrophil counts, and the exclusion criteria which excluded patients with other causes of anemia or other clinical comorbidities, excluded patients who may be treatment candidates in a real-world setting. The clinical expert noted that while there are certain clinical characteristics alongside persistent anemia whose presence indicate that EVH is the likely cause, there is no standard diagnostic definition of the condition. The cut-off used in the ALPHA study to define anemia was a level at which the clinical experts speculated patients would likely feel symptoms and could require intervention but was not based on a known standard. In addition, the clinical experts noted that transfusion practices vary greatly and are partially dependent on patient factors such as lifestyle or comorbidities. Therefore, the study population included in the ALPHA study may not represent all patients with PNH who have EVH.

There are also some limitations regarding the generalizability of the results to clinical situations. The frequency of visits used in the trial setting may not exactly reflect daily clinical practice in Canada and therefore the efficacy and safety profile during the trial may not be extrapolatable to the general patient population. In addition, the additional dosing information in the product monograph includes the phrase “or to achieve an appropriate hemoglobin response based on clinical judgment” for dose increases; this was not in the dosing criteria for the trial, and it is not clear what impact it might have in clinical practice. During the trial, the approved C5i dose was not permitted to be increased, nor the interval shortened, which also may not reflect clinical practice. FACIT-F and EORTC QLQ-C30 are validated tools in patients with PNH, but the EQ-5D-3L is not validated in PNH specifically, therefore changes in health status reflected in this score may not translate perfectly to changes in health status in PNH. Furthermore, there were no MIDs provided by the sponsor or the clinical experts for all but 1 of the outcomes in patients with PNH, therefore information on clinically meaningful change for the majority of outcomes remains lacking.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform the CDA-AMC expert committee’s deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^38,39

• 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), inconsistency across studies, 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). The target of the certainty of evidence assessment was based on thresholds informed by the sponsor submission, input from the clinical experts, and/or thresholds identified in the literature. 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.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for danicopan plus C5i therapy versus placebo plus C5i therapy.

Long-Term Extension

Information available to date from the LTE1 phase of the ALPHA study has been reported and appraised in the Systematic Review section.

Indirect Evidence

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

Objectives for the Summary of Indirect Evidence

Indirect evidence was required to be considered as part of the submission because the ALPHA trial compared danicopan plus C5i therapy with placebo plus C5i therapy, however comparative data against pegcetacoplan, the other second-line therapeutic option for PNH, remained lacking.

Description of Indirect Comparison(s)

The submission included an SLR and feasibility assessment to undertake a MAIC with the PEGASUS trial, which compared pegcetacoplan with eculizumab in adult patients with PNH.

Table 16: Study Selection Criteria and Methods for the SLR Submitted by the Sponsor

AE = adverse event; BTH = breakthrough hemolysis; EVH = extravascular hemolysis; LDH = lactate dehydrogenase; PNH = paroxysmal nocturnal hemoglobinuria; PRISMA = Preferred Reporting Items for Systematic reviews and Meta-Analyses; RBC = red blood cell; RCT = randomized controlled trial; SAE = serious adverse event; SLR = systematic literature review.

^aPer the submission, the focus of the systematic review was on patients with PNH and EVH; however, studies describing investigational treatments of interest in patients not treated with complement component inhibitors- (i.e., those who have not experienced EVH) were also considered for inclusion as part of the full evidence base for these treatments.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence and SLR Report.⁷⁷

Indirect Treatment Comparison Design

Objectives

The objective of the SLR was to characterize the efficacy, safety, and humanistic impact of currently available and future (in phase III) treatments for EVH in patients with PNH.

Study Selection Methods

Full details of the SLR search strategy, study inclusion or exclusion, data extraction, and quality assessment can be found in Table 16. Briefly, a systematic search of the literature was undertaken on November 1, 2022, and re-run on June 12, 2023. The evidence base for EVH was expected to be small, therefore the search strategy was designed not to include the comparators, outcomes, or study designs; these were instead screened for at the abstract screening and full-text review stages. A supplemental search of the grey literature was also undertaken.

Clinical outcomes were selected according to their relevance in assessing treatment benefit for patients with PNH experiencing EVH and sought to capture outcomes related to IVH, BTH, thrombosis hematological response, and anemia in the evidence base. The submission did not provide any information on whether a specific definition of EVH was used to identify relevant studies during screening, or whether the list of clinical outcomes was prespecified before screening or compiled during screening.

During the data extraction, data which were unavailable was considered missing and was not reported for that outcome. For studies with multiple time points, only the data from the last assessment were summarized.

Indirect Comparison Analysis Methods

Feasibility Study

The submission included a feasibility assessment on the possibility of comparing patient-level data from the ALPHA trial to aggregate data from the PEGASUS study, a phase III trial RCT comparing pegcetacoplan with eculizumab in patients with PNH being treated with a C5i. The submission assessed the feasibility of comparing the 2 studies via a trimmed MAIC (anchored or unanchored) and a trimmed naive comparison. The feasibility assessment consisting of a comparison of the between-trial heterogeneity was conducted for trial design, trial end points, patient eligibility criteria, and baseline patient characteristics.

The submission did not provide further details on whether the list of factors considered in the feasibility assessment were prespecified or compiled based on the studies, and whether there were statistical tests or systematic margins used to determine differences between the ALPHA and PEGASUS studies for individual characteristics.

MAIC Analysis

The MAIC analysis compared a subset of the ALPHA study population which was trimmed to meet the additional inclusion criteria which were a part of the PEGASUS study but not the ALPHA study:

• body mass index less than 40 kg/m²

• platelet count greater than 50,000/µL.

The MAIC used a weighting approach which approximates a propensity score approach as per the methodology reported by Signorovitch et al.⁴³ as well as an alternate weighting approach proposed by Jackson et al.,⁷⁸ which was proposed by the submission to maximize effective sample size (ESS), and qualitatively reported on the 2 methods in terms of balancing characteristics. The model used to produce weights included baseline Hb and baseline reticulocyte count. The submission did not provide further details on why these 2 characteristics were selected but noted that overall that the ALPHA and PEGASUS trials contained several differences which would make indirect comparison challenging. Weights were calculated at the level of the trial.

