CADTH Reimbursement Review

Etranacogene Dezaparvovec (Hemgenix)

Sponsor: CSL Behring Canada Inc.

Therapeutic area: Hemophilia B

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Clinical Review

Executive Summary

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

Table 1: Background Information for the Application Submitted for Review

FIX = factor IX; gc = genome copy; NOC = Notice of Compliance.

Sources: Sponsor’s summary of clinical evidence¹ and etranacogene dezaparvovec product monograph.²

Introduction

Hemophilia is a serious X chromosome–linked, lifelong genetic disorder that leaves patients vulnerable to blood loss and organ damage due to impaired functioning of the coagulation cascade.^3,4 Hemophilia B is the second-most common type of hemophilia (after hemophilia A) and is characterized by an absence or shortage of coagulation factor IX (FIX) resulting from a mutation in the F9 gene.^3,4 An FIX deficiency in hemophilia B prevents or reduces the ability of the coagulation cascade to produce fibrin.⁵ The severity of hemophilia B generally correlates with the degree of clotting factor deficiency.⁶ Patients with moderate and severe hemophilia B are defined by the World Federation of Hemophilia as having 1% to 5% and less than 1% of normal enzymatic FIX activity, respectively.⁶ However, according to the clinical experts consulted by CADTH, severity in clinical practice is defined by the patient’s phenotype (i.e., tendency to bleed) and not simply their factor activity levels; the decision to initiate prophylaxis with clotting factor concentrates takes into account their clinical phenotype and factor activity levels as well as lifestyle and professional activities. As of 2021, there were 704 patients with hemophilia B (with recorded severity) in Canada, 535 of whom were adult male patients. Of the adult male patients, 218 had moderate and 145 had severe hemophilia B.⁷ The estimated prevalence at birth per 100,000 males in Canada from 1991 to 2015 was 3.9 for all severities of hemophilia B and 1.3 for severe disease only.⁸

Current treatment strategies for hemophilia B are based on replacing the missing factor and can be done either as needed when bleeding episodes occur (on-demand therapy) or in a preventive manner (prophylaxis). FIX prophylaxis can be administered regularly, with the aim of keeping plasmatic FIX levels above a certain threshold (regular prophylaxis) or, occasionally, to increase plasmatic FIX levels in high-risk situations, such as during physical activity (situational prophylaxis). The goal of prophylaxis is to prevent bleeding in patients with hemophilia while allowing them to live an active life and achieve a quality of life comparable to that of people without hemophilia.⁹ According to the clinical experts consulted by CADTH, FIX prophylaxis therapy is the preferred management approach for patients with moderately severe or severe hemophilia.

Both recombinant FIX and plasma-derived FIX are used for FIX prophylactic therapy.⁶ Recombinant FIX products are manufactured using genetically engineered cells and recombinant technology, while plasma-derived FIX products are made from plasma donated by human blood donors in Canada. One plasma-derived product (Immunine) is reimbursed; however, recombinant FIX products are predominantly used to treat patients with hemophilia B.¹⁰

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of etranacogene dezaparvovec (Hemgenix) (1 × 10¹³ genome copies [gc]/mL, suspension for IV infusion) for the treatment of adults (aged 18 years or older) with hemophilia B (congenital FIX deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Stakeholder Perspectives

The information in this section is a summary of the input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Patient input was gathered by the Canadian Hemophilia Society (CHS) from an online survey conducted from July 10 to 31, 2023. In total, 17 responses were gathered by the CHS. All respondents were affected by severe or moderately severe hemophilia B without inhibitors. In addition, in September 2022, the CHS conducted an online survey of people in Canada with severe hemophilia A and B. The CHS received 39 responses, including 31 with hemophilia A, 7 with hemophilia B, and 1 not specified.

Joint damage, primarily to knees, ankles, and elbows, caused by repeated internal hemarthroses, was reported to be the primary physical health impact of hemophilia B. Regarding currently available treatments, 5 patients who responded to the 2023 CHS survey reported being very satisfied, 17 said they were satisfied, 7 said they were neither satisfied nor dissatisfied, and 1 indicated they were very dissatisfied. The patients from this survey noted that treatments greatly complicate their everyday life, travel, and leisure activities. They also mentioned difficulty in receiving infusion treatments due to problems with vein visibility, issues with poor veins, and side effects. Patients also reported facing socioeconomic problems caused by, for example, having to miss work due to the need for regular visits to the hospital, travel and insurance issues, and access issues.

Patients hope gene therapy will lead to fewer FIX infusions, minimal needle injections, less stress, less bleeding, and fewer restrictions on activities, and make it easier to travel. In addition, about 63% of the respondents from the 2022 survey indicated they expect gene therapy to be effective in preventing bleeding for at least 10 years. The 2022 survey asked if people would choose to receive gene therapy knowing there would be frequent blood draws in the weeks and months following administration, and they would need to be followed up in a registry for 10 to 20 years. In response, 66% answered yes, 10% answered no, and 24% indicated they did not know.

The CHS mentioned that a small number of people in Canada (approximately 5) have undergone gene therapy for hemophilia B, but the organization knows nothing about the experience of these patients outside the preliminary data from the trials.

Clinician Input

Input From Clinical Experts Consulted by CADTH

According to the clinical experts consulted by CADTH, there are several unmet needs for hemophilia B. First, people with hemophilia B have a life disadvantage and quality of life disadvantage compared with the general population because there is no treatment available to reverse the course of disease. In addition, a therapy is needed that reduces the burden of treatment (e.g., need for recurrent IV injections, delayed or missed doses, and overall suboptimal treatment due to poor venous access and other difficulties related to the preparation for the FIX regimen) and improves adherence.

The clinical experts consulted by CADTH noted that the current standard of care in Canada for hemophilia B is IV replacement therapy with the missing clotting factor (i.e., FIX) and, unlike hemophilia A, there are currently no approved subcutaneous nonfactor therapies for patients with hemophilia B. The clinical experts noted that etranacogene dezaparvovec is a gene therapy for hemophilia B that would provide a potential curative option (i.e., a long-term phenotypic cure) by addressing the underlying disease process, which may represent a shift in the current treatment paradigm.

The clinical experts consulted by CADTH noted it is conceivable to give priority to those patients who have a severe bleeding phenotype, have difficult venous access and/or experience a high treatment burden with FIX prophylaxis, have recurrent bleeds despite prophylaxis or have difficulty being adherent to a prophylaxis regimen, or need to have sustained FIX levels because of comorbidities (e.g., joint disease or cardiovascular issues that require antiplatelets or anticoagulants). Eligible patients should meet criteria on levels of neutralizing antibodies (nAbs) against FIX and adeno-associated virus (AAV). The clinician would also complete an assessment of the patient’s eligibility based on their clinical judgment and lab tests (e.g., complete blood count and differential, liver and kidney functions, FIX activity, and FIX inhibitor status). The other tests that would be required would be for infectious diseases, including HIV, hepatitis B, and hepatitis C. According to the clinical experts consulted by CADTH, etranacogene dezaparvovec should not be given to pediatric patients with hemophilia B (aged < 18 years), while there is no concern using etranacogene dezaparvovec in patients aged 65 years and older with hemophilia B.¹⁵

The clinical experts consulted by CADTH noted that the most important assessment for treatment response is to monitor patients’ bleeding to observe whether etranacogene dezaparvovec prevents bleeding events and allows patients to live the lifestyle they want without concern for risk of bleeding. The clinical experts consulted by CADTH noted that FIX activity level may also be monitored for assessing response to treatment, which could allow clinicians to determine the degree to which the deficiency in FIX has been corrected by etranacogene dezaparvovec. The clinical experts consulted by CADTH noted that follow-up should focus on both efficacy and safety through clinical follow-ups (e.g., checking patients’ bleeding events and joint status via phone, virtual, or in-person check-ups) and lab tests (e.g., liver enzymes, FIX activity levels, liver ultrasound to detect hepatocarcinomas). The length of follow-up for hepatic function and FIX activity levels post infusion of etranacogene dezaparvovec should be lifelong.

To define treatment failure of etranacogene dezaparvovec, the clinical experts consulted by CADTH noted that the composite of FIX level (e.g., patient’s baseline FIX level before receiving etranacogene dezaparvovec) and return to prophylaxis with hemostatic therapy (e.g., return to regular administration of prohemostatic products to prevent any bleeding episode for at least 6 months per year) could be used to determine whether a treatment failure has occurred in patients treated with etranacogene dezaparvovec. According to the clinical experts consulted by CADTH, etranacogene dezaparvovec should be prescribed based on the judgment of a multidisciplinary team (e.g., consisting of specialists such as a hematologist with experience in treating patients with hemophilia, a physiotherapist to assess joint function, a hepatologist for liver-related issues, pharmacy support, and an HIV specialist if the patient is HIV positive), and can be administered in a specialty clinic in the outpatient setting, with longitudinal follow-up.

Clinician Group Input

A total of 8 clinicians from the Association of Hemophilia Clinic Directors of Canada (AHCDC) provided input for the CADTH review of etranacogene dezaparvovec. The AHCDC highlighted some unmet needs for patients with hemophilia with the severe bleeding phenotype and, specifically, hemophilia B. The AHCDC mentioned that with currently available treatments in Canada, patients with hemophilia B are dependent on regular IV infusions of FIX to prevent and treat bleeding for their whole life. In addition, the AHCDC noted there can be a major challenge with frequent venipuncture for routine prophylaxis for patients with poor venous access, as well as long-term complications with the placement of a central venous catheter, including risks of infection, bleeding, thromboembolism, and loss of function, requiring catheter removal.

The AHCDC noted that gene therapy provides the possibility of a long-term phenotypic cure for patients with hemophilia B. If effective, the new treatment option could provide a 1-time treatment leading to sustained FIX production. This may represent a paradigm shift in the treatment of hemophilia B. The AHCDC also mentioned that in contrast to patients with hemophilia A, who have the option of emicizumab, patients with hemophilia B have no current alternatives to coagulation factor concentrates (CFCs) outside of clinical trials, making the need for gene therapy greater for patients with hemophilia B.

The AHCDC indicated that eligible candidates for the gene therapy under review include those with a clinically severe bleeding phenotype requiring prophylaxis, no history of inhibitory antibodies, no significant comorbidities, and an anti-AAV nAb titre of less than 1:900. The group also added that patients with hemophilia who are not currently receiving prophylactic therapy (e.g., due to poor venous access or adherence issues with routine prophylaxis), but who experience repeated, serious spontaneous bleeding episodes, or have a history of life-threatening hemorrhage, are also candidates for gene therapy.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH Reimbursement Review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for etranacogene dezaparvovec:

• relevant comparators

• consideration for initiation of therapy

• consideration of continuation or renewal of therapy

• consideration for prescribing of therapy

• generalizability

• care provision issues

• system and economic issues.

Clinical Evidence

Systematic Review

Description of Studies

One phase III, single-arm, open-label clinical trial, HOPE-B (N = 54), was included in the systematic literature review (SLR) conducted by the sponsor. HOPE-B consisted of a screening phase, lead-in phase, etranacogene dezaparvovec infusion phase, and posttreatment follow-up phase. The HOPE-B study included 67 adult male patients with moderately severe to severe hemophilia B (defined as a normal circulation FIX of ≤ 2%) who had been on a stable prophylaxis regimen for at least 2 months before screening. The patients were enrolled into the lead-in phase, during which they received continuous FIX prophylaxis and were followed up for at least 6 months (i.e., 26 weeks). Those with a history of FIX inhibitors or who tested positive for FIX inhibitors during the screening period and at the last visit of the lead-in period for the HOPE-B trial were excluded. Pre-existing nAbs against adeno-associated virus serotype 5 (AAV5) was not used as an exclusion criterion in the HOPE-B study. Thirteen patients discontinued or were excluded during the lead-in phase. A total of 54 patients from 33 study sites globally received etranacogene dezaparvovec and were followed for efficacy and safety.

The primary objective of the HOPE-B trial was to demonstrate the noninferiority of etranacogene dezaparvovec to reduce the annualized bleeding rate (ABR) for all bleeding events between month 7 and month 18 post infusion, compared with continuous routine FIX prophylaxis. Other efficacy end points included proportion of patients with no bleeds, ABR for spontaneous bleeds, ABR for joint bleeds, annualized infusion rate (AIR) of FIX replacement therapy, annualized consumption of FIX replacement therapy, Hemophilia Joint Health Score (HJHS), and Patient Reported Outcomes Burdens and Experiences (PROBE). Safety outcomes such as treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse event (TESAEs), withdrawals due to adverse events (AEs), mortality, and notable harms (e.g., alanine transaminase [ALT] increased, aspartate aminotransferase [AST] increased) were also reported. Data collected during the lead-in phase served as comparison against etranacogene dezaparvovec for some safety and efficacy outcomes (e.g., ABR for all bleeding events, ABR for spontaneous bleeds, ABR for joint bleeds, AIR, and annualized FIX consumption).

In the 54 patients who received etranacogene dezaparvovec, the majority were white (74.1%) and had a mean age of 41.5 years (standard deviation [SD] = 15.8). Twenty-one patients (38.9%) had pre-existing nAbs against AAV5 before infusion of etranacogene dezaparvovec. The last testing before infusion of etranacogene dezaparvovec showed that 21 of the 54 patients (38.9%) had an anti-AAV5 nAb titre between 1:9 and 1:3,212 (median = 1:56.9). Excluding 1 patient with an anti-AAV5 titre greater than 1:3,000 (i.e., 1:3,212), the remaining 20 patients had a titre of between 1:9 and 1:678 (median = 1:49.1). There were 33 patients (62.3%) with an anti-AAV5 nAb titre below the lower limit of detection (i.e., 1:7).

The HOPE-B study is ongoing and expected to be completed in 2025. A postdose analysis at up to 36 months (data cut-off date of June 6, 2023) was used to support the sponsor’s present submission to CADTH.