The distribution of calculated weights from both methods was reported, as well as the baseline characteristics after adjustment by both methods. After weighting, anchored and unanchored MAICs were undertaken for the following efficacy outcomes:

• change in Hb from baseline

• change in absolute reticulocyte count from baseline

• change in LDH from baseline

• change in FACIT-F scores from baseline

• transfusion avoidance.

Efficacy results were reported in the anchored MAICs as differences of TD for each trial (danicopan plus C5i minus placebo plus C5i, or pegcetacoplan minus eculizumab). The unanchored MAICs reported efficacy results as TDs between the danicopan plus C5i arm and the pegcetacoplan arm. The submission did not provide additional information on the definition used for transfusion avoidance.

Anchored and/or unanchored MAICs were also undertaken for the following safety outcomes:

• BTH AEs and BTH over extended follow-up (safety outcome).

Time to discontinuation due to BTH, BTH AEs, and BTH AEs over extended follow-up were also reported in an unweighted population and were not appraised. All analyses compared results from the ALPHA study at 12 weeks to results from the PEGASUS study at 20 weeks (the study design consisted of a 4-week run-in with C5i monotherapy followed by a 16-week randomized period).

Results

Summary of Included Studies

The original search identified 35 articles for inclusion in the SLR, 31 of which described clinical, humanistic, and/or economic outcomes, and 4 of which were cost-effectiveness analyses. The search was re-run on June 12, 2023, yielding 385 abstracts from the databases and 25 from grey literature. Following this additional screening and full-text review, 15 articles were retained for descriptive synthesis and combined with the original 35, resulting in 50 studies ultimately being included. Of these articles, 32 described a PNH population that was previously treated with a C5i; these included the phase III trial comparing pegcetacoplan to eculizumab (PEGASUS), and the ALPHA trial. Both the PEGASUS trial and the ALPHA trial were assessed in the SLR to have high risk of bias in the quality assessment; the PEGASUS study because of the open-label nature of the study and the ALPHA study because the only available reference was a conference abstract which did not provide detail on the methods. The IA of the ALPHA study has been appraised by CDA-AMC in the systematic review section.

After excluding conference abstracts, 13 manuscripts were retained. Of these, 2 were MAICs, and their references were screened for additional studies (none were found).

Results

Feasibility Study Results

Full details of the feasibility study conducted by the sponsor are included in Table 17. Briefly, the sponsor detailed differences in trial design, inclusion criteria, baseline characteristics, and treatment duration between the ALPHA trial and the PEGASUS trial.

Table 17: Results of Feasibility Assessment for the MAIC — Study Differences

C5i = complement component 5 inhibitor; Hb = hemoglobin; MAIC = multiple-adjusted indirect comparison; RCT = randomized controlled trial; SD = standard deviation.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence and the MAIC Feasibility Assessment.⁷⁹

A comparison of the full baseline characteristics from the ALPHA study, trimmed ALPHA study, and the PEGASUS study are included in Table 18. A difference in the mean baseline Hb was highlighted by the sponsor in the baseline characteristics between the trimmed ALPHA study population (7.7 g/dL in the danicopan plus C5i arm, 7.8 g/dL in the placebo plus C5i arm) and the PEGASUS study population (8.69 g/dL in the pegcetacoplan arm, 8.68 g/dL in the eculizumab arm). Apart from this, there were numeric differences between the trimmed ALPHA study population and the PEGASUS study population in the proportion of Asian patients (47.4% in the danicopan plus C5i arm and 31.6% in the placebo plus C5i arm of the ALPHA study, versus 12% in the pegcetacoplan arm and 18% in the eculizumab arm of PEGASUS study), proportion of white patients (42.1% in the danicopan plus C5i arm and 47.4% in the placebo plus C5i arm in the ALPHA study, versus 59% in the pegcetacoplan arm and 64% in the eculizumab arm in the PEGASUS study), absolute reticulocyte count (238.8 × 10⁹/L in the danicopan plus C5i arm and 242.9 × 10⁹/L in the placebo plus C5i arm in the ALPHA study, versus 217.5 × 10⁹/L in the pegcetacoplan arm and 216.2 × 10⁹/L in the eculizumab arm in the PEGASUS study), and total bilirubin (33.2 µmol/L in the danicopan plus C5i arm and 34.8 µmol/L in the placebo plus C5i arm in the ALPHA study, and 42.5 µmol/L in the pegcetacoplan arm and 40.5 µmol/L in the eculizumab arm in the PEGASUS study). There was no information on the potential clinical importance of these differences in the submission.

Table 18: Comparison of Patient Characteristics Between the ALPHA and PEGASUS Studies

BMI = body mass index; C5i = complement component 5 inhibitor; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; IEAS = interim efficacy safety analysis set; LDH = lactate dehydrogenase; MAIC = multiple-adjusted indirect comparison; PNH = paroxysmal nocturnal hemoglobinuria; SD = standard deviation.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence and the MAIC Feasibility Assessment.⁷⁹

MAIC Efficacy Results

Results for the MAICs weighted by the Signorovitch et al.⁴³ methods were reported, as this method is referenced in the NICE Decision Support Unit Technical Support documents and results of the MAICs weighted using Jackson et al.⁷⁸ were very similar. The ESS reported for the Signorovitch weighting method was 20.276, and the ESS reported for the Jackson weighting method was 22.610.

Table 19 describes the trials included and key efficacy results for the anchored and unanchored MAICs is in Table 20. Briefly, the conclusions for the anchored and unanchored MAICs were numerically similar for most efficacy outcomes, with 2 exceptions: transfusion avoidance, where the unanchored MAIC showed that danicopan was favoured for transfusion avoidance, but the anchored MAIC did not; and absolute reticulocyte count, where pegcetacoplan was favoured over danicopan in both MAICs. The overall conclusions of the MAICs were that neither danicopan add-on therapy nor pegcetacoplan were favoured for the outcomes of Hb change from baseline, LDH change from baseline, change in FACIT-F scores from baseline, or transfusion avoidance (anchored MAIC only).

Table 19: Summary of Trial Arms Included in the MAIC

C5i = complement component 5 inhibitor; MAIC = multiple-adjusted indirect comparison; RCT = randomized controlled trial; SC = subcutaneous; t.i.d. = 3 times a day.