Efficacy Results

Bleeding Outcomes

From month 7 to month 18 post etranacogene dezaparvovec infusion, 34 of the 54 patients (63.0%) treated with etranacogene dezaparvovec had no bleeds, compared with 14 of the same 54 patients (25.9%) who received FIX prophylaxis during the lead-in phase. The adjusted mean difference in ABR for all bleeding events between etranacogene dezaparvovec and routine FIX prophylaxis was −2.68 (95% confidence interval [CI], −3.81 to −1.55) from month 7 to month 18 post etranacogene dezaparvovec infusion, favouring etranacogene dezaparvovec. From month 7 to month 36 post infusion, 23 of the 54 patients (42.6%) treated with etranacogene dezaparvovec had no bleeds compared with 14 of the same 54 patients (25.9%) who received FIX prophylaxis during the lead-in phase. The adjusted mean difference in ABR for all bleeding events from month 7 to month 36 was −2.65 (95% CI, −3.83 to −1.47) in favour of etranacogene dezaparvovec.

The adjusted mean difference in ABR for spontaneous bleeds between etranacogene dezaparvovec and routine FIX prophylaxis was −1.08 (95% CI, −1.72 to −0.44) from month 7 to month 18 post etranacogene dezaparvovec infusion in favour of etranacogene dezaparvovec. The adjusted mean difference in ABR for spontaneous bleeds from month 7 to month 36 was −0.93 (95% CI, −1.62 to −0.25), in favour of etranacogene dezaparvovec.

The adjusted mean difference in ABR for joint bleeds between etranacogene dezaparvovec and routine FIX prophylaxis was −1.84 (95% CI, −2.54 to −1.13) from month 7 to month 18 post infusion in favour of etranacogene dezaparvovec. The adjusted mean difference in ABR for joint bleeds from month 7 to month 36 was −1.87 (95% CI,−2.54 to −1.20), favouring etranacogene dezaparvovec.

Use of FIX After Etranacogene Dezaparvovec Infusion

From month 7 to month 18 post etranacogene dezaparvovec infusion, the adjusted mean difference in AIR between etranacogene dezaparvovec and routine FIX prophylaxis was −69.96 (95% CI, −79.77 to −60.16), which favoured etranacogene dezaparvovec. Similarly, from month 7 to month 36 post infusion, the adjusted mean difference in AIR was −69.89 (95% CI, −79.70 to −60.08), which favoured etranacogene dezaparvovec. From month 7 to month 36 post etranacogene dezaparvovec infusion, the adjusted mean difference in annualized consumption of FIX replacement therapy between etranacogene dezaparvovec and routine FIX prophylaxis was −3,037.6 IU/kg (95% CI, −3,617.4 to −2,457.9) in favour of etranacogene dezaparvovec.

Hemophilia Joint Health Score

The mean change from baseline in HJHS score was −1.6 at month 12 (SD = 5.1), −2.6 at month 24 (SD = 5.0), and −3.0 at month 36 (SD = 7.4) post etranacogene dezaparvovec infusion. All patients treated with etranacogene dezaparvovec showed improvements in HJHS total score.

Patient Reported Outcomes Burdens and Experiences Score

Change from baseline at month 12 (mean = 0.040; SD = 0.097) and at month 24 (mean = 0.034; SD = 0.113) post infusion of etranacogene dezaparvovec both showed improvements in the PROBE summary score in patients treated with etranacogene dezaparvovec. Data from month 36 were not available.

Harms Results

The data cut-off date for harm results was June 6, 2023 (i.e., 36-month data cut-off); the harms results at the 24-month data cut-off were generally consistent.

At 36 months post infusion of etranacogene dezaparvovec, all patients had at least 1 TEAE. The system organ classes with the highest incidence of reported TEAEs were infections and infestations (87.0%), followed by musculoskeletal and connective tissue disorders (72.2%), and general disorders and administration-site conditions (59.3%). The TEAEs that were reported in more than 20% of the safety population in the HOPE-B trial were arthralgia (44.4%), headache (33.3%), nasopharyngitis (27.8%), fatigue (27.8%), ALT increased (24.1%), and back pain (22.2%). During the lead-in period (excluding discontinuers), 68.5% patients experienced at least 1 TEAE. The system organ classes with the highest incidence of reported TEAEs were infections and infestations (35.2%), followed by musculoskeletal and connective tissue disorders (22.2%) and gastrointestinal disorders (13.0%). The only AE reported in more than 10% of patients was nasopharyngitis (14.8%).

At 36 months post infusion of etranacogene dezaparvovec, 27.8% of the safety population had at least 1 TESAE. The system organ classes with the most frequently reported TESAEs were infections and infestations (7.4%, consisting of 5 events: infected biloma, COVID-19, cellulitis, device-related infection, and diverticulitis intestinal hemorrhagic) and musculoskeletal and connective tissue disorders (5.6%, consisting of 3 events: hemarthrosis, musculoskeletal chest pain, and osteoarthritis). During the lead-in period (excluding discontinuers), 7.4% of the patients experienced TESAEs, of which 5.6% were reported in the system organ classes of musculoskeletal and connective tissue disorders.

One patient discontinued infusion of the study drug due to an event of hypersensitivity after approximately 10% of the full dose of the study drug had been administered; this patient did not have FIX expression. One patient died due to a fatal event of cardiogenic shock 464 days (approximately 15 months) post infusion of etranacogene dezaparvovec. According to the product monograph,² the patient, who had numerous cardiovascular and urologic risk factors and age 75 years at screening, died of urosepsis and cardiogenic shock at month 15 post dose (at age 77 years), an event that was determined to be not treatment related.

Post infusion of etranacogene dezaparvovec, an increase in ALT occurred in 24.1% (13 of 54) of the patients, followed by an increase in AST (16.7%, 9 of 54), anemia (9.3%, 5 of 54), and infusion-related reaction (5.6%, 3 of 54). Only 1 patient had anemia during the lead-in period when receiving FIX prophylaxis.

Critical Appraisal

Overall, the trial design of the pivotal HOPE-B trial (i.e., a nonrandomized, open-label, single-arm design) was considered appropriate and acceptable in the field of hemophilia B, although the interpretation of the study findings could be challenging. According to the clinical experts consulted by CADTH, the inclusion and exclusion criteria of the HOPE-B trial were appropriate and reflective of the patients they would have expected in clinical practice. It was noted that 67 patients were enrolled in the lead-in phase and only 54 patients were treated with etranacogene dezaparvovec and assessed for efficacy and safety, although it was determined by CADTH that the potential selection bias due to a considerable number of patients being excluded was low. Due to the single-arm, open-label design, reliable assessments of patient-reported outcomes, such as health-related quality of life (HRQoL) end points, could not be made. In the primary analyses, the documentation of bleeding events in the HOPE-B study relied on the use of an electronic diary (e-diary) by patients, which was also reviewed and assessed by the investigator. Based on details provided by the sponsor upon request, CADTH determined that the potential risk of bias that could lead to the exaggeration of treatment effects of etranacogene dezaparvovec (i.e., ABR outcomes) was likely low. According to the clinical experts consulted by CADTH, there were no serious concerns with the use of corticosteroids post infusion of etranacogene dezaparvovec. The conditions for the use of FIX post infusion of etranacogene dezaparvovec were generally considered appropriate and the definition of “return to routine FIX prophylaxis” in the context of the HOPE-B trial was acceptable. In the HOPE-B study, multiple statistical testing was conducted for several end points in a fixed sequence. However, multiplicity was controlled only for analyses that used data from the month 18 data cut-off and not for analyses that used data from the month 24 or month 36 data cut-offs, which might have resulted in potential inflation of the type I error rates. There were some concerns about the statistical models and assumptions adopted for bleeding outcomes in the HOPE-B study, which may pose challenges in interpreting the magnitude of the effect estimates of etranacogene dezaparvovec compared with FIX prophylaxis.

There are several considerations related to the generalizability of the HOPE-B trial. First, evidence from the currently available follow-up period (i.e., 36 months) in the HOPE-B study may not be adequate to inform long-term efficacy and safety, given the expectation of the long-lasting effects of etranacogene dezaparvovec. In addition, the HOPE-B trial included patients who had congenital hemophilia B with known severe or moderately severe FIX deficiency (≤ 2% of normal circulating FIX) and who had been on stable prophylaxis for at least 2 months before screening. However, the indication is not restricted to patients with severe or moderately severe hemophilia B (≤ 2% of normal circulating FIX), nor does it require eligible patients to have been on a stable FIX prophylaxis regimen for 2 months. According to the clinical experts consulted by CADTH, the eligibility criteria of patients in the HOPE-B study were generally aligned with the indication. However, the clinical experts consulted by CADTH noted that some patients, including those who have an FIX level greater than 2% and present severe clinical symptoms, and those who require but are not receiving stable FIX prophylaxis, may also benefit from etranacogene dezaparvovec.

According to the product monograph for etranacogene dezaparvovec, to be eligible to receive etranacogene dezaparvovec, the titre of pre-existing nAbs against AAV5 should be tested. However, patients enrolled in the pivotal HOPE-B trial were not selected based on their titre value for pre-existing nAbs against AAV5. In correspondence with CADTH, the sponsor claimed that a threshold for an acceptable AAV5 nAb, which is below 1:900, is expected to screen patients for eligibility to receive etranacogene dezaparvovec. According to the sponsor, there was no exclusion criterion in the HOPE-B study regarding the eligibility of patients with anti-AAV5 nAbs. In other words, all patients with detectable pre-existing AAV5 nAbs were enrolled. Regarding how the threshold (1:900) was determined, according to the sponsor, a cut-off at an AAV5 nAb titre of greater than 1:678 was selected based on the highest titre recorded in the subgroup of patients in the HOPE-B study with pre-existing AAV5 nAbs who showed clinically meaningful increases in FIX activity. The 1:678 titre was obtained from an in vitro cell-based assay custom-developed by the sponsor. The sponsor confirmed with Health Canada that the assay method was later validated to extend the linear measuring range with additional dilutions of the samples to be analyzed, with an improved test accuracy, especially at higher titres. The nAb titre value of 678 (rounding off to 1:700), is equivalent to a 9-point nAb titre value of 898 (rounding off to 1:900). The new 1:900 titre value is based on the updated nAb analytical validation assay with an extended linear measuring range (9-point dilution curve assay), versus the investigational clinical study assay at 7-point dilution. This does not represent a change in the concentration of the AAV5 nAb in the serum sample, but rather that the improved assay response curve of the validated method yields a comparatively higher titre.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for Grading of Recommendations Assessment, Development and Evaluation (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: ABR for all bleeding events (including percentage of patients without any bleeds), ABR for spontaneous bleeds, ABR for joint bleeds, AIR, annualized FIX consumption, HJHS, PROBE, and harms. According to the GRADE guidance, nonrandomized comparative evidence starts at low certainty and noncomparative evidence starts at very low certainty. The GRADE summary of findings is presented in Table 2 and Table 3.

Table 2: Summary of Findings for Etranacogene Dezaparvovec for Patients With Hemophilia B (Outcomes With Comparative Data)

ABR  ₌ annualized bleeding rate; AIR = annualized infusion rate; ALT = alanine transaminase; AST = aspartate aminotransferase; CI = confidence interval; FIX = factor IX; SD = standard deviation; TESAE = treatment-emergent serious adverse event.

^aThe start point for the study design (single arm with comparative data) was low certainty. Risk of bias was not rated down. Although not optimal, the study design adopted by HOPE-B was considered to be of sufficiently low risk of confounding and sampling bias. The differences between patients in the proposed indication and patients in pivotal trial were not considered sufficient by the clinical experts consulted by CADTH to result in important differences in the observed effect. Imprecision was not rated down, as the improvement was considered clinically meaningful by the clinical experts consulted by CADTH.

^bThe start point for the study design (single arm with comparative data) was low certainty. Rated down 1 level for imprecision due to the small sample size, although the safety profile was considered acceptable by the clinical experts consulted by CADTH.

^cBased on a comparison between harms data from the lead-in period and harms data from post infusion of etranacogene dezaparvovec. The median duration of the lead-in phase was 7.129 months (range, 6.05 to 10.61). The data cut-off date for harm results post infusion of etranacogene dezaparvovec was June 6, 2023 (i.e., 36-month data cut-off).

Sources: HOPE-B Clinical Study Report²⁹ and drug Reimbursement Review sponsor submission.⁵⁵

Table 3: Summary of Findings for Etranacogene Dezaparvovec for Patients With Hemophilia B (Outcomes Without Comparative Data)

HJHS = Hemophilia Joint Health Score; MID = minimal important difference; PROBE = Patient Reported Outcomes Burdens and Experiences; SD = standard deviation.

^aIn the absence of a comparator arm, certainty of evidence started at very low. The differences between patients in the proposed indication and patients in pivotal trial were not considered sufficient by the clinical experts consulted by CADTH to result in important differences in the observed effect. There was no MID identified. Imprecision was not rated down as the improvement was considered clinically meaningful by the clinical experts consulted by CADTH.

^bIn the absence of a comparator arm, certainty of evidence started at very low. Rated down 1 level for risk of bias due to potential for bias arising from the open-label nature of the study and the subjective nature of the outcome. Indirectness was not rated down, as PROBE is commonly used in Canada. Imprecision was rated down 2 levels due to change from baseline was not considered clinically relevant by the clinical experts consulted by CADTH.

Sources: HOPE-B Clinical Study Report²⁹ and drug Reimbursement Review sponsor submission.⁵⁵

Indirect Comparisons

Description of Studies

The sponsor submitted an indirect treatment comparison (ITC) report containing a feasibility assessment and analysis of etranacogene dezaparvovec relative to 4 comparator therapies: recombinant FIX albumin fusion protein (rIX-FP, Idelvion), recombinant FIX Fc fusion protein (rFIXFc, Alprolix), pegylated nonacog beta pegol (Rebinyn), and nonacog alfa (BeneFIX), using a previously published SLR to identify studies. No information was provided with respect to the search strategy, data extraction process, or quality assessment of included studies. The sponsor concluded that no connected network of evidence could be established and assessed the feasibility of unanchored comparisons. For the comparison against rIX-FP, the sponsor had patient-level data and adopted an inverse probability of treatment weighting (IPTW) approach. For comparisons against rFIXFc and pegylated nonacog beta pegol, only aggregate-level data were available, and the sponsor opted for an unanchored matching-adjusted indirect comparison (MAIC) approach. Further, for rFIXFc and pegylated nonacog beta pegol, the primary analysis population of interest — patients receiving prophylaxis — limited information was available with respect to clinical outcomes of interest and clinically relevant covariates. Owing to challenges in the reporting of data for nonacog alfa, the sponsor noted that significant limitations may confound any conclusions drawn. Accordingly, the sponsor indicated these results as a sensitivity analysis, and comparisons with nonacog alfa are not summarized in this report.