Source: Information included in the table is from the sponsor’s MAIC presentation.⁸⁰

MAIC Safety Results

Weighted MAICs were reported for the time to BTH AEs and the probability of a BTH event; an unweighted MAIC was reported for the time to discontinuation because of BTH and the probability of BTH over extended follow-up (not appraised). The time-to-event curve for the time-to-hemolysis AE is reported in Figure 2. Briefly, based on the information provided, there was no significant difference between the time to BTH AE for patients in the trimmed ALPHA study sample or in the PEGASUS study.

Based on the extended follow-up from the PEGASUS study (48 weeks) and a median follow-up of 34.6 weeks from patients in the danicopan-emergent arm of the ALPHA study, the probability of experiencing a BTH event was calculated and reported in Table 21. Briefly, the results from the weighted, unanchored MAIC did not favour either treatment in the probability of BTH between the 2 trials.

Table 20: Anchored and Unanchored MAIC Efficacy Results

C5i = complement component 5 inhibitor; CI = confidence interval; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; LDH = lactate dehydrogenase; MAIC = multiple-adjusted indirect comparison.

Source: Details included in the table are from the sponsor’s MAIC presentation.⁸⁰

Table 21: BTH Adverse Events During Extended Follow-up — MAIC-Adjusted

AE = adverse event; BTH = breakthrough hemolysis; C5i = complement component 5 inhibitor; CI = confidence interval; MAIC = multiple-adjusted indirect comparison.

Source: Details included in the table are from the sponsor’s MAIC presentation.⁸⁰

Figure 2: Time to BTH Adverse Event — MAIC-Adjusted

BTH = breakthrough hemolysis; MAIC = multiple-adjusted indirect comparison.

Source: Details included in the figure are from the sponsor’s MAIC presentation.⁸⁰

Critical Appraisal

The submission provided an SLR, feasibility assessment for a MAIC, naive comparison, and both anchored and unanchored MAICs for select efficacy and safety outcomes. The SLR searched multiple databases and grey literature sources using search terms that were provided in the submission, carried out study selection and data extraction using accepted methods, and provided a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) diagram of the study selection. There are some limitations of note. The SLR did not provide a preregistered protocol, and so it is not known whether the search criteria, study selection, or subgroups of interest were prespecified before the search.

The results of the SLR informed the feasibility assessment for conducting a MAIC comparing danicopan add-on to pegcetacoplan monotherapy. The feasibility assessment provided a comprehensive description for the justification of a MAIC over other methods such as reweighting and network meta-analyses. Based on the feasibility assessment, the sponsor concluded that a MAIC was infeasible for comparing danicopan add-on to pegcetacoplan monotherapy. However, it is not known whether statistical testing was undertaken to determine differences in study population or whether there was a prespecified threshold to determine the meaningfulness of differences between populations. Since the clinical experts noted that the differences identified between the study populations were not clinically meaningful, the rationale for the sponsor’s conclusion would have provided additional context. Furthermore, other differences across the trials such as race and total bilirubin were not discussed in the feasibility assessment and the submission provided little discussion of whether these or other patient characteristics have prognostic or meaningful impact to study outcomes. Per the clinical experts consulted by CDA-AMC, the differences highlighted in the feasibility assessment for inclusion criteria and baseline characteristics did not represent clinically meaningful differences. They noted that the anemia and platelet cut-offs being different was not overly meaningful from a clinical perspective as the mean values for both in the baseline characteristics were similar; they also noted that patient-specific factors such as lifestyle and important symptoms are often a driver of treatment choices. As this information was not included in the submission, the impact of these factors on patient differences is unknown. Ravulizumab is the suggested C5i therapy over eculizumab when both are available; however, the 2 therapies have similar efficacy results.³⁷ Therefore, there is enough overlap between the study populations to suggest that the reported characteristics do not represent enough of a source of heterogeneity to rule out a MAIC. Furthermore, infeasibility of a MAIC would not be appropriate justification for relying on a naive comparison for drawing conclusions. A naive comparison would be subject to significant limitations: it would break randomization by using a subset of the ALPHA study patient population, provide a narrative comparison with no statistical testing for differences, and would not address any of the concerns highlighted by the feasibility assessment. Thus, drawing conclusions based on a naive comparison would not be more appropriate in this setting.

MAICs would be justified over alternative indirect comparisons such as network meta-analysis due primarily to the size of the network and the number of comparator treatments for EVH. An anchored MAIC was possible as there is a common C5i monotherapy arm used in both trials. However, the sponsor noted key differences in the comparator arms of each trial which could undermine the internal validity of the anchored comparison. The ALPHA study C5i monotherapy arm included patients assigned to both ravulizumab and eculizumab whereas the PEGASUS study C5i monotherapy arm only included patients assigned to eculizumab. Thus, for an anchored comparison to be appropriate, the efficacy of these 2 C5i therapies would need to be the same; the clinical experts consulted by CDA-AMC and the literature suggested that this assumption may be appropriate for efficacy end points.^37,47,50 In addition, since the ALPHA study reported comparative results at 12 weeks from baseline whereas the PEGASUS trial reported comparative results at 20 weeks, the anchored comparison compared differences in end points at these time points. This would only be appropriate if the efficacies of the drugs were considered stable after 12 weeks of treatment, which may not be an appropriate assumption. The anchored MAICs provided control on 2 treatment effect modifiers and the sponsor noted that these were the only effect modifiers able to be adjusted on, citing limitations in the study population reporting. In addition, they carried out MAIC weighting using 2 methods, 1 of which would maximize the ESS; results were overall very similar between the 2 methods for the outcomes assessed. However, the clinical experts noted that the modifiers used in weighting were not a comprehensive list of possible modifiers or prognostic factors. Therefore, the anchored MAICs likely did not account for all possible sources of heterogeneity between the study populations. This increases the uncertainty in the results, and thus, drawing firm conclusions about the comparative effectiveness of danicopan add-on and pegcetacoplan therapy based on the results of the anchored MAIC would not be recommended.