Efficacy Results

For the comparison against rFIXFc, the ABR among the unadjusted etranacogene dezaparvovec population (ABR = 0.38; N = 51) was lower than patients receiving rFIXFc (ABR = 2.99; N = 32), corresponding to a relative risk (RR) of 0.13 (95% CI, 0.07 to 0.25). When adjusted for ABR, the sponsor reported a similar trend, with the ABR-adjusted MAIC population receiving etranacogene dezaparvovec (ABR = 0.43; effective sample size [ESS] = 28.2) being lower than that of patients receiving rFIXFc (ABR = 2.99; N = 32), corresponding to an RR of 0.14 (95% CI, 0.08 to 0.25). Other efficacy end points were not available in the primary analysis population.

For the comparison against pegylated nonacog beta pegol, the unadjusted ABR for etranacogene dezaparvovec (N = 51) was 0.36, which was lower than for pegylated nonacog beta pegol (N = 17), which had an ABR of 3.33 (RR = 0.11; 95% CI, 0.06 to 0.22). A similar trend was seen following univariable adjustment for prior ABR: the RR for etranacogene dezaparvovec (ESS = 8.5) relative to pegylated nonacog beta pegol (N = 17) was 0.24 (95% CI, 0.07 to 0.82); following univariable adjustment for prior FIX product class, the RR for etranacogene dezaparvovec (ESS = 21) relative to pegylated nonacog beta pegol (N = 17) was 0.10 (95% CI, 0.03 to 0.27). Other efficacy end points were not available in the primary analysis population.

Comparisons against rIX-FP demonstrated a consistent trend in favour of etranacogene dezaparvovec with respect to ABR, ABR for spontaneous bleeds, ABR for joint bleeds, proportion of patients with no bleeds, and FIX utilization.

Harms Results

Harms were not assessed in the ITC.

Critical Appraisal

With respect to indirect treatment efficacy, the sponsor-provided ITC reported favourable comparative efficacy for the available outcomes relative to rIX-FP, pegylated nonacog beta pegol, and rFIXFc. These comparisons should be considered uncertain owing to methodological limitations due to the lack of a common comparator, which necessitated unanchored comparisons. These comparisons rely on strong assumptions of complete reporting and statistical adjustment for all plausible characteristics, which may be effect modifiers or prognostic factors. This assumption cannot be tested, and for the comparison relative to pegylated nonacog beta pegol and rFIXFc, there was a substantial proportion of missing data on key covariates. Accordingly, the results of this ITC are subject to significant uncertainty.

Conclusions

One phase III, single-arm, open-label trial (HOPE-B) investigated the efficacy and safety of etranacogene dezaparvovec in 54 male patients who had moderately severe or severe hemophilia B (defined as a normal circulation FIX of ≤ 2%) and who had been on continuous routine FIX prophylaxis. Compared with the lead-in period when patients received FIX prophylaxis, etranacogene dezaparvovec may result in a decrease in ABR for all bleeding events, ABR for spontaneous bleeds, ABR for joint bleeds, AIR, and annualized FIX consumption post infusion of the gene therapy. The effects observed for all of these outcomes were considered clinically relevant by the clinical experts consulted by CADTH. However, there is uncertainty associated with interpretating the clinical significance of the magnitude of the treatment differences due to limitations such as the nonrandomized comparative design, potential risk of bias in self-recording bleeding events caused by the open-label design, multiplicity was not controlled for in the analyses using the 24 months and 36 months data cut-offs, and potential biases introduced by assumptions in the statistical models used to make the comparisons. The harms profile of etranacogene dezaparvovec during the follow-up period was considered acceptable by the clinical experts consulted by CADTH, despite that more harms events occurred post infusion of etranacogene dezaparvovec than those when patients were receiving FIX prophylaxis during the lead-in period. The harms evidence is limited, given the relatively short follow-up period and small sample size. A key gap in the pivotal trial evidence is that results remain unknown with respect to the long-term efficacy and safety of etranacogene dezaparvovec relative to FIX prophylaxis due to the current duration of follow-up (i.e., 36 months). One ITC provided efficacy data on the estimated effect of etranacogene dezaparvovec relative to rIX-FP (Idelvion), rFIXFc (Alprolix), and pegylated nonacog beta pegol (Rebinyn). No conclusions could be drawn on the relative efficacy from the ITC. The interpretation of the effect magnitude is uncertain and hindered by the lack of available connected evidence and potential confounding due to the lack of reporting of potentially influential prognostic and predictive factors. No safety data were reported in the sponsor-submitted ITC; therefore, no conclusions could be drawn on the comparative safety of etranacogene dezaparvovec versus other products based on this evidence.

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 etranacogene dezaparvovec (Hemgenix) 1 × 10¹³ gc/mL suspension for IV infusion for the treatment of adults (aged 18 years or older) with hemophilia B (congenital FIX deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

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 CADTH review team.

Hemophilia is a serious X chromosome–linked, lifelong genetic disorder that leaves patients vulnerable to blood loss and organ damage due to impaired functioning of the coagulation cascade.^3,4 In general, hemophilia is inherited through an X chromosome with an F8 or F9 gene mutation, while approximately 30% of all cases result from spontaneous mutations.⁶ Hemophilia B is the second-most common type of hemophilia (after hemophilia A) and is characterized by an absence or shortage of FIX resulting from a mutation in the F9 gene.^3,4 FIX is a vital component of the intrinsic coagulation cascade pathway, which is activated in response to vascular endothelium surface damage.¹¹ Once initiated, the enzymes in the coagulation cascade activate in sequence until fibrin, a clot-forming protein, is produced.^11,12 A FIX deficiency in hemophilia B prevents or reduces the ability of the coagulation cascade to produce fibrin.⁵

The severity of hemophilia B generally correlates with the degree of clotting factor deficiency.⁶ Moderate and severe hemophilia B cases are defined by the World Federation of Hemophilia as having 1% to 5% and less than 1% of normal enzymatic FIX activity, respectively.⁶ Moderately severe hemophilia has also been defined in previous clinical trials that have investigated treatment with prophylaxis as having a factor level of 1% to 2%.¹³ However, according to the clinical experts consulted by CADTH, in clinical practice, severity is determined based not only on FIX activity level but also on clinical phenotype. The development of FIX inhibitors is considered the most serious complication in patients with hemophilia B, since it renders current treatments ineffective and is associated with risks of anaphylaxis and nephrotic syndrome.⁶ The development of FIX inhibitors in hemophilia B is a rare event (1.5% to 3.0% of all patients) but is associated with significant morbidity.¹⁴

The clinical manifestations of hemophilia B are easy bruising and episodes of prolonged bleeding from surgery or trauma.⁴ In patients with moderate or severe hemophilia, spontaneous, serious, and life-threatening internal bleeding into joints, muscles, and vital organs may also occur.⁴ The frequency of spontaneous bleeding episodes is variable in patients with severe disease but may occur up to 20 or 30 times per year after minor trauma.^4,15 The majority of spontaneous bleeds occur in the joints (70% to 80%) and muscles (10% to 20%).⁶ Less than 5% of bleeds occur in the central nervous system, e.g., intracranial hemorrhage, but these are particularly serious and debilitating, potentially leading to seizures, impaired motor function, or death in up to 20% of cases.^6,16,17 Individuals with moderately severe to severe hemophilia frequently experience bleeding events and recurrent spontaneous bleeding into muscle, soft tissue, and joints (hemarthroses) starting in infancy and continuing throughout adulthood.^4,18 However, bleeds can occur in any organ, and affected organs can include kidneys, stomach, intestines, and brain.^4,6,19 Hemarthrosis is the most common manifestation of moderately severe to severe hemophilia B.^4,6

As of 2021, there were 704 patients with hemophilia B (with recorded severity) in Canada, 535 of whom were adult males. Of the adult male patients, 218 had moderate and 145 had severe hemophilia B.⁷ The mean prevalence per 100,000 males in Canada from 1998 to 2006 was 3.23.²⁰ The estimated prevalence at birth per 100,000 males in Canada from 1991 to 2015 was 3.9 for all severities of hemophilia B and 1.3 for severe disease only.⁸ According to a Statistics Canada report in 2021, around 30% of patients with hemophilia B had severe disease.²¹

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 CADTH review team.

Current treatment strategies for hemophilia B target symptom relief and prevention of permanent tissue damage and are based on replacing the missing coagulation factor, which can be done either as needed when bleeding episodes occur (on-demand therapy) or in a preventive manner (prophylaxis). The goal of prophylaxis is to prevent bleeding in patients with hemophilia while allowing them to live an active life and achieve a quality of life comparable to that of people without hemophilia.⁹ According to the clinical experts consulted by CADTH, FIX prophylaxis therapy, involving lifelong regular IV administration of FIX, is the preferred management approach for patients with moderately severe or severe hemophilia.

Both recombinant FIX and plasma-derived FIX are used for FIX prophylactic therapy.⁶ Recombinant FIX products are manufactured using genetically engineered cells and recombinant technology, while plasma-derived FIX products are made from plasma donated by human blood donors in Canada. One plasma-derived product (Immunine) is reimbursed; however, recombinant FIX products are predominantly used to treat patients with hemophilia B.¹⁰ The recombinant FIX products approved by Health Canada include rFIXFc (Alprolix), nonacog alfa (BeneFIX), rIX-FP (Idelvion), pegylated nonacog beta pegol (Rebinyn), and recombinant FIX nonacog gamma for injection (Rixubis).²² Among these products, rFIXFc, nonacog alfa, and pegylated nonacog beta pegol are funded by CADTH-participating drug programs; rIX-FP and recombinant FIX nonacog gamma for injection are only available in Quebec.²² Patients have access to FIX prophylaxis therapy through Canadian Blood Services.

Drug Under Review

Key characteristics of etranacogene dezaparvovec compared with other treatments available for adults (aged 18 years or older) with hemophilia B (congenital FIX deficiency) are summarized in Table 4.

Etranacogene dezaparvovec is a gene therapy designed to introduce a copy of the human FIX gene into hepatocytes to address the root cause of hemophilia B disease.² Etranacogene dezaparvovec consists of a codon-optimized coding DNA sequence of the gain-of-function Padua variant of human FIX, under control of the liver-specific LP1 promoter, encapsulated in a nonreplicating recombinant AAV5.

Etranacogene dezaparvovec is indicated for the treatment of adults (aged 18 years or older) with hemophilia B (congenital FIX deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.²³ Etranacogene dezaparvovec must be administered intravenously as a single dose of 2 × 10¹³ genome copies per kilogram (gc/kg) of body weight after dilution with 0.9% sodium chloride solution (normal saline).²³ Following a single IV infusion, etranacogene dezaparvovec preferentially targets liver cells, where the vector DNA resides almost exclusively in episomal form. Subsequent to transduction, etranacogene dezaparvovec directs long-term liver-specific expression of the FIX Padua protein using a liver-specific promoter (LP1). As a result, etranacogene dezaparvovec partially or completely ameliorates the deficiency of circulating FIX procoagulant activity found in patients with hemophilia B, restoring the hemostatic potential and limiting bleeding episodes and the need for exogenous FIX treatment.²³

Of note, according to the product monograph for etranacogene dezaparvovec, to be eligible to receive etranacogene dezaparvovec, the titre of pre-existing nAbs against AAV5 should be tested. However, patients enrolled in the pivotal HOPE-B trial were not selected based on a titre of pre-existing nAbs against AAV5. In correspondence with CADTH, the sponsor claimed that a threshold for an acceptable AAV5 nAb, which is below 1:900, is expected to be used to screen patients in clinical practice for eligibility to receive etranacogene dezaparvovec. According to the sponsor, there was no exclusion criterion in the HOPE-B study regarding the eligibility of patients with anti-AAV5 nAbs. In other words, all patients with detectable pre-existing AAV5 nAbs were enrolled. Regarding how the threshold (1:900) was determined, according to the sponsor, a cut-off of greater than 1:678 AAV5 nAbs was selected based on the highest titre recorded in the subgroup of patients in the HOPE-B study with pre-existing AAV5 nAbs who showed clinically meaningful increases in FIX activity. The 1:678 titre was obtained from an in vitro cell-based assay custom-developed by the sponsor. The sponsor confirmed with Health Canada that the assay method was later validated to extend the linear measuring range with additional dilutions of the samples to be analyzed, with an improved test accuracy, especially at higher titres. The nAb titre value of 678 (rounding off to 1:700), is equivalent to a 9-point nAb titre value of 898 (rounding off to 1:900). The new 1:900 titre value is based on the updated nAb analytical validation assay with an extended linear measuring range (9-point dilution curve assay), versus the investigational clinical study assay at 7-point dilution. This does not represent a change in the concentration of the AAV5 nAb in the serum sample, but rather that the improved assay response curve of the validated method yields a comparatively higher titre.

Table 4: Key Characteristics of Etranacogene Dezaparvovec, rFIXFc, Pegylated Nonacog Beta Pegol, Nonacog Alfa, and FIX Concentrate (Human)

AAV = adeno-associated virus; Fc = fusion protein; FIX = factor IX; FXIa = activated factor XI; gc = genome copy; rFIXFc = recombinant factor IX Fc fusion protein.

^aHealth Canada–approved indication.

^bFor comparators, dose is for prophylaxis in adult patients.