Unanchored MAICs were also undertaken for all efficacy and safety outcomes. This method requires the assumption that all prognostic factors and treatment effect modifiers are accounted for, which is a strong assumption largely considered impossible to meet — failure of this assumption leads to an unknown amount of bias in the effect estimate.⁸¹ The unanchored comparison should ideally provide sufficient evidence on the likely extent of error because of unaccounted for covariates,⁸¹ which this analysis did not do. Cross-validation methods or other sensitivity analyses are suggested methods to explore the impact of the lack of anchoring.⁸¹ However, these were not reported in the current submission, which imparts additional uncertainty in the results. The weighted model for the unanchored MAIC included the same covariates as were included for the anchored MAIC. As noted previously, the 2 included covariates were not considered sufficient to account for all effect modifiers and prognostic factors in this setting. Thus, drawing conclusions based on the results of the unanchored MAIC would not be recommended either.

Lastly, the ALPHA and PEGASUS trials differ in other ways that were not accounted for in any of the indirect comparison approaches and which may impact the risk of bias and the generalizability of the results. Patients in the PEGASUS study were exposed to pegcetacoplan monotherapy for 4 weeks longer than patients were exposed to danicopan in the ALPHA study, which may bias the efficacy results to favour pegcetacoplan. Furthermore, the trial design for pegcetacoplan was an open-label trial, which may bias the reporting of FACIT-F, a subjective outcome, and would not provide an appropriate contrast to the ALPHA study which used a double-blinded design. No information is available on the ascertainment of outcomes in the PEGASUS study; however, the ascertainment of the other efficacy outcomes in the ALPHA study was likely at low risk of bias because of the use of a central laboratory. The results from the MAICs are also subject to the same concerns about generalizability to the PNH population as the ALPHA study population, and without detailed information from the PEGASUS study, the generalizability of that study population to the wider PNH population is not known. Results were only reported for efficacy outcomes at week 20 for the PEGASUS study and week 12 for the ALPHA study, and so any information on efficacy past this time is not known. For BTH events, these were reported up to 48 weeks in the PEGASUS study and 34.5 weeks for the ALPHA study, therefore longer-term data on safety and information on other harms is unknown. Of note, the MAICs also did not include comparative information on several outcomes included in the pharmacoeconomic model such as iron overload, proportion of patients with Hb greater or less than 9.5 g/dL, or BTH by severity, which also limits the generalizability of this indirect comparison to the pharmacoeconomic analysis.

Summary

The body of evidence submitted for the indirect comparison consisted of an SLR, feasibility assessment for conducting an indirect comparison of danicopan plus a C5i to pegcetacoplan, a naive comparison of the trimmed ALPHA study population with the full sample from the PEGASUS study, as well as anchored and unanchored MAICs on select efficacy and safety outcomes. Briefly, the sponsor submission trimmed the patient sample in the ALPHA trial to meet 2 additional inclusion criteria from the PEGASUS study and compared the characteristics of the studies and the patient populations to ascertain whether a MAIC would be feasible to undertake. The sponsor concluded that the assumptions required for a MAIC would not be satisfied and provided a naive comparison of the trimmed ALPHA study sample with the PEGASUS study sample by study arm. However, feedback from the clinical experts noted that the differences highlighted by the sponsor were not clinically meaningful as reported, although the CDA-AMC appraisal noted that the trial designs still differed in ways that risk biasing the results. Furthermore, the infeasiblity of a MAIC would not be an appropriate justification for relying on results of a naive comparison. The CDA-AMC appraisal concluded that a naive comparison would be largely uninformative and the information too uncertain to make firm conclusions on efficacy or safety and therefore did not include it in the indirect evidence appraisal although it makes up the base case in the pharmacoeconomic analysis. As it would be possible with a MAIC to control for treatment effect modifiers in the 2 studies, the CDA-AMC team appraised the unanchored and anchored MAICs undertaken on the trimmed ALPHA study sample and the PEGASUS study sample after weighting by the Signorovitch method.⁴³ The efficacy outcomes of interest were change from baseline in Hb levels, absolute reticulocyte count, LDH, FACIT-F, and transfusion avoidance. The safety outcomes of interest analyzed with the MAIC were BTH AEs and BTH AEs during extended follow-up (48 weeks for the PEGASUS study, median follow-up 34.6 weeks for the ALPHA study). The MAICs concluded that neither danicopan plus C5i nor pegcetacoplan were favoured for any of the efficacy or safety outcomes, with the exception of transfusion avoidance in an unanchored MAIC. However, the limitations associated with the indirect evidence overall did not allow for firm conclusions on the relative effectiveness or safety of danicopan plus C5i therapy relative to pegcetacoplan, and information on the comparative effectiveness remains lacking. The MAICs also did not include comparative information on several outcomes included in the pharmacoeconomic model such as iron overload, proportion of patients with Hb greater or less than 9.5 g/dL, or BTH by severity, which also limits the generalizability of this indirect comparison to the pharmacoeconomic analysis.

Discussion

Summary of Available Evidence

This report summarizes the evidence for danicopan as an add-on therapy to ravulizumab or eculizumab for the treatment of signs and symptoms of EVH in patients with PNH. The evidence appraisal was based on 1 IA from an ongoing phase III double-blind, placebo-controlled RCT with single-arm extensions and 1 body of indirect evidence consisting of a series of naive comparisons, using anchored and unanchored MAICs.

The pivotal trial, the ALPHA study, was a phase III RCT with a 12-week placebo-controlled, double-blind portion plus a 12-week single-arm extension and an additional LTE. Data from an interim efficacy analysis containing 75% of the total sample of patients was submitted (42 patients randomized to receive danicopan add-on therapy and 21 patients randomized to receive placebo add-on). An interim safety analysis provided data from the full patient sample enrolled in the trial (57 patients randomized to receive danicopan add-on and 29 patients randomized to receive placebo add-on) and their information collected up until interim database lock on September 20, 2022. The primary outcome of the study was the change in Hb levels from baseline to 12 weeks. Key secondary outcomes were the change from baseline to week 12 in the proportion of patients with Hb increase of 2 g/dL or more in the absence of transfusion, the proportion of patients achieving transfusion avoidance, FACIT-F scores, and absolute reticulocyte counts. Secondary outcomes were the change from baseline in transfusion burden (number of RBC units transfused and the number of transfusion instances), the percentage of patients with Hb normalization (defined as achieving the lower limit of normal reference range [110 g/L for female patients and 125 g/L for male patients]), and the change from baseline in LDH. Exploratory outcomes were the change from baseline to weeks 12 and 24 in EORTC QLQ-C30 scores and EQ-5D-3L scores. The sponsor also submitted interim results from the ALPHA study LTE for those patients in the ALPHA study who had completed an additional 52 weeks of follow-up in a single-arm, open-label format where all patients were receiving danicopan add-on therapy. The change from baseline in Hb, absolute reticulocyte count, LDH, FACIT-F, EQ-5D-3L, and EORTC QLQ-C30 were the outcomes reported. Lastly, the sponsor-submitted indirect evidence consisting of MAICs comparing a sample of the ALPHA study population trimmed to meet the inclusion criteria of the PEGASUS study, a phase III, open-label RCT that assessed the efficacy and safety of pegcetacoplan compared with eculizumab. Change from baseline to week 12 (ALPHA) or week 20 (PEGASUS) in Hb, absolute reticulocyte count, FACIT-F scores, transfusion avoidance, and LDH were efficacy outcomes, while time-to-hemolysis AEs and probability of BTH during extended follow-up were safety outcomes.

Baseline characteristics were generally well balanced between the study arms in the ALPHA study, with the exception of some imbalances in the proportion of patients receiving each C5i (a greater proportion of patients in the danicopan plus C5i arm were receiving ravulizumab as their C5i), sex (more males and fewer females in the danicopan plus C5i arm), race (more Asian patients in the danicopan plus C5i arm and more patients whose race was unknown in the placebo plus C5i arm), and transfusion history (more patients in the danicopan plus C5i arm had received a transfusion within 24 weeks of receiving the study drug, and more patients in the placebo plus C5i arm had received a transfusion within 12 weeks of starting the study drug). The majority of patients (90.5% in the danicopan plus C5i arm and 81.0% in the placebo plus C5i arm) had received a transfusion within 24 weeks of receiving the study drug. In addition, the majority of patients (69.0% of patients in the danicopan plus C5i arm and 71.4% of patients in the placebo plus C5i arm) had received a transfusion in the 12 weeks before receiving the study drug. The inclusion criteria was generally applicable to a Canadian context, although the clinical experts consulted by CDA-AMC noted that the inclusion and exclusion criteria may exclude certain patients with PNH in their practice; specifically, patients in the ALPHA study were required to have a platelet count greater than 30,000/µL and a neutrophil count greater than 500/L, and the exclusion criteria did not specify a list of comorbidities or laboratory values for exclusion. The experts noted that this may exclude patients with PNH with bone marrow suppression or other complex cases who may be candidates for danicopan therapy, although they also noted this was standard practice for clinical research. In addition, there is no accepted standardized definition for EVH according to the clinical experts, therefore the inclusion criteria for EVH may not encompass all patients with the condition.

Interpretation of Results

Efficacy

PNH is a rare disease and both the clinical experts and clinician group inputs consulted by CDA-AMC noted that patients with PNH are frequently complex, their PNH symptoms can be variable, and control can change due to complement-activating situations such as infection or suboptimal dosing, which would require clinical intervention but which might not be considered treatment failure. Improvement in Hb relative to the baseline for a given patient could be used to assess effectiveness of therapy. Overall, results from the ALPHA study for hematologic outcomes suggested that for patients with PNH meeting the study definition for EVH, treatment with danicopan plus C5i likely resulted in greater positive impact on these outcomes when compared to placebo plus C5i after 12 weeks of treatment. Danicopan therapy likely increased Hb levels from baseline to week 12 relative to treatment with placebo plus C5i therapy, with a trend toward further numeric increases at 24 weeks. At week 12, danicopan add-on therapy also likely increased the proportion of patients with a Hb increase of 2 g/dL or greater without transfusion, and may also result in an increase in the proportion of patients attaining Hb normalization (the lower limit of the sex-specific normal Hb range), when compared to placebo plus C5i. Results from 24 weeks suggested a trend toward maintained improvements in these Hb outcomes. The change in Hb from baseline surpassed the MID provided by the sponsor for clinically meaningful change. While no MIDs were available for the other Hb outcomes, the clinical experts noted that any improvement to hematologic outcomes would be clinically meaningful to them and on this basis, the improvements in Hb-related outcomes at 12 weeks appear to meet this criterion. Comparative results at later time points remain uncertain, however, predominantly due to the lack of a comparator arm after 12 weeks and the fact that not all patients had completed the LTE at the time that the ALPHA study was submitted for appraisal.

Reduction in transfusion dependence was highlighted by the clinical experts, the clinician input, and the patient input as important for treatment. Overall, danicopan add-on therapy likely decreased measures of transfusion burden (number of transfusion instances and number of RBCs transfused) and absolute reticulocyte count at 12 weeks. Results from transfusion outcomes suggest that the proportion of patients with transfusion avoidance was maintained at 24 weeks in the danicopan-emergent arm (not measured in the placebo-emergent arm), and a numerically small but non-null reduction in the number of transfusion instances and the number of RBC units transfused was also maintained at 24 weeks, along with an observed reduction in absolute reticulocyte counts. Similar to Hb-related outcomes, the clinical experts noted that any change in transfusion needs would be clinically meaningful to them, and the results at 12 and 24 weeks appear to meet this criterion. Transfusion outcomes at later time points remain uncertain due to the same limitations (lack of comparator arm after 12 weeks, very low number of patients completing LTE1 to date).

Changes in LDH levels was a biomarker outcome of interest in the ALPHA study; the clinical experts noted that if LDH was normal it would not be expected to change during therapy, and the clinician group input highlighted reduction in LDH (LDH ratio < 1.5 × ULN) as a marker for improvement. The results from 12 weeks suggested that treatment with danicopan plus C5i therapy may result in little to no difference in LDH levels when compared with placebo plus C5i therapy. This would align with the expectations noted by clinical experts. Observed changes in LDH from baseline to 24 weeks showed variable changes in the danicopan-emergent and placebo-emergent arms; a numeric decrease in LDH was observed in the danicopan-emergent arm and the placebo-emergent arm had little to no change in LDH from baseline to 24 weeks. Results from the LTE were reported for only a fraction of patients and were too uncertain to conclude the impact of ongoing danicopan therapy. In general, results are uncertain at later time points because of the study-level limitations noted for Hb and transfusion outcomes.