Sources: CSL Behring Canada,²³ Sanofi (2021),²⁴ Novo Nordisk (2022),²⁵ Pfizer (2017),²⁶ Takeda Canada Inc.²⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section of this report.

Patient input was gathered by the CHS from an online survey conducted from July 10 to October 12, 2023. A total of 49 responses were gathered by the CHS. All respondents were affected by severe or moderately severe hemophilia B without inhibitors. Prior to this, in September 2022, the CHS conducted an online survey of people in Canada with severe hemophilia A or B. It received 39 responses: 31 patients reported having hemophilia A, 7 had hemophilia B, and 1 respondent did not specify their hemophilia type.

Joint damage, primarily to knees, ankles, and elbows, caused by repeated internal hemarthroses, was reported to be the primary physical health impact of hemophilia B. Regarding the currently available treatments, 5 patients who responded to the 2023 CHIS survey reported being very satisfied, 14 said they were satisfied, 7 said they were neither satisfied nor dissatisfied, and 1 indicated they were very dissatisfied. The patients from this survey noted that treatments greatly complicate their everyday life, travel, and leisure activities. They also mentioned the difficulty in receiving infusion treatments due to problems with vein visibility, issues with poor veins, and side effects. Patients also reported facing socioeconomic problems caused by, for example, having to miss work due to the need for regular visits, travel and insurance issues, and access issues.

When the patients with hemophilia B and caregivers who responded to the July 2023 CHS survey were asked how gene therapy could potentially change their lives, all respondents provided positive feedback. Patients hope gene therapy would lead to fewer FIX infusions, minimal needle injections, less stress, less bleeding, and fewer restrictions on activities, and enable them to travel more easily. In addition, more than 6 out of 10 respondents (63%) from the 2022 survey indicated they expected gene therapy to be effective in preventing bleeding for at least 10 years. The 2022 survey asked whether respondents would choose to receive gene therapy knowing there would be frequent blood draws in the weeks and months following administration, and they would need to be followed up in a registry for 10 to 20 years. In response, 66% answered yes, 10% answered no, and 24% indicated they did not know.

The CHS mentioned that a small number of people in Canada (approximately 5) have undergone gene therapy for hemophilia B, but the organization knows nothing about the experience of these patients outside the preliminary data from the trials.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH 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). In addition, as part of the review of etranacogene dezaparvovec, a panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with this condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion follows.

Unmet Needs

The goal of treatment of hemophilia B, according to the clinical experts consulted by CADTH, is to not only prevent major bleeds and long-term joint damage but also to give patients living with hemophilia B the freedom to participate in physical and social activities without restrictions, pursue the career or job to which they aspire, and provide patients with physical and mental well-being (essentially, to enable them to live a normal life). The clinical experts consulted by CADTH noted that the current standard of care in Canada for hemophilia B is IV replacement therapy with the missing clotting factor (i.e., FIX) and, unlike hemophilia A, there are currently no approved subcutaneous nonfactor therapies for patients with hemophilia B.

According to the clinical experts consulted by CADTH, there are several unmet needs for hemophilia B. First, people with hemophilia B have a life disadvantage and quality of life disadvantage compared with the general population, as there is no treatment available to reverse the course of the disease. In addition, a therapy that reduces the burden of treatment and improves adherence is needed. Although effective in restoring hemostasis, current FIX replacement therapy requires recurrent IV injections, which may result in a high burden of treatment and hinder adherence for people with hemophilia B (e.g., delayed or missed doses and overall suboptimal treatment due to poor venous access and other difficulties related to the preparation for the FIX regimen). Moreover, even with good adherence to treatment, bleeding events still happen in many patients because not all patients with hemophilia B respond to currently available treatments.

Place in Therapy

According to the clinical experts consulted by CADTH, etranacogene dezaparvovec is a gene therapy for hemophilia B that would provide a potential curative option (i.e., a long-term phenotypic cure) by addressing the underlying disease process, which may represent a shift in the current treatment paradigm.

The clinical experts consulted by CADTH noted that given the novel mechanism and the curative intent, etranacogene dezaparvovec should be offered to all patients who are eligible, and it is not necessary to reserve etranacogene dezaparvovec only for people with hemophilia B who are intolerant to other treatments or only if other treatments are contraindicated. According to the clinical experts consulted by CADTH, it is not necessary to recommend that patients try other treatments before initiating treatment with etranacogene dezaparvovec, given that the only current alternative for patients with hemophilia B with no FIX inhibitors is FIX replacement therapy, and given that etranacogene dezaparvovec is indicated for adult patients who would have been treated with FIX replacement therapy for many years. The clinical experts consulted by CADTH noted that patients’ values and preferences and considerations about how to manage health resources should play an important role in the use of etranacogene dezaparvovec, considering that the current efficacy and safety evidence on etranacogene dezaparvovec is limited (e.g., small number of participants in the pivotal HOPE-B trial, uncertainty about the long-term efficacy and safety).

Patient Population

Regarding the patients with hemophilia B who may be best suited for this therapy, the clinical experts consulted by CADTH noted it is conceivable to give priority to those patients who: have a severe bleeding phenotype, have difficult venous access or experience a high treatment burden with FIX prophylaxis, have recurrent bleeds despite prophylaxis or have difficulty being adherent to a prophylaxis regimen, or need to have sustained FIX levels because of comorbidities (e.g., joint disease, cardiovascular issues that require antiplatelets or anticoagulants). In addition to meeting criteria on nAbs against FIX and AAV, the clinical experts consulted by CADTH noted that the ideal patient should be willing and available to comply with requirements, such as the need to attend follow-up visits at the hemophilia treatment centre, allow laboratory monitoring, and abstain from alcohol post infusion.

According to the clinical experts consulted by CADTH, patients suitable for etranacogene dezaparvovec should be identified at a hemophilia treatment centre. The clinician would complete an assessment of eligibility based on their clinical judgment and lab tests (e.g., complete blood count and differential, liver and kidney functions, FIX activity, and FIX inhibitor status). The other tests that would be required would be for infectious diseases, including HIV, hepatitis B, and hepatitis C. The availability of results on pre-existing nAbs against AAV5 vectors is the first step in eligibility assessment, as the only patients who are eligible must have a pre-existing neutralizing AAV5 antibody titre below 1:900. In their assessment, the clinician may include the ABR; the HJHS, utilization of factor replacement therapy, and the annualized number of FIX infusions, the patient’s adherence to the prescribed treatment, the patient’s venous access, and HRQoL outcome measures. Imaging studies, such as abdominal ultrasound and liver ultrasound with elastography (i.e., FibroScan), will be needed to assess liver health before the infusion of this liver-directed gene therapy.

According to the clinical experts consulted by CADTH, etranacogene dezaparvovec should not be given to pediatric patients with hemophilia B (aged < 18 years), while there is no concern using etranacogene dezaparvovec in patients aged 65 years and older with hemophilia B. Additionally, patients with uncontrolled HIV infection or advanced liver fibrosis may not be eligible for etranacogene dezaparvovec.

The clinical experts consulted by CADTH noted there are currently no clinical or laboratory predictors of the treatment response. According to these experts, a recent study conducted by Shah et al. (2023)²⁸ that was based on statistical modelling may provide some perspective: the models predicted that no more than 6 of 55 (10.91%) of observed participants would have FIX activity levels of less than 2% up to 25.5 years post etranacogene dezaparvovec infusion.

Assessing the Response Treatment

The clinical experts consulted by CADTH noted that the most important assessment for treatment response is to monitor patients’ bleeding to observe whether etranacogene dezaparvovec prevents bleeding events and allows patients to live the lifestyle they want without concern for the risk of bleeding. The clinical experts further noted that FIX activity level may also be monitored to assess response to treatment, which could allow clinicians to determine the degree to which the deficiency in FIX has been corrected by etranacogene dezaparvovec. Of note, the clinical experts consulted by CADTH noted that, in general, higher FIX activity level is associated with better bleeding outcomes (e.g., no bleeding). However, in some cases, there is a discrepancy between FIX activity level and bleeding outcomes.

The clinical experts consulted by CADTH noted that follow-up should focus on both efficacy and safety through clinical follow-ups (e.g., checking patients’ bleeding events and joint status via phone, virtual, or in-person check-ups) and lab tests (e.g., liver enzymes, FIX activity levels, liver ultrasound to detect hepatocarcinomas). The length of follow-up for hepatic function and FIX activity levels post infusion of etranacogene dezaparvovec should be lifelong. In terms of frequency, the clinical experts consulted by CADTH noted that postinfusion monitoring of etranacogene dezaparvovec will be more frequent in the short term (e.g., for the first 3 months post infusion, monitoring will include twice-a-week lab tests, mainly for liver enzymes and FIX level, starting around week 3 post infusion, or the lab tests will be conducted twice weekly initially and then once weekly) and less frequently over the long term (e.g., after the first 3 months, quarterly visits for the balance of the first year and then yearly visits for life, or monthly visits for the balance of the first year and then only as clinically indicated). The clinical experts consulted by CADTH noted that testing of FIX levels may not start immediately post infusion, given that the production of FIX by etranacogene dezaparvovec is unlikely to happen immediately after treatment, although it would be reasonable to monitor FIX activity level and liver function tests twice a week at the early postinfusion stage.

The clinical experts consulted by CADTH noted that post etranacogene dezaparvovec infusion, it will also be important to monitor changes in HJHS as well as in end points related to quality of life (QoL) (e.g., improvement in activities of daily living and physical activity and functioning, decrease in development of disability, improvement in psychosocial health and functioning). Of note, the clinical experts stated that, for measuring QoL among patients with hemophilia B in the Canadian setting, the PROBE tool is usually used instead of the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) and Hemophilia Activities List, although these instruments are very much aligned in measuring QoL, and PROBE includes questions that cover activities of daily life.

Discontinuing Treatment

“Discontinuation of treatment” is not a concept that is applicable to gene therapy, which is a 1-time treatment. To define treatment failure of etranacogene dezaparvovec, the clinical experts consulted by CADTH further noted that the composite of FIX level (e.g., patient’s baseline FIX level before receiving etranacogene dezaparvovec) and return to prophylaxis with hemostatic therapy (e.g., per the definition provided in the HOPE-B trial) could be used to determine whether a treatment failure occurred in patients treated with etranacogene dezaparvovec. The clinical experts consulted by CADTH also noted that determining treatment failure should be done case by case and based on the judgment of the treating clinician.

Prescribing Considerations

The clinical experts consulted by CADTH noted that the prescribing of etranacogene dezaparvovec should be based on the judgment of a multidisciplinary team, organized by a comprehensive hemophilia treatment centre and consisting of specialists such as a hematologist with experience in treating patients with hemophilia, a physiotherapist to assess joint function, a hepatologist for liver-related issues, pharmacy support, and an HIV specialist if the patient is HIV positive.

According to the clinical experts consulted by CADTH, etranacogene dezaparvovec can be administered in a specialty clinic in the outpatient setting, with longitudinal follow-up. Currently, according to the clinical experts consulted by CADTH, all patients in Canada with clinically severe hemophilia are routinely followed in Canadian hemophilia treatment centres.

With respect to the roles of hemophilia treatment centres in administering etranacogene dezaparvovec and following up patients, the clinical experts consulted by CADTH did not reach consensus, noting 2 possible models. The first is a hub-and-spoke model in which selected hemophilia treatment centres in Canada would serve as infusion sites; patients would travel to the closest dosing site for infusion. The setting would likely be in the hospitals where the hemophilia clinics are located (outpatient clinics). Following infusion, the patients would then be monitored by their local hemophilia treatment centre.

Another model is that every hemophilia treatment centre in Canada would be able to infuse etranacogene dezaparvovec without the need for a hub-and-spoke model, given that these centres have always operated independently in incorporating innovative therapies into their clinical contexts and there is nothing special about the infusion of etranacogene dezaparvovec itself. Regarding the second model, the clinical experts consulted by CADTH acknowledged that it is the ideal scenario, as every hemophilia treatment centre would be able to administer etranacogene dezaparvovec. In reality, some hemophilia treatment centres will set up more quickly than others. The clinical experts consulted by CADTH noted that no matter which model is adopted, it should not create inequities between provinces and territories.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by the clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section of this report.

A total of 8 clinicians from the AHCDC provided input for this CADTH review of etranacogene dezaparvovec. The AHCDC highlighted some unmet needs for patients with hemophilia with the severe bleeding phenotype, specifically, hemophilia B. The AHCDC mentioned that the currently available treatments in Canada do not modify or alter the underlying disease process, thus making patients with hemophilia B dependent on regular IV infusions of FIX to prevent and treat bleeding for their whole life. In addition, the AHCDC highlighted the frequent venipuncture required for prophylactic CFC replacement. The group noted this can be a major challenge to routine prophylaxis for patients with poor venous access, and there can be long-term complications with the placement of a central venous catheter, including a risk of infection, bleeding, thromboembolism, and loss of function, requiring catheter removal. The group emphasized that all these factors lead to the need for patients with hemophilia B and a severe bleeding phenotype to restore the coagulation factor to clinically effective levels without the need for frequent venipunctures on a regular basis throughout their lifespan. The AHCDC also mentioned the variability of the efficacy of prophylaxis with CFCs across individuals, which makes some patients susceptible to breakthrough bleeding into joints and muscles. The group noted that these breakthrough bleeds result in pain, loss of function, absences from work or school, reduced QoL and, more importantly, disability from progressive joint damage. Lastly, the AHCDC highlighted that the FIX trough levels associated with prophylaxis regimens are often insufficient to allow for safe anticoagulation or dual antiplatelet therapy.

The AHCDC noted that gene therapy provides a possibility of long-term phenotypic cure for patients with hemophilia B. If effective, the new treatment option could provide a 1-time treatment leading to sustained FIX production, thus addressing the underlying disease process. This may represent a paradigm shift in the treatment of hemophilia B. The AHCDC also mentioned that in contrast to patients with hemophilia A, who have the option of emicizumab, patients with hemophilia B have no current alternatives to treatment with CFCs outside of clinical trials, making the need for gene therapy greater for patients with hemophilia B.

The AHCDC indicated that eligible candidates for the gene therapy under review include those with a clinically severe bleeding phenotype requiring prophylaxis, no history of inhibitory antibodies, no significant comorbidities, and an anti-AAV nAb titre of less than 1:900. The group also added that patients with hemophilia who are not currently receiving prophylactic therapy (e.g., due to poor venous access or adherence issues with routine prophylaxis) but who experience repeated, serious spontaneous bleeding episodes or have a history of life-threatening hemorrhage, are also candidates for gene therapy. The AHCDC highlighted that it is difficult to estimate the proportion of patients with hemophilia who would be eligible for gene therapy once it becomes commercially available due to the need for an anti-AAV antibody assay, a detailed liver assessment, and an assessment of the patient’s attitudes and perceptions.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s 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 CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

AAV5 = adeno-associated virus serotype 5; CDEC = Canadian Drug Expert Committee; FIX = factor IX; nAb = neutralizing antibody.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of etranacogene dezaparvovec (Hemgenix) 1 × 10¹³ gc/mL suspension for IV infusion for the treatment of adults (aged 18 years or older) with hemophilia B (congenital FIX deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The focus will be placed on comparing etranacogene dezaparvovec with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence provided by the sponsor for this review of etranacogene dezaparvovec is presented in 2 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and randomized controlled trials that were selected according to the sponsor’s systematic review protocol. CADTH’s 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 indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 1 pivotal phase III, open-label, single-arm study (including a lead-in phase before the infusion of etranacogene dezaparvovec to prospectively collect efficacy and safety data that served as a comparison) was identified in the systematic review

• 1 ITC containing analyses of etranacogene dezaparvovec relative to 4 comparator therapies: rIX-FP (Idelvion), rFIXFc (Alprolix), pegylated nonacog beta pegol (Rebinyn), and nonacog alfa (BeneFIX).

Systematic Review

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

Description of Studies

One study (HOPE-B)²⁹ met the inclusion criteria of the sponsor-submitted SLR. The characteristics of the HOPE-B trial are summarized in Table 6.

HOPE-B is a phase III, open-label, single-dose, single-arm, multicentre trial investigating the use of etranacogene dezaparvovec for the treatment of adult male patients with moderately severe to severe hemophilia B (defined as normal circulation FIX ≤ 2%).^1,30 A total of 54 patients from 33 study sites globally received etranacogene dezaparvovec and were followed for efficacy and safety. The primary objective of the HOPE-B trial was to demonstrate the noninferiority of etranacogene dezaparvovec to reduce ABR for all bleeding events during the 52 weeks following establishment of stable FIX expression (months 7 to 18) compared with standard of care (i.e., continuous routine FIX prophylaxis). The superiority of etranacogene dezaparvovec was also examined.

The HOPE-B study is ongoing and expected to be completed in 2025. An analysis performed 36 months post dose (data cut-off date of June 6, 2023) was used to support the sponsor’s present reimbursement request to CADTH.¹ Of note, regardless of the date of initiation into the study, the data cut included up to 36 months of patient follow-up information.

Table 6: Details of Study Included in the Systematic Review

AAV5 = adeno-associated virus of serotype 5; ABR = annualized bleeding rate; AIR = annualized infusion rate; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; EQ-5D-5L = 5-Level EQ-5D; FIX = factor IX; gc = genome copy; Haem-A-QoL = Haemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HBV = hepatitis C virus; HCV = hepatitis C virus; HJHS = Hemophilia Joint Health Score; IMP = investigational medicinal product; nAb = neutralizing antibody; RNA = ribonucleic acid; ULN = upper limit of normal; VAS = visual analogue scale.

Note: Visit L-Final refers to the final visit of the lead-in phase.

Sources: HOPE-B Clinical Study Protocol Version 8.0³⁰ and the HOPE-B Clinical Study Report.²⁹ Details included in the table are from the sponsor’s summary of clinical evidence.¹

The study design schema of the HOPE-B trial is shown in Figure 1. In general, the HOPE-B study consists of the screening phase, lead-in phase, etranacogene dezaparvovec infusion phase, and posttreatment follow-up phase. During the lead-in phase, patients received continuous FIX prophylaxis and were followed up for at least 6 months (i.e., 26 weeks). A predefined washout period of 3 days for regular-acting FIX products and 10 days for extended half-life (EHL) FIX products occurred between screening and the lead-in phase. Outcome data collected from the lead-in phase served as the comparator for etranacogene dezaparvovec for some efficacy end points. For patients who completed the lead-in phase and received etranacogene dezaparvovec infusion (n = 54), the median duration of the lead-in phase was 7.129 months (range, 6.05 to 10.61). According to the sponsor’s clarification,³⁴ monitoring of treatment compliance during the lead-in phase was captured in patient diaries, but no summary-level statistics were generated from these diaries.

Figure 1: Study Design Schema of the HOPE-B Study

ABR = annualized bleeding rate; FIX = factor IX; GC = genome copy; SOC = standard of care; vs = versus.

^a At least quarterly contact (± 2 weeks) between site staff and patients to monitor occurrence of adverse events.

Source: Sponsor’s summary of clinical evidence.¹

Populations

Inclusion and Exclusion Criteria

Eligible patients in the HOPE-B study were male, aged 18 years or older, with a diagnosis of congenital hemophilia B that was classified as a moderately severe or severe FIX deficiency (defined as ≤ 2% of normal circulation FIX) for which patients had received continuous routine treatment with an FIX prophylaxis totalling more than 150 exposure days. Patients had to have been on stable prophylaxis treatment for at least 2 months before screening. Patients were excluded if they had a history of FIX inhibitors or tested positive for FIX inhibitors at the last visit of the lead-in period and during the screening period of the HOPE-B trial. Of note, according to the sponsor, pre-existing nAbs against AAV5 were not used as an exclusion criterion in the HOPE-B study.

Interventions

In the HOPE-B study, etranacogene dezaparvovec was administered as a single IV infusion at a dose of 2 × 10¹³ gc/kg of body weight over approximately 3 hours.

Outcomes

A list of the efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. The summarized end points are based on the outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review, according to the clinical experts consulted by CADTH and the input received from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team listed the end points considered to be most relevant to inform CADTH’s expert committee deliberations, in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Table 7: Outcomes Summarized From the HOPE-B Trial

ABR = annualized bleeding rate; AIR = annualized infusion rate; FIX = factor IX; HJHS = Hemophilia Joint Health Score; PROBE = Patient Reported Outcomes Burdens and Experiences; QoL = quality of life.

^aPROBE data were obtained from patients who volunteered to participate in the optional PROBE questionnaire substudy. The objective of this substudy was to provide data complementary to the compendium of established patient-reported outcome tools regarding the impact of gene therapy on patient-relevant outcomes and QoL over time. According to the sponsor, the 36-month data for PROBE are not available.

Source: HOPE-B Clinical Study Protocol Version 8.0.³⁰

Descriptions of efficacy and safety outcomes presented in the HOPE-B study and appraised in the CADTH Clinical Review are as follows.^30,35

Efficacy Outcomes

Annualized Bleeding Rate

In its correspondence,³⁶ the sponsor specified that ABR for all bleeding events refers to any untreated and treated bleeds regardless of bleeding types. Spontaneous bleeds are unprovoked bleeding events, which means there are no known reasons for a bleed.

The ABR is a ratio calculated as the number of bleeds divided by the length of observation (in years). Bleeding events were recorded in an e-diary by patients. According to clarification from the sponsor, the e-diary includes the infusion and bleeding diary and the daily evening diary. Patients were required to complete the infusion and bleeding diary to report any new information as it became available (e.g., reporting an FIX infusion, bleeding as soon as it occurred, or bleeding cessation). The patients were also required to complete the evening diary once a day. The purpose of the evening diary was to remind patients to enter new information, if they had forgotten to add necessary documentation to the infusion and bleeding diary during the day, or confirm that no new information needed to be entered. When a bleeding event was recorded, the study centre was contacted to review the record and assess the bleeding event. However, bleeds were counted irrespective of assessments by the investigator as to the trueness or newness of the bleed, except in the case of certain sensitivity analyses.

Annualized Infusion Rate

The yearly infusion rate of FIX replacement therapy, excluding replacement for invasive procedures, was determined for the lead-in and posttreatment periods. The number of infusions of exogenous FIX was counted for each patient during both the lead-in and postinfusion periods.

Annualized Consumption of FIX Replacement Therapy

The annualized consumption of FIX replacement therapy was calculated as the normalized amount of drug administered per baseline weight (before the lead-in period); these data were extrapolated, when necessary, for any time period that was less than or greater than 1 year. “Therapy administered” included the total amount of FIX given as replacement therapy, excluding any FIX administered for invasive procedures. Having no record of exogenous FIX use meant zero consumption.

Descriptions of the HJHS and PROBE measures are shown in Table 8.

Table 8: Summary of Outcome Measures and Their Measurement Properties

EQ VAS = EQ visual analogue scale; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score; HRQoL = health-related quality of life; MID = minimal important difference; PROBE = Patient Reported Outcomes Burdens and Experiences; WFH = World Federation of Hemophilia.

Harms Outcomes

The harms outcomes assessed in the HOPE-B study included TEAEs, TESAEs, withdrawals due to AEs, mortality, and notable harms (e.g., ALT increased, AST increased). An AE was considered to be a TEAE if the event occurred after the administration of etranacogene dezaparvovec, or if the AE worsened during the study after the infusion of etranacogene dezaparvovec (e.g., intensity and/or severity changed to a worse grade). AEs were coded using the Medical Dictionary for Regulatory Activities.

Statistical Analysis

In the HOPE-B trial, the primary objective was to test for noninferiority of etranacogene dezaparvovec against FIX prophylaxis for the treatment of ABR. Post treatment, all bleeding events between month 7 and month 18 post infusion of etranacogene dezaparvovec were counted toward the reported ABR. A simulation study of ABR was conducted using a negative binomial distribution with a yearly event rate of 2.4 for the lead-in period and a rate of 1.9 for the period post infusion of etranacogene dezaparvovec. An individual-level Pearson correlation of 0.05 was used to induce a relationship between the number of events occurring within the 2 periods and a common dispersion parameter of 1.5. The results of the simulation study informed a necessary sample size of at least 50 analyzable patients to reject a null hypothesis of noninferiority using a noninferiority margin of 1.8 for the rate ratio of ABR and a power of 82.0% at the 0.025 significance level.

For analyses with data from the month 18 data cut-off, formal statistical testing of the efficacy end points was performed using the closed testing principle for type I error control for multiple testing. Unless otherwise specified, each end point tested for statistical significance was tested for superiority at a 1-sided alpha level of 0.025. Fixed sequential testing was performed using a hierarchical approach that continued until a nonsignificant result was obtained. The following is the order of the fixed sequential tests:

1. ABR comparison between etranacogene dezaparvovec and prophylaxis for noninferiority between the lead-in and the 52 weeks following 7 to 18 months of stable FIX expression post treatment (etranacogene dezaparvovec).

2. Endogenous FIX activity 6 months after etranacogene dezaparvovec dosing.

3. Endogenous FIX activity 12 months after etranacogene dezaparvovec dosing.

4. Endogenous FIX activity 18 months after etranacogene dezaparvovec dosing.

5. Annualized consumption of FIX replacement therapy, excluding FIX replacement for invasive procedures, during the 52 weeks following 7 to 18 months of stable FIX expression post treatment compared with the lead-in phase.

6. AIR of FIX replacement therapy, excluding FIX replacement for invasive procedures, during the 52 weeks following 7 to 18 months of stable FIX expression post treatment compared with the lead-in phase.

7. Comparison of the percentage of patients with a trough FIX activity of less than 12% of normal between the lead-in phase and after treatment with etranacogene dezaparvovec 52 weeks after 7 to 18 months of stable FIX expression.

8. ABR comparison between etranacogene dezaparvovec and prophylaxis for superiority between the lead-in and the 52 weeks following 7 to 18 months of stable FIX expression post treatment.

9. Rate of spontaneous bleeding events during the 52 weeks following 7 to 18 months of stable FIX expression post treatment compared with the lead-in phase.

10. Rate of joint bleeding events during the 52 weeks following 7 to 18 months of stable FIX expression post treatment compared with the lead-in phase.

11. Patient-reported outcome questionnaire scores from the International Physical Activity Questionnaire (total physical activity score) during the 12 months following etranacogene dezaparvovec dosing compared with the lead-in phase.

12. Patient-reported outcome questionnaire scores from the EQ visual analogue scale during the 12 months following etranacogene dezaparvovec dosing compared with the lead-in phase.

Of note, according to the sponsor, no tabulations pertaining to type I error control were required for analyses using data generated from follow-up after month 18 post infusion of etranacogene dezaparvovec (e.g., the month 36 analyses), and all P values and associated statements of significance were not controlled for multiplicity. Details on the statistical analysis of efficacy end points in the HOPE-B study are presented in Table 9.

Table 9: Statistical Analysis of Efficacy End Points in the HOPE-B Study

AAV5 = adeno-associated virus serotype 5; ABR = annualized bleeding rate; AIR = annualized infusion rate; CI = confidence interval; FAS = full analysis set; FIX = factor IX; HJHS = Hemophilia Joint Health Score; NA = not applicable; NR = not reported; PP = per protocol; PROBE = Patient Reported Outcomes Burdens and Experiences.

Sources: HOPE-B Clinical Study Protocol Version 8.0,³⁰ HOPE-B Statistical Analysis Plan, version 5.0,³⁵ sponsor’s summary of clinical evidence.¹

Analysis Populations

The analysis populations of the HOPE-B trial are summarized in Table 10.

Table 10: Analysis Populations of the HOPE-B Trial

FAS = full analysis set; NA = not applicable; PP = per protocol.