The clinician group input noted that PNH improvements should be accompanied by decreased fatigue, improved HRQoL, and improved overall survival. The patient input also highlighted that slowing disease progression and improving long-term outcomes and HRQoL were desired. Two measures of HRQoL (EQ-5D-3L and EORTC QLQ-C30) and 1 measure of fatigue (FACIT-F) were assessed in the ALPHA study. With regards to patient-reported outcomes of fatigue at 12 weeks, treatment with danicopan plus C5i therapy may result in an increase in FACIT-F scores when compared to placebo plus stable C5i therapy, based on an MID of 5 points provided in the submission, with results of a similar magnitude observed at 24 weeks. Evidence from the EQ-5D-3L and EORTC QLQ-C30 measures suggested danicopan add-on treatment may also result in little to no difference in scores from baseline to 12 weeks. Results from 24 weeks suggested a trend toward an increase in both scores, with variable results at LTE1, which may suggest a lagging improvement in HRQoL. Based on MIDs for patients with cancer, the score changes at 12 weeks in both arms in the EORTC QLQ-C30 measures were within the margin considered to be a small change. At 24 weeks, the change in scores in the placebo-emergent arm marginally passed the MID to be considered a medium change; the danicopan-emergent arm score at 24 weeks was considered a small change. However, the clinical meaningfulness of the EQ-5D-3L and EORTC QLQ-C30 score changes in patients with PNH is unclear as there was no MID available. In general, because of study limitations such as the small number of patients who have completed the LTE phases to date, the impact of danicopan add-on therapy on long-term HRQoL and fatigue outcomes remains unclear.

The body of evidence submitted for the indirect comparison consisted of an SLR, feasibility assessment for conducting an indirect comparison of danicopan plus a C5i to pegcetacoplan, a naive comparison of the trimmed ALPHA study population with the full sample from the PEGASUS study, as well as anchored and unanchored MAICs on select efficacy and safety outcomes. Briefly, the sponsor submission trimmed the patient sample in the ALPHA trial to meet 2 additional inclusion criteria from the PEGASUS study and compared the characteristics of the studies and the patient populations to ascertain whether a MAIC would be feasible to undertake. The sponsor concluded that the assumptions required for a MAIC would not be satisfied and provided a naive comparison of the trimmed ALPHA study sample with the PEGASUS study sample by study arm. However, feedback from the clinical experts noted that the differences highlighted by the sponsor were not clinically meaningful as reported, although the CDA-AMC appraisal noted that the trial designs still differed in ways that risk biasing the results. Furthermore, the infeasibility of a MAIC would not be an appropriate justification for relying on results of a naive comparison. The CDA-AMC appraisal concluded that a naive comparison would be largely uninformative and the information too uncertain to make firm conclusions on efficacy or safety and therefore did not review it or include it in the indirect evidence appraisal, although it makes up the base case in the pharmacoeconomic analysis. As it would be possible with a MAIC to control for treatment effect modifiers in the 2 studies, the CDA-AMC team appraised the unanchored and anchored MAICs undertaken on the trimmed ALPHA study sample and the PEGASUS study sample after weighting by the Signorovitch method.⁴³ The efficacy outcomes of interest were change from baseline in Hb levels, absolute reticulocyte count, LDH, FACIT-F, and transfusion avoidance. The safety outcomes of interest analyzed with the MAIC were BTH AEs and BTH AEs during extended follow-up (48 weeks for the PEGASUS study, median follow-up 34.6 weeks for the ALPHA study). The MAICs concluded that neither danicopan plus C5i nor pegcetacoplan were favoured for any of the efficacy or safety outcomes, with the exception of transfusion avoidance in an unanchored MAIC. However, the limitations associated with the indirect evidence overall precluded firm conclusions on the relative effectiveness or safety of danicopan plus stable C5i therapy relative to pegcetacoplan, and information on the comparative effectiveness remains lacking.

Pegcetacoplan is the main comparator for danicopan, and the clinical experts as well as clinician input referenced the potential for treatment burden associated with SC administration and the possibility of severe BTH because of the nature of the proximal complement blockade when discussing unmet needs. The clinical experts noted that under the approved indication for danicopan, patients would be required to have residual hemolytic anemia due to EVH, while the indication for pegcetacoplan does not specifically require EVH. However, there was no evidence provided in the submission about the comparability of these treatments with respect to BTH severity or adherence, therefore it is not known whether danicopan would address these concerns. The indirect comparison also did not include comparative information on several other outcomes included in the pharmacoeconomic model such as iron overload, proportion of patients with Hb greater or less than 9.5 g/dL, or BTH by severity, which also limits the generalizability of this indirect comparison to the pharmacoeconomic analysis.

Efficacy results from the full analysis (FA) of the ALPHA study are in Appendix 1 and initial findings are presented here. Of note, the patient disposition reported that a total of 70 (81.4%) patients (46 [80.7%] patients initially randomized to danicopan plus C5i and 24 [82.8%] patients initially randomized to placebo plus C5i) completed the study, including years 1 and 2 of the LTE phase (study design available in Figure 1). Results at TP1 were either numerically similar for the FA compared to the IA, or the numeric changes observed did not materially impact the interpretation of the evidence, with some exceptions. A numeric increase in the LS mean TD for the proportion of patients with transfusion avoidance was reported in the FA relative to the IA (IA result = 40.80%; 95% CI, 21.08% to 60.58% and FA result = 48.40%; 95% CI, 31.79% to 64.94%). A slight numeric increase, sufficient to attain statistical significance, was reported for the TD in the proportion of patients with Hb normalization (IA result = 18.40; 95% CI, –0.84 to 37.71; P = 0.008 and FA result = 19.20; 95% CI, 3.34 to 35.10; P = 0.0023).

Results at TP2 and LTE were available in the FA which provided insight into the longer-term impacts of danicopan plus C5i on efficacy outcomes. Results for the proportion of patient with Hb normalization and the proportion of patients with Hb increase of 2 g/dL or greater were numerically similar between TP2 and LTE, suggesting a maintained effect. There was slight numeric reduction in the observed change in Hb from baseline between TP2 and LTE in the placebo-emergent arm (FA observed mean change from baseline at TP2 = 25.00; SD = 14.46 and FA observed mean change from baseline at LTE = 22.70; SD = 18.27) which was not observed in the danicopan-emergent arm. There was a notable reduction in the proportion of patients with transfusion avoidance at LTE in the danicopan-emergent arm relative to the result at TP2 (FA result at TP2 = 69.10; 95% CI, 55.19 to 80.86 and FA result at LTE = 59.30; 95% CI, 45.03 to 72.43). Both results at TP2 and LTE represented a numeric decrease from TP1 in the danicopan-emergent arm. Results for this outcome were not reported from TP2 to LTE for the placebo-emergent arm. LTE results were not reported for the FA for LDH. In terms of the measures of HRQoL, there were observed numeric decreases in both treatment arms between TP2 and LTE for EQ-5D-3L and EORTC QLQ-C30 scores. Overall, the efficacy results are still subject to the limitations (except for those inherent to interim analyses) which were highlighted in the critical appraisal. The clinical experts noted that any improvement to hematologic outcomes would be clinically meaningful to them and on this basis, the additional data from FA demonstrate that the results from the majority of outcomes still meet this criterion, although decreases in some Hb markers and the patient-reported outcomes are reported in the longer term and remain important to note.

Harms

Harms reporting was submitted as part of the IA in the ALPHA study; as of the data cut-off date, a total of 4 patients were still receiving placebo in TP1 and 2 patients discontinued before the switch to danicopan in TP2. Overall, a majority of patients reported any TEAE, with a numerically greater proportion in the danicopan-emergent arm (93.0% of patients) than the placebo-emergent arm (82.6% of patients). However, the proportion of patients with severe AEs or greater was numerically lower. Grade 3 TEAEs was generally balanced between treatment arms during TP1 (17.5% in the danicopan plus C5i arm, 13.8% in the placebo plus C5i arm), and TP2 (12.5% in the danicopan-emergent arm, 13.0% in the placebo-emergent arm). Grade 4 and 5 events during these times were rare (1.8% of patients in the danicopan plus C5i arm had a grade 4 TEAE during TP1, and 4.3% of patients in the placebo-emergent arm had grade 4 TEAEs during TP2); no other grade 4 or 5 TEAEs were reported. During the LTE, there was a numeric difference in the danicopan-emergent arm and the placebo-emergent arm for grade 3 TEAEs (7.5% of patients in the danicopan-emergent arm, 15.0% of patients in the placebo-emergent arm). Grade 4 events were generally balanced between treatment arms for grade 4 TEAEs (2.5% of patients in the danicopan-emergent arm, 5.0% of patients in the placebo-emergent arm). There were no grade 5 TEAEs reported during the LTE. A numerically greater proportion of patients in the placebo-emergent arm (26.1%) relative to the danicopan-emergent arm (12.3%) experienced SAEs while being treated with danicopan. A total of 4 patients (2 per arm) withdrew due to AEs and AEs led to discontinuation of the study drug in some patients during the trial, however those were evenly distributed between treatment arms. No deaths were reported.

Meningococcal infections and liver enzyme abnormalities were the 2 AEs of special interest prespecified in the ALPHA study. The product monograph of danicopan includes a serious warning and precaution about serious infections caused by encapsulated bacteria and elaborates that this may include organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B; only meningococcal infections were reported as AEs of special interest in the ALPHA study. During the trial there were no reports of meningococcal infections; susceptibility to meningococcal infection with complement inhibitor therapy is known and was declared on the product monograph. The clinical experts also noted that it is common practice for patients with PNH to be routinely vaccinated for several meningitis strains although access to other vaccines may vary by province. Liver enzyme elevations occurred to a similar extent between treatment arms in patients during TP1; a numerically greater proportion of patients in the placebo arm experienced liver enzyme elevations during TP2 and the same number of patients in the LTE experienced liver enzyme elevations. Of note, during TP1, 2 (3.5%) patients stopped treatment due to liver enzyme abnormalities in the danicopan plus C5i arm, and 1 (3.4%) patient in the placebo plus C5i arm; during TP2, 1 (5.0%) patient in the placebo-emergent arm stopped treatment due to hepatic function abnormality. During LTE, 1 (4.8%) patient in the placebo-emergent arm stopped treatment due to hepatic function abnormality, and 1 (1.8%) patient each stopped treatment due to alanine transaminase and aspartate transaminase increases, respectively, in the danicopan arm. These numbers are overall numerically low, but these discontinuations may be important in the context of the small sample size. An additional AE of special interest identified by CDA-AMC was BTH; overall 4 BTH events were reported in the danicopan-emergent arm during the ALPHA study to date. No BTH events were reported to be serious; 1 hemolysis event was reported as serious, and the patient received a transfusion.

BTH events were also the safety outcome assessed as part of the indirect evidence; no other safety events were assessed. Of note, similar to the efficacy analysis, the limitations in the indirect evidence preclude firm conclusions about the comparative safety of danicopan plus C5i therapy relative to pegcetacoplan monotherapy.

The reporting of harms in the main body of the clinical report is subject to an important limitation in that the ALPHA trial is still ongoing, therefore potential additional safety signals are possible which would not be captured by this review, and the data from the full sample of patients are not available for TP2 (n = 48 patients in the danicopan-emergent arm and n = 23 patients in the placebo-emergent arm) and LTE (n = 40 patients in the danicopan-emergent arm and n = 20 patients in the placebo-emergent arm). A summary of safety data from the FA of the ALPHA study are presented in Appendix 1 and initial findings summarized here. Briefly, the most common AEs during the entire study as per the FA were similar to the IA, with the most common being COVID-19 (26.3% patients in the danicopan-emergent arm, 40.7% patients in the placebo-emergent arm), pyrexia (33.3% patients in the danicopan-emergent arm, 11.1% patients in the placebo-emergent arm), headache (26.3% patients in the danicopan-emergent arm, 11.1% in the placebo-emergent arm), nausea (17.5% in the danicopan-emergent arm, 11.1% in the placebo-emergent arm), and asthenia (10.5% patients in the danicopan-emergent arm, 18.5% patients in the placebo-emergent arm).