Sources: HOPE-B Clinical Study Protocol Version 8.0³⁰ and HOPE-B Clinical Study Report.²⁹ Details included in the table are from the sponsor’s summary of clinical evidence.¹

Protocol Amendments and Deviations

In total, there were 8 versions of the study protocol, including the original protocol (February 16, 2018) and 7 amendments (the seventh amendment was made on June 21, 2021). In the original protocol, endogenous FIX activity at 6 months post infusion of etranacogene dezaparvovec was the only primary end point. In protocol amendment 4, ABR following 52 weeks post infusion of etranacogene dezaparvovec was added as a primary end point. In protocol amendment 6, FIX activity was removed from primary outcomes, and ABR following 52 weeks post infusion of etranacogene dezaparvovec was revised to ABR from months 7 to 18 post infusion of etranacogene dezaparvovec (i.e., 52 weeks following establishment of stable FIX expression). The majority of protocol deviations were related to the timing of study visits, questionnaire completion, or absence or incorrect performance of laboratory tests.

Results

Patient Disposition

A summary of patient disposition in the HOPE-B study is presented in Table 11. In the HOPE-B trial, 67 patients met the eligibility criteria and entered the lead-in phase. Of the 67 patients, 53 received etranacogene dezaparvovec, 1 patient received a partial dose (i.e., 10%) of etranacogene dezaparvovec due to hypersensitivity but remained for posttreatment follow-up, and 13 patients discontinued or were excluded before infusion of etranacogene dezaparvovec. The reasons for the discontinuation or exclusion of the 13 patients included ineligible due to screen failure (8 patients), withdrawal of consent (3 patients), and other (i.e., 2 patients withdrew due to COVID-19 pandemic-related concerns).

Overall, 52 of 54 patients completed 24 months of follow-up post administration of etranacogene dezaparvovec. Among the 2 patients who received the full dose etranacogene dezaparvovec but did not complete 24 months of follow-up, 1 patient died 464 days (approximately 15 months) post infusion and 1 patient remained on routine prophylaxis and withdrew consent 24 months post infusion of etranacogene dezaparvovec (month 24 visit not completed). As of the data cut-off date for the 36-month follow-up, 52 patients had been followed for at least 3 years post treatment and were continuing in the study.

Table 11: Summary of Patient Disposition From the HOPE-B Trial Included in the Systematic Review

FAS = full analysis set; NA = not applicable; PP = per protocol; PROBE = Patient Reported Outcomes Burdens and Experiences.

Sources: HOPE-B Clinical Study Protocol Version 8.0³⁰ and Clinical Study Report.²⁹ Details included in the table are from the sponsor’s summary of clinical evidence.¹

Baseline Characteristics

The baseline characteristics outlined in Table 12 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. All patients in the HOPE-B trial were adult males. Among the 54 patients who received etranacogene dezaparvovec (posttreatment safety population or full analysis set), the majority of patients were white (74.1%) with a mean age of 41.5 (SD = 15.8) years. Among the 54 patients at baseline, 21 (38.9%) had pre-existing nAbs against AAV5 before infusion of etranacogene dezaparvovec, while 33 (61.1%) did not.

The last testing before infusion of etranacogene dezaparvovec showed that 21 of the 54 patients (38.9%) had a titre between 1:9 and 1:3,212 (median = 1:56.9). Excluding 1 patient with an anti-AAV5 titre greater than 1:3,000 (i.e., 1:3,212), the remaining 20 patients had a titre between 1:9 and 1:678 (median = 1:49.1). There were 33 patients (62.3%) with an anti-AAV5 nAb titre below the lower limit of detection (i.e., 1:7).

Exposure to Study Treatments

In the HOPE-B study, of the 54 patients who received etranacogene dezaparvovec, 53 received a single full dose of 2 × 10¹³ gc/kg etranacogene dezaparvovec. One patient received a partial dose (about 10% of the expected dose) before the patient withdrew due to hypersensitivity that occurred during infusion.

Prior and Concomitant Treatments

Prior to the infusion of etranacogene dezaparvovec, among the 54 patients who completed the lead-in period, 4 patients (7.4%) were treated with corticosteroids. The mean number of days with corticosteroid treatment was 1.3 days (SD = 0.6 days), with a range of between 1 and 2 days.

Chronic administration of corticosteroids was not allowed during the HOPE-B study; however, the use of corticosteroids for conditions such as an increase in AST or ALT was permitted.³⁰ During the 24-month postinfusion period, 20 out of 54 patients (37.0%) received systemic corticosteroids. The mean number of days with corticosteroid use was 41.6 days (SD = 45.6 days) and ranged from 1 to 130 days. Reasons for corticosteroid use included transaminase elevation (9 of 54 patients; 16.7%), infusion reactions (3 of 54; 5.6%), and other (11 of 54; 20.4%), such as dental rehabilitation, surgery prophylaxis, immune response against the vector, allergies, pain, preoperative anti-inflammatory use, nephrolithiasis, tendovaginitis stenosans, liver transplant, left mandibular fracture, shoulder pain, facet joint injection to the L4 or L5 vertebrae, and prevention of postoperative nausea and vomiting. The mean number of days with corticosteroid use was 81.4 days (SD = 28.6) and ranged from 51 to 130 days during the 36-month postinfusion period. Between 24 and 36 months after the infusion period, no additional patients received systemic corticosteroids for transaminase elevation.

Table 12: Summary of Baseline and Clinical Characteristics From the HOPE-B Trial

BMI = body mass index; FAS = full analysis set; FIX = factor IX; SD = standard deviation.

^aAge was the age at the time of informed consent.

^bDuration was calculated based on the date the patient was initially diagnosed with hemophilia B according to the case report form.

^cUnknown as to whether spontaneous or traumatic.

^dFIX replacement therapy in the year before screening; patients may have received on-demand and then prophylactic FIX replacement therapy in this time period.

^ePrior or ongoing per reported medical history. All patients tested negative predose.

^fPatients positive at screening were given a rating of “hepatitis C virus RNA = detected” for hepatitis. Patients were positive at screening and negative at the final visit during the lead-in phase.

Sources: HOPE-B Clinical Study Report.²⁹ Note details included in the table are from the sponsor’s summary of clinical evidence.¹

Use of FIX Treatment Post Etranacogene Dezaparvovec Infusion

Patients were permitted to continue administration of their continuous routine FIX treatment on the day of etranacogene dezaparvovec infusion and in the first weeks following infusion to provide sufficient FIX coverage for the initial days post treatment. During the follow-up post infusion, if the endogenous FIX activity result was 5% or greater, continuous routine FIX prophylaxis was discontinued, and further management was based on the investigator’s clinical judgment and patient preference. Continuation or reinitiation of continuous routine FIX prophylaxis could be considered if the endogenous FIX activity was between 2% and 5% in at least 2 consecutive laboratory tests, based on the investigator’s clinical judgment and patient preference. If endogenous FIX activity was less than 2%, continuous routine prophylaxis was continued or reinstated. Additional on-demand and/or intermittent prophylactic FIX treatment could be given after treatment with etranacogene dezaparvovec, if considered necessary.³⁰

Return to routine FIX prophylaxis was defined as having at least 80% of the time being “contaminated” by an exogenous FIX treatment administered during a contiguous 3-month period on or subsequent to the start of month 7 post infusion. At 24 months post infusion of etranacogene dezaparvovec, 52 of the 54 patients had not resumed FIX prophylaxis treatment (i.e., remained free of the previous FIX prophylaxis treatment they had received); as of the 36-month cut-off, 51 patients had not resumed FIX prophylaxis treatment.

Efficacy

Key efficacy results in the full analysis set of the HOPE-B trial are presented in Table 13.

ABR for All Bleeding Events

During the lead-in phase while they were being treated with FIX prophylaxis, 14 of the 54 patients (25.9%) in the study experienced no bleeds; from month 7 to month 18 post etranacogene dezaparvovec infusion, 34 of the same 54 patients (63.0%) experienced no bleeds. The adjusted mean difference in ABR for all bleeding events between etranacogene dezaparvovec and routine FIX prophylaxis was −2.68 (95% CI, −3.81 to −1.55) from month 7 to month 18 post etranacogene dezaparvovec infusion, favouring etranacogene dezaparvovec.

From month 7 to month 36 post infusion of etranacogene dezaparvovec, 23 of the 54 patients (42.6%) treated with etranacogene dezaparvovec had no bleeds compared with 14 of the same 54 patients (25.9%) who did not experience bleeds during the lead-in period while receiving FIX prophylaxis. The adjusted mean difference in ABR for all bleeding events from month 7 to month 36 was −2.65 (95% CI, −3.83 to −1.47) in favour of etranacogene dezaparvovec.

Results from the sensitivity analysis that included only FIX-treated bleeds showed that from month 7 to month 18 post infusion of etranacogene dezaparvovec, the adjusted ABR for etranacogene dezaparvovec and FIX prophylaxis was 0.84 (95% CI, 0.41 to 1.72) and 3.62 (95% CI, 2.79 to 4.71), respectively (rate ratio = 0.23; 95% CI, 0.12 to 0.45). From month 7 to month 36 post infusion of etranacogene dezaparvovec, the adjusted ABR for etranacogene dezaparvovec and FIX prophylaxis was 1.15 (95% CI, 0.53 to 2.51) and 3.62 (95% CI, 2.79 to 4.71), respectively (rate ratio = 0.32; 95% CI, 0.15 to 0.67).

Results from the sensitivity analysis that included only bleeds assessed to be new and true by the investigator showed that from month 7 to month 18 post etranacogene dezaparvovec infusion, the adjusted ABR for etranacogene dezaparvovec and FIX prophylaxis was 1.04 (95% CI, 0.52 to 2.09) and 3.83 (95% CI, 2.93 to 5.01), respectively (rate ratio = 0.27; 95% CI, 0.14 to 0.52). From month 7 to month 36 post etranacogene dezaparvovec infusion, the adjusted ABR for etranacogene dezaparvovec and FIX prophylaxis was 1.04 (95% CI, 0.57 to 1.89) and 3.83 (95% CI, 2.93 to 5.01), respectively (rate ratio = 0.27; 95% CI, 0.16 to 0.47).

One of the 54 patients had an anti-AAV5 titre greater than 1:3,000 during the last testing before the infusion of etranacogene dezaparvovec. In the 53 patients who had an anti-AAV5 nAb titre of less than 3,000 (median = 49.1; range, 1:9 to 1:678), ABR results showed that from months 7 to 18 post etranacogene dezaparvovec infusion, the adjusted ABR for etranacogene dezaparvovec and FIX prophylaxis was 1.07 (95% CI, 0.63 to 1.81) and 3.88 (95% CI, 2.90 to 5.17), respectively (rate ratio = 0.27; 95% CI, 0.17 to 0.43). From months 7 to 36 post infusion, the adjusted ABR for etranacogene dezaparvovec and FIX prophylaxis was 1.07 (95% CI, 0.65 to 1.76) and 3.88 (95% CI, 2.90 to 5.17), respectively (rate ratio = 0.28; 95% CI, 0.17 to 0.46).

ABR for Spontaneous Bleeds

The adjusted mean difference in ABR for spontaneous bleeds between etranacogene dezaparvovec and routine FIX prophylaxis was −1.08 (95% CI, −1.72 to −0.44) from month 7 to month 18 post etranacogene dezaparvovec infusion in favour of etranacogene dezaparvovec. The adjusted mean difference in ABR for spontaneous bleeds from month 7 to month 36 was −0.93 (95% CI, −1.62 to −0.25), in favour of etranacogene dezaparvovec.

ABR for Joint Bleeds

The adjusted mean difference in ABR for joint bleeds between etranacogene dezaparvovec and routine FIX prophylaxis was −1.84 (95% CI, −2.54 to −1.13) from month 7 to month 18 post etranacogene dezaparvovec infusion in favour of etranacogene dezaparvovec. The adjusted mean difference in ABR for joint bleeds from month 7 to month 36 was −1.87 (95% CI, −2.54 to −1.20), favouring etranacogene dezaparvovec.

AIR of FIX Replacement Therapy

From month 7 to month 18 post etranacogene dezaparvovec infusion, the adjusted mean difference in AIR between etranacogene dezaparvovec and routine FIX prophylaxis was −69.96 (95% CI, −79.77 to −60.16) in favour of etranacogene dezaparvovec. Similarly, from month 7 to month 36 post etranacogene dezaparvovec infusion, the adjusted mean difference in AIR was −69.89 (95% CI, −79.70 to −60.08), which favoured etranacogene dezaparvovec.

Annualized Consumption of FIX Replacement Therapy

From month 7 to month 36 post etranacogene dezaparvovec infusion, the adjusted mean difference in annualized consumption of FIX replacement therapy between etranacogene dezaparvovec and routine FIX prophylaxis was −3,037.6 IU/kg (95% CI, −3,617.4 to −2,457.9) in favour of etranacogene dezaparvovec.

Hemophilia Joint Health Score

All patients treated with etranacogene dezaparvovec showed improvement in total HJHS score, with a mean change from baseline of −1.6 (SD = 5.1) at month 12, −2.6 (SD = 5.0) at month 24, and −3.0 (SD = 7.4) at month 36 post infusion.

Patient Reported Outcomes Burdens and Experiences

Change from baseline at month 12 (mean = 0.040; SD = 0.097) and month 24 (mean = 0.034; SD = 0.113) post infusion of etranacogene dezaparvovec both showed improvements in the PROBE summary score in patients treated with etranacogene dezaparvovec. Data from month 36 were not available.

Table 13: Summary of Key Efficacy Results From the HOPE-B Trial (Full Analysis Set)

ABR = annualized bleeding rate; AIR = annualized infusion rate; CI = confidence interval; FIX = factor IX; HJHS = Hemophilia Joint Health Score; PROBE = Patient Reported Outcomes Burdens and Experiences; SD = standard deviation.

^aPostinfusion period refers to the number of days of observation within the time interval, excluding information before day 21.

^bUnadjusted ABR was calculated as the ratio of the number of bleeds to the time of observation (in years).

^cAdjusted ABR (parametric model estimate) and comparison of ABR between the lead-in and posttreatment period were estimated from a repeated measures generalized estimating equations negative binomial regression model accounting for the paired design of the trial with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate.