The proportion of patients with TEAEs during TP1 did not change notably; during TP1 there was 1 additional SAE reported (cholelithiasis) in the danicopan arm. The proportion of patients with any TEAE during TP2 increased from 64.6% to 74.5% of patients in the danicopan-emergent arm and from 56.5% to 66.7% of patients in the placebo-emergent arm; there were additional SAEs reported of hemolysis, cholecystitis, and femur fracture (1 report of each, placebo-emergent arm). The proportion of patients with any TEAE during LTE (entire study) increased from 62.5% to 88.9% in the danicopan-emergent arm and from 80.0% to 92.3% in the placebo-emergent arm. There were additional SAE reports in the danicopan-emergent arm of anemia, abdominal pain, nausea, vomiting, noncardiac chest pain, pyrexia, COVID-19, and decreased platelet count (1 report of each). There were additional SAE reports in the placebo-emergent arm of hemorrhagic diathesis, upper abdominal pain, COVID-19, pneumonia, cystitis, neutropenic sepsis, arthralgia, and PNH (1 report of each). Relative to the IA, there were additional increases in the proportion of patients who withdrew from the study drug due to AEs or SAEs during all treatment periods; information in the FA was split into withdrawals due to AEs and SAEs instead of because of specific events. During TP1, in the danicopan plus C5i arm 3 (5.3%) patients discontinued due to AEs and 1 (1.8%) discontinued because of SAEs (overall increase of 1 patient who withdrew from the study drug relative to IA); 1 (3.4%) patient withdrew from the study drug due to AEs in the placebo-emergent arm (unchanged from IA). During TP2, 1 (3.7%) patient withdrew from the study drug due to AEs in the placebo-emergent arm (overall increase of 1 patient relative to the IA). During LTE, 1 (1.9%) patient in the danicopan-emergent arm withdrew from the study drug due to AEs, and 1 (3.8%) patient in the placebo-emergent arm withdrew due to AEs (increase of 1 patient in the danicopan-emergent arm relative to IA). There was 1 death reported in the placebo-emergent arm during the study in the FA, which took place in the LTE; the patient had an SAE of pneumonia (increase of 1 patient relative to the IA). The FA did not report any additional AEs of meningococcal infections but reported 1 additional patient in the danicopan-emergent arm with liver enzyme elevations in the LTE. Overall, the safety results from the FA provided additional safety signals including 1 death; however, the overall proportion of patients with SAEs and the proportion of patients who withdrew from the study drug due to AEs or SAEs remained numerically low and broadly similar between study arms, similar to results from the IA.

Conclusion

PNH is a rare disease with significant morbidity and mortality — mortality is predominantly due to thrombosis related to IVH and is treated by C5i therapies (ravulizumab or eculizumab). Approximately 20% of patients with PNH who were clinically stable on C5i treatment develop clinically significant EVH.²⁶ Evidence from the IA of the ALPHA study, a phase III RCT with a 12-week placebo-controlled, double-blind portion plus a 12-week single-arm, open-label extension and a LTE for an additional 52 weeks, was appraised to assess the impact of danicopan added on to C5i therapy versus placebo plus C5i therapy. The results demonstrated that over 12 weeks, when compared with placebo plus C5i therapy, danicopan plus C5i therapy likely increased Hb levels, the proportion of patients with Hb increase of 2 g/dL or more in the absence of transfusion, and the proportion of patients with transfusion avoidance. In addition, danicopan plus C5i therapy likely decreased markers of transfusion burden and absolute reticulocyte counts, and may increase the proportion of patients attaining Hb normalization. Results from week 24, the open-label, single-arm treatment period of the ALPHA study where all patients were receiving danicopan therapy, suggested this trend was maintained for most hematologic outcomes. Danicopan plus C5i therapy may result in an increase in FACIT-F scores, however may result in little to no difference in EQ VAS scores or EORTC QLQ-C30 global health status/quality of life scores at week 12 when compared to placebo plus C5i therapy. Results from week 24 suggest that score increases were maintained for FACIT-F in both treatment arms and suggest a trend toward increased scores in both treatment arms for EQ-5D-3L and EORTC QLQ-C30 scores. Results from the LTE portion were only available from a fraction of patients for all outcomes and therefore remain highly uncertain. With regards to safety, the majority of patients in both trial arms experienced any TEAE, and there was a numerically higher proportion of patients in the placebo-emergent arm who experienced SAEs while being treated with danicopan; there were also imbalances between the treatment arms in the proportion of patients with some TEAEs. However, a numerically low proportion of SAEs led to withdrawal of the study drug across treatment arms. Study limitations include that the ALPHA study is an IA and some missing data were reported for efficacy outcomes; it is unknown whether the missing data are informative or not. There is also no standard clinical definition for danicopan’s indication of EVH, and the study definition as well as the inclusion and exclusion criteria may leave out patients who would be treatment candidates in a clinical context. The safety results are particularly limited by the fact that the ALPHA study is an ongoing trial, therefore potential additional safety signals are possible which would not be captured by this review, particularly since the data from the full sample of patients are not available for the TP2 and LTE phases of the trial. The limitations associated with the indirect evidence submitted did not allow for firm conclusions on the effectiveness of danicopan plus C5i therapy relative to pegcetacoplan, and therefore conclusive information on the comparative effectiveness between danicopan and pegcetacoplan remains lacking.

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Appendix 1: Additional Outcome Data

Please note that this appendix has not been copy-edited.

The following additional data from the FA of the ALPHA trial.

Efficacy

Table 22: Summary of Key Efficacy Results From the ALPHA Study During TP1 — FAS

C5i = complement component 5 inhibitor; CI = confidence interval; CMH = Cochran Mantel-Haenszel; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; Hb = hemoglobin; LDH = lactate dehydrogenase; LS = least squares; NR = not reported; RBC = red blood cell; SD = standard deviation; TP = treatment period.

^aP value adjusted for multiple comparisons.

^bResults reported for 56 patients in the danicopan + C5i arm.

^cResults reported for 26 patients in the placebo + C5i arm.

Source: details included in the table are from additional information provided by the sponsor.⁸²

Table 23: Summary of TP2 and LTE Efficacy Results From the ALPHA Study — FAS