^dUnadjusted AIR was calculated as the ratio of the number of infusions of FIX to the time of observation (in years). Usage related to invasive procedures is not included.

^eAdjusted AIR (parametric model estimate) and comparison of infusion rate between the lead-in and posttreatment period were estimated from a repeated measures generalized estimating equations negative binomial regression model accounting for the paired design of the trial with an offset parameter to account for the differential collection periods. Treatment period is included as a categorical covariate.

^fThe HJHS total score ranges from 0 to 124. A higher score is considered unfavourable.

^gThe PROBE summary score ranges from 0 to 1.00. A higher score indicates better health.

Sources: HOPE-B Clinical Study Report²⁹ and drug Reimbursement Review sponsor submission.⁵⁵

Harms

A summary of harms in the HOPE-B study is shown in Table 14. The data cut-off date for harm results was June 6, 2023 (i.e., 36-month data cut-off). Harms results at the 24-month data cut-off were generally consistent.

Adverse Events

At 36 months post infusion of etranacogene dezaparvovec, all patients had at least 1 TEAE. The system organ classes with the highest incidence of reported TEAEs were infections and infestations (87.0%), followed by musculoskeletal and connective tissue disorders (72.2%) and general disorders and administration-site conditions (59.3%). The TEAEs reported in more than 20% of the safety population of the HOPE-B trial were arthralgia (44.4%), headache (33.3%), nasopharyngitis (27.8%), fatigue (27.8%), ALT increased (24.1%), and back pain (22.2%).

During the lead-in period (excluding discontinuers), 68.5% patients experienced at least 1 TEAE. The system organ classes with the highest incidence of reported TEAEs were infections and infestations (35.2%), followed by musculoskeletal and connective tissue disorders (22.2%) and gastrointestinal disorders (13.0%). The only AE reported in more than 10% of patients was nasopharyngitis (14.8%).

Serious Adverse Events

At 36 months post infusion of etranacogene dezaparvovec, 27.8% of the safety population had at least 1 serious TESAE. The system organ classes with the highest incidence of reported TESAEs were infections and infestations (7.4% of patients), consisting of 5 events (biloma infected, COVID-19, cellulitis, device-related infection, diverticulitis intestinal hemorrhagic), and musculoskeletal and connective tissue disorders (5.6% of patients), consisting of 3 events (hemarthrosis, musculoskeletal chest pain, osteoarthritis).

During the lead-in period (excluding discontinuers), 7.4% of patients experienced TESAEs, of which 5.6% were reported in the system organ classes of musculoskeletal and connective tissue disorders.

Withdrawals Due to Adverse Events

One patient discontinued infusion of the study drug due to an event of hypersensitivity after approximately 10% of the full dose of study drug was administered; this patient did not have FIX expression.

Mortality

One patient died due to a fatal event of cardiogenic shock 464 days (approximately 15 months) post infusion of etranacogene dezaparvovec. According to the product monograph,² the patient, who was aged 75 years at screening and had numerous cardiovascular and urologic risk factors, died of urosepsis and cardiogenic shock at month 15 post dose (aged 77 years), an event that was determined to be not treatment related.

Notable Harms

Post infusion of etranacogene dezaparvovec, an increase in ALT occurred in 24.1% of patients (13 of 54), followed by an increase in AST (9 of 54; 16.7%), anemia (5 of 54; 9.3%), and infusion-related reaction (3 of 54; 5.6%). Only 1 patient had anemia during the lead-in period when receiving FIX prophylaxis.

Table 14: Summary of Harms Results in the HOPE-B Study (Safety Population)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; FIX = factor IX.

^aDiscontinuers were excluded from the lead-in period.

Sources: HOPE-B Clinical Study Report²⁹ and drug Reimbursement Review sponsor submission.⁵⁵

Internal Validity

The only eligible study identified in the sponsor-conducted SLR was HOPE-B (N = 54), a phase III, nonrandomized, single-arm, open-label clinical trial that included a lead-in phase (i.e., patients were on FIX prophylaxis for at least 6 months) before the infusion of etranacogene dezaparvovec. The data collected from patients during the lead-in phase were used as a self-control to measure some etranacogene dezaparvovec safety and efficacy outcomes (e.g., ABR for all bleeding events, ABR for spontaneous bleeds, ABR for joint bleeds, AIR, and annualized FIX consumption). Overall, the trial design (e.g., nonrandomized, open label, single arm) was considered appropriate and acceptable in the field of hemophilia B, although the interpretation of the study findings could be challenging and limited.

According to the clinical experts consulted by CADTH, the inclusion and exclusion criteria for the HOPE-B trial were appropriate and generally reflected the patients they would expect to treat in clinical practice. It was noted that 67 patients were enrolled in the lead-in phase and only 54 patients were treated with etranacogene dezaparvovec, which was assessed for efficacy and safety. However, it was determined by CADTH that the potential selection bias, due to a considerable number of patients being excluded, was low. First, the reasons for excluding 13 patients during the lead-in phase were considered reasonable. Second, according to the clinical experts consulted by CADTH, the baseline and clinical characteristics for the 54 patients who received etranacogene dezaparvovec versus the 67 patients who entered the lead-in phase were generally similar, suggesting that the population receiving treatment was not expected to be systematically different from the lead-in study population.

Patient compliance with FIX prophylaxis treatment during the lead-in phase remained unclear, as the sponsor stated in its correspondence with CADTH that summary-level statistics on compliance were not available. Due to the single-arm, open-label design, reliable assessments of patient-reported outcomes (e.g., HRQoL end points) could not be made. In the primary analyses, the documentation of bleeding events in the HOPE-B study relied on the use of an e-diary by patients, the contents of which were reviewed and assessed by the investigator. Based on details provided by the sponsor upon request, CADTH determined that the potential risk of bias that might lead to the exaggeration of the treatment effects of etranacogene dezaparvovec (i.e., ABR outcomes) was likely low. Results from the sensitivity analyses, which included only bleeds assessed to be new and true by the investigator, were consistent with the results from the primary analyses.

In the HOPE-B trial, participants were allowed to receive corticosteroids post infusion of etranacogene dezaparvovec for conditions such as an increase in AST or ALT. According to the clinical experts consulted by CADTH, there were no serious concerns with the use of corticosteroids post infusion. In addition, the rate ratios from the sensitivity analysis for etranacogene dezaparvovec and FIX prophylaxis for ABR for all bleeding events, which excluded periods with systemic corticosteroid use post infusion of etranacogene dezaparvovec, were similar to the rate ratios from the primary analyses (data not shown).

According to the clinical experts consulted by CADTH, the conditions for use of FIX prophylaxis post infusion of etranacogene dezaparvovec were generally considered appropriate, and so was the definition of “return to routine FIX prophylaxis” in the context of the HOPE-B trial. A sensitivity analysis that included time intervals for exogenous FIX use during the postinfusion period shows similar results for ABR for all bleeding events, suggesting that a postinfusion FIX prophylaxis regimen may not modify the treatment effects of etranacogene dezaparvovec.

In the HOPE-B study, multiple statistical tests were conducted for several end points in a fixed sequence. However, multiplicity was controlled only for analyses using data from the month 18 data cut-off and not for analyses with data from the month 24 or month 36 data cut-offs, which might have resulted in potential inflation of the type I error rates. There were some concerns about the assumptions for the statistical model that were adopted to inform the relative efficacy of etranacogene dezaparvovec against FIX prophylaxis. The first assumption was that the rate of bleeding during FIX prophylaxis in the lead-in phase would be comparable to the bleeding rate post infusion of etranacogene dezaparvovec during the follow-up phase, provided FIX prophylaxis had not been discontinued and etranacogene dezaparvovec had not been given as an intervention. This assumption was considered reasonable by the clinical experts consulted by CADTH. This assumption is required to interpret the differences observed in bleeding rates before and after treatment with etranacogene dezaparvovec in the HOPE-B study. The second assumption — that the negative binomial mixed model implies a constant bleed rate within each period of study — can make it challenging to interpret the magnitude of the effect estimates of etranacogene dezaparvovec compared with FIX prophylaxis. Specifically, the reported estimates of the relative ABRs describe a weighted average of the rate of bleeding over time that is dependent on the observed censoring mechanism. This weighted average can be overly optimistic and fail to accurately capture waning efficacy over time.

External Validity

There are several considerations related to the generalizability of the HOPE-B trial. First, the evidence from the currently available follow-up period (i.e., 36 months) in the HOPE-B study may not be adequate to inform long-term efficacy and safety, given the expectation of the long-lasting effects of etranacogene dezaparvovec.

In addition, the HOPE-B trial included patients who had congenital hemophilia B with known severe or moderately severe FIX deficiency (≤ 2% of normal circulating FIX) and who had been on stable prophylaxis for at least 2 months before screening. However, the indication does not restrict treatment to patients with severe or moderately severe hemophilia B (≤ 2% of normal circulating FIX) or require eligible patients to have been on a stable FIX prophylaxis regimen for 2 months. According to the clinical experts consulted by CADTH, the eligibility criteria for patients in the HOPE-B study were generally aligned with the indication. However, the clinical experts also noted that some patients, including those who have a FIX level greater than 2% and present severe clinical symptoms, and patients who require but are not receiving stable FIX prophylaxis treatment, may also benefit from etranacogene dezaparvovec.

The indication does not specify sex or gender (i.e., it includes both men and women), while the product monograph states that etranacogene dezaparvovec is not intended for administration in women. The pivotal HOPE-B trial enrolled only male patients, per the trial protocol.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and randomized controlled trials identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^56,57

• 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.”

According to GRADE guidance, nonrandomized comparative evidence starts at low certainty and noncomparative evidence starts at very low certainty. The CADTH review team carefully assessed the risk of selection bias and the potential for unmeasured confounding of the pivotal intrapatient single-arm trial, which compared bleeding pre- and post intervention. The GRADE report captures the study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of assessment of the certainty of the evidence 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 reference points for the assessment of the certainty of the evidence for ABR for all bleeding events were set according to the presence or absence of an important effect based on thresholds informed by the sponsor and agreed upon by the clinical experts consulted by CADTH for this review. The target of the assessment of the certainty of the evidence was the presence or absence of any (non-null) effect for ABR for spontaneous bleeds, ABR for joint bleeds, AIR, and annualized FIX consumption due to the lack of a formal MID estimate. The certainty of the evidence was summarized narratively for HJHS, PROBE, and harms outcomes either due to lack of comparators or lack of formal statistical testing.

Results of GRADE Assessments

Table 2 and Table 3 present the GRADE summary of findings in the HOPE-B study for etranacogene dezaparvovec versus FIX prophylaxis in adult patients with hemophilia B.

Indirect and Other Comparative Evidence

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

Objectives for the Summary of Indirect Evidence

Evidence for the efficacy of etranacogene dezaparvovec was assessed using the pivotal single-arm HOPE-B trial. Accordingly, head-to-head comparative efficacy has not been established against products that may be relevant to patients in Canada with hemophilia B. As such, the sponsor provided an ITC and other comparative evidence using patient-level data as evidence of the comparative efficacy of etranacogene dezaparvovec versus other therapies.

Description of the Indirect Treatment Comparison

The sponsor submitted 1 ITC report for review that used a previously conducted SLR published in a peer-reviewed journal in 2019 as its source of information on available trial evidence within the same analysis population.⁵⁸ Owing to a lack of connected evidence, the sponsor performed a feasibility assessment on conducting an ITC between etranacogene dezaparvovec and the following comparator therapies and their associated clinical trials: rIX-FP (Idelvion) from the PROLONG-9FP study,⁵⁹ rFIXFc (Alprolix) from the B-LONG study,⁶⁰ pegylated nonacog beta pegol (Rebinyn) from the Paradigm 2 study,⁶¹ and nonacog alfa (BeneFIX) from the study NCT00093171.⁶² The sponsor noted that none of the identified trials had shared treatment nodes, and therefore indicated that approaches such as network meta-analysis were not feasible. Owing to limitations in reporting data, the sponsor did not conduct indirect comparisons relative to nonacog alfa, as the sponsor was unable to identify sufficient information on patient baseline characteristics or outcome definitions for comparison. For the setting in which patient-level data were available for both etranacogene dezaparvovec and rIX-FP, the sponsor used an inverse-weighted estimator of group differences; for rFIXFc and pegylated nonacog beta pegol, the sponsor used an unanchored MAIC approach to overcome the absence of patient-level data.

Indirect Treatment Comparison Design

Objectives

The objective of the sponsor-submitted ITC was to determine the comparative efficacy of etranacogene dezaparvovec against rIX-FP, rFIXFc, pegylated nonacog beta pegol, and nonacog alfa for the prophylactic treatment of severe or moderately severe hemophilia B.

Study Selection Methods

The sponsor utilized a published SLR⁵⁸ for its evidence generation (Table 15). The sponsor reported that this published review accessed PubMed and Embase for data, but no information was provided on the review process with respect to duplicate reviews or adjudications. No further details were provided regarding the process used to extract data or to assess quality.

Table 15: Study Selection Criteria and Methods for ITCs Submitted by the Sponsor

ABR = annualized bleeding rate; FIX = factor IX; gc = genome copy; ITC = indirect treatment comparison; pdFIX = plasma-derived factor IX; rFIX = recombinant factor IX; rFIXFc = recombinant factor IX Fc fusion protein; rIX-FP = recombinant factor IX albumin fusion protein.

Sources: Sponsor-submitted ITC;⁶³ details included in the table are from the sponsor’s summary of clinical evidence.¹

ITC and Other Comparative Analysis Methods

The ITC and other comparative analysis methods are summarized in Table 16. The sponsor noted that among the included studies, no common comparator was identified. As unanchored comparisons were necessary, the sponsor described a process to identify potentially clinically relevant covariates that could be considered as part of the feasibility assessment and adjusted for in subsequent analyses. To identify the relevant covariates to adjust for in treating bleeding rates in patients with hemophilia B, the sponsor conducted a ranked order questionnaire. The questionnaire was completed by 5 clinicians, 3 from the sponsor’s organization and 2 external physicians from unspecified UK organizations outside of the sponsor’s organization. The physicians were asked to consider which covariates were relevant prognostic factors or treatment-effect modifiers and to rank them in order of importance for each of the efficacy outcomes considered: ABR, ABR for spontaneous bleeds, and ABR for joint bleeds. The top 5 ranked factors for ABR were severity of hemophilia B, prior ABR, prior FIX regimen (prophylactic versus on demand), prior presence of target joints, and age. For FIX consumption, the top 5 ranked factors were severity of hemophilia B, prior FIX regimen (prophylactic versus on demand), prior ABR, prior presence of target joints, and prior FIX product class (EHL versus standard half-life [SHL]). For patient-reported outcomes, the top 5 ranked factors were severity of hemophilia B, prior ABR, prior FIX regimen (prophylactic versus on demand), prior presence of target joints, and age. No quantitative data or references were provided with respect to the impact of any of the listed covariates of potential interest.

For ABR, ABR for spontaneous bleeds, and ABR for joint bleeds, the remaining clinical factors that were assessed were, in order: prior FIX product class (EHL versus SHL), body mass index (BMI), weight, prior exposure days of treatment with an FIX protein, prior FIX product use, ALT threshold, AST threshold, history of FIX inhibitor antibodies, HIV status, total bilirubin threshold, family member with FIX inhibitor antibodies, and duration of diagnosed hemophilia B. For FIX consumption, the remaining clinical factors assessed were, in order: BMI, age, prior exposure days of treatment with an FIX protein, weight, ALT threshold, prior FIX product use, total bilirubin threshold, history of FIX inhibitor antibodies, family member with FIX inhibitor antibodies, HIV status, AST threshold, and duration of diagnosed hemophilia B.

The order of assessment was considered during model selection. The sponsor provided univariable adjustments performed sequentially, with MAIC or IPTW analyses run separately, adjusting for 1 additional factor at a time as per the ranked importance scale noted previously. The sponsor indicated it had attempted to balance ESS against improvements in the between-treatment standardized mean differences, although the criteria for what qualified as balance were not provided.

For ABR, ABR for spontaneous bleeds, and ABR for joint bleeds, the remaining clinical factors that were assessed were, in order: prior FIX product class (EHL versus SHL), BMI, weight, prior exposure days of treatment with an FIX protein, prior FIX product use, ALT threshold, AST threshold, history of FIX inhibitor antibodies, HIV status, total bilirubin threshold, family member with FIX inhibitor antibodies, and duration of diagnosed hemophilia B. For FIX consumption, the remaining clinical factors that were assessed were, in order: BMI, age, prior exposure days of treatment with an FIX protein, weight, ALT threshold, prior FIX product use, total bilirubin threshold, history of FIX inhibitor antibodies, family member with FIX inhibitor antibodies, HIV status, AST threshold, and duration of diagnosed hemophilia B. During the sponsor’s feasibility assessment, it was noted that the trial data for nonacog alfa were not considered appropriate for use in an unanchored MAIC analysis. Specifically, the sponsor noted that within the nonacog alfa trial, patient demographic details were available only for age, race, prior FIX product class status, and family members with a history of FIX inhibitor antibodies. As such, many of the identified prognostic and treatment effect–modifying factors were not available to be incorporated within the sponsor’s model. Further, the sponsor noted that these characteristics were reported only for the total trial population and not just the population utilizing nonacog alfa in the prophylactic setting. With respect to outcomes, the identified trial assessing nonacog alfa prophylaxis was not noted as having a definition for how bleeds were counted for ABR. As such, the sponsor did not conduct any formal analyses for the comparison of etranacogene dezaparvovec versus nonacog alfa. The sponsor did provide unadjusted comparisons within the methods section for nonacog alfa but, owing to the methodological issues identified by the sponsor, these comparisons are not reported within this CADTH review.

For the inverse-weighted comparison of etranacogene dezaparvovec versus rIX-FP, the sponsor excluded patients from the rIX-FP trial to ensure the population included in the analysis aligned with the enrolment criteria of the HOPE-B trial. Specifically, patients from the PROLONG-9FP study were removed if: they were aged 12 to 17 years (n = 7), had an ALT level greater than twice the upper limit of normal (n = 2), or had an AST level greater than twice the upper limit of normal (n = 2).

For the ITCs comparing etranacogene dezaparvovec with rFIXFc and pegylated nonacog beta pegol, each analysis consisted of different patient populations. For the rFIXFc trial, the primary analysis population was restricted to a subset of patients receiving weekly prophylaxis. For the pegylated nonacog beta pegol trial, the primary analysis population was restricted to patients who had received background prophylaxis with FIX products before the trial. In both cases, the primary analysis population lacked detailed patient demographics. Secondary analyses were conducted in a broader patient population without focusing solely on patients who received prophylaxis with FIX products before the trial. This was done because there was more comprehensive reporting on patient baseline characteristics for the broader patient population. Two patients out of 53 (4%) from the HOPE-B trial (assessing etranacogene dezaparvovec) were not included in any of the ITCs. One patient was excluded due to data protection requirements, and 1 patient was excluded because they had an anti-AAV5 nAb titre greater than 3,000 at baseline, whereas the planned etranacogene dezaparvovec label will exclude patients with anti-AAV5 nAb titres greater than 700. The sponsor noted that, before reviewing any data from the submitted analyses, both patients were excluded by study teams that were outside of those involved in the generation of the report.

Statistical Methods for rIX-FP Comparison

For the IPTW approach comparing etranacogene dezaparvovec with rIX-FP, the sponsor utilized entropy balancing⁶⁴ using first and second (mean and variance) moments for patient weights, an equivalent methods-of-moment estimator. Weighted generalized linear regression with negative binomial distribution and a log link were used for rate outcomes, or a logit link for binary outcomes, and linear regression was used for continuous outcomes. A binomial distribution with a logit link function (i.e., logistic regression) was used for binary outcomes containing the proportion of patients with no events during the randomized period (i.e., percentage with 0 ABR events, percentage with 0 ABR events for spontaneous bleeds, and percentage with 0 ABR events for joint bleeds). Standard errors were estimated using the sandwich estimator. A Gaussian (normal) distribution with an identity link function (i.e., linear regression) was used for the continuous annualized FIX consumption outcome. Standard errors were estimated using the sandwich estimator.⁶⁵ These sandwich standard errors were used to construct 2-sided 95% Wald CIs and the associated testwise P values for comparisons. Relative treatment effects were transformed into the natural scale (e.g., RR, odds ratio, mean difference) after estimation.

Statistical Methods for rFIXFc Comparison

For the comparison of etranacogene dezaparvovec versus rFIXFc, the propensity score was estimated using a method-of-moments estimator. The comparative estimate from the HOPE-B study was derived using a weighted, intercept-only generalized linear model. A negative binomial distribution with a log link function was used for the following rate outcomes: ABR (total), ABR for spontaneous bleeds, and ABR for joint bleeds. the model-reported intercept is an estimate of the ABR-related outcome on the log scale in a hypothetical scenario in which patients from the respective comparator trial received etranacogene dezaparvovec. Specifically, a binomial distribution with logit link function (i.e., logistic regression) was used for a binary outcome and the percentage with 0 ABR events (i.e., the proportion of patients who did not experience any ABR events in the trial period), where the intercept represents the log odds of the outcome of interest had patients from the respective comparator trial received etranacogene dezaparvovec. Standard errors were estimated using the sandwich estimator.⁶⁵ These sandwich standard errors were used to construct 2-sided 95% Wald CIs and the associated testwise P values for comparisons.

Statistical Methods for Pegylated Nonacog Beta Pegol Comparison

For the comparison of etranacogene dezaparvovec versus pegylated nonacog beta pegol, the propensity score was estimated using a method-of-moments estimator. The comparative estimate from the HOPE-B study was derived using a weighted, intercept-only generalized linear model, and appropriate distributions and link functions were used to ensure that a suitable scale was used for estimation per outcome, applying the patient weights. The model-reported intercept is an estimate of the ABR-related outcome on the log scale in a hypothetical scenario in which patients from the respective comparator trial received etranacogene dezaparvovec. Specifically, a binomial distribution with a logit link function (i.e., logistic regression) was used for binary outcomes containing the percentage of patients with 0 ABR events (i.e., the proportion of patients who did not experience any ABR events in the trial period), where the intercept represents the log odds of the outcome of interest had patients from the respective comparator trial received etranacogene dezaparvovec. A Poisson distribution with log link function was used for ABR (total) and ABR for spontaneous bleeds outcomes. The choice of model was based on the assumed model of the reported estimates within the pegylated nonacog beta pegol trial. Standard errors were estimated using the sandwich estimator.⁶⁵ These sandwich standard errors were used to construct 2-sided 95% Wald CIs and the associated testwise P values for comparisons.

Table 16: ITC Analysis Methods

ABR = annualized bleeding rate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATC = average treatment effect in the comparator; ATT = average treatment effect in the treated; BMI = body mass index; ESS = effective sample size; FIX = factor IX; Haem-A-QoL = Haemophilia Quality of Life Questionnaire for Adults; IPD = individual patient data; IPTW = inverse probability of treatment weighting; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; rFIXFc = recombinant factor IX Fc fusion protein; rIX-FP = recombinant factor IX albumin fusion protein; SMD = standardized mean difference.

^aFor univariable analysis with multiple covariates, the sponsor provided multiple univariable-adjusted comparisons individually.

Sources: Sponsor-submitted ITC;⁶³ details included in the table are from the sponsor’s summary of clinical evidence.¹

Results of Sponsor-Submitted ITC

Summary of Included Studies

The assessment of homogeneity for the sponsor-submitted ITC is shown in Table 17. None of the included trials were found to have shared treatment regimens. Trials were broadly similar with respect to hemophilia B severity, though there was noted variability in ABR before randomization and treatment across the trials, ranging from 3.35 (PROLONG-9FP study) through to 7.49 (Paradigm 2 study). Clinical definitions were broadly similar across the trials, although the PROLONG-9FP study’s primary analysis definitions for bleeding events were noted by the sponsor to be more restrictive compared with other studies. The duration of follow-up and design varied, predominantly because the PROLONG-9FP study had a treatment run-in period that was absent in other trials.

Table 17: Assessment of Homogeneity for Sponsor-Submitted ITC

ABR = annualized bleeding rate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; FAS = full analysis set; FIX = factor IX; gc/kg = genome copy per kilogram; ITC = indirect treatment comparison; LOCF = last observation carried forward; rFIXFc = recombinant factor IX Fc fusion protein; rIX-FP = recombinant factor IX albumin fusion protein; ULN = upper limit of normal.

Sources: Sponsor-submitted ITC;⁶³ details included in the table are from the sponsor’s summary of clinical evidence.¹

Results

The methods, analysis populations, outcome definitions, and covariate balancing varied across the 3 comparative analyses considered in this report. This section is divided into results for each individual comparison.

Etranacogene Dezaparvovec Versus rIX-FP (Idelvion)

For the comparison of etranacogene dezaparvovec versus rIX-FP, the sponsor provided a summary of the baseline characteristics of the 2 trials of interest, presented in Table 18. Before adjustment, the following characteristics were imbalanced (defined as a standardized mean difference [SMD] > 0.2): severity of hemophilia B, prior ABR, age, prior FIX product class (EHL versus SHL), BMI, weight, HIV status, ALT and AST thresholds, prior FIX product use, total bilirubin threshold, family members with FIX inhibitor antibodies, and duration of diagnosed hemophilia B. Following IPTW, the following characteristics remained imbalanced (defined as an SMD > 0.2): prior FIX product class (EHL versus SHL), BMI, weight, HIV status, ALT and AST thresholds, prior FIX product use, total bilirubin threshold, family members with FIX inhibitor antibodies, and duration of diagnosed hemophilia B. For the PROLONG-9FP study, the ESS of the ITC analysis population following IPTW was 18.2.

Table 18: Baseline Characteristics of Patients in the HOPE-B Study and PROLONG-9FP Study (Base-Case Analysis)

ABR = annualized bleeding rate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; EHL = extended half-life; ESS = effective sample size; FIX = factor IX; IPTW = inverse probability of treatment weighting; ITC = indirect treatment comparison; pdFIX = plasma-derived factor IX; rFIX = recombinant factor IX; rFIXFc = recombinant factor IX Fc fusion protein; rIX-FP = recombinant factor IX albumin fusion protein; SD = standard deviation; SHL = standard half-life; SMD = standardized mean difference.

^aThe data for the covariate were taken at screening for the HOPE-B study and the comparator trial.

^bThe data for the covariate were taken during the lead-in period for the HOPE-B study and were taken at screening for the comparator trial.

^cThe data for the covariate were taken after the lead-in period for the HOPE-B study and were taken at screening for the comparator trial.

Source: Sponsor-submitted ITC.⁶³

Results for the comparison of etranacogene dezaparvovec versus rIX-FP are summarized in Table 19; both an unadjusted and an IPTW-adjusted analysis are presented. In both cases, results are provided for a subset of patients who met the eligibility criteria of the HOPE-B trial. The multivariable-adjusted analysis was conducted among matched patients. For ABR, ABR for spontaneous bleeds, and proportion of patients with 0 ABR events was adjusted for prior ABR, severity of hemophilia B, and age. For ABR for joint bleeds, the multivariable propensity score analysis was adjusted for (in order): severity of hemophilia B, prior ABR, and age. For annualized FIX consumption (excluding surgical FIX consumption), a multivariable-adjusted analysis was conducted among matched patients and sequentially adjusted for (in order): severity of hemophilia B, prior ABR, and prior FIX product class (EHL versus SHL).

In the multivariable-adjusted model, when comparing ABR, the rate for etranacogene dezaparvovec (ABR rate = 0.38) versus rIX-FP (ABR rate = 1.97) had an associated RR of 0.19 (95% CI, 0.09 to 0.41). When comparing ABR for joint bleeds, the rate for etranacogene dezaparvovec (ABR for joint bleeds = 0.14) versus rIX-FP (ABR for joint bleeds = 1.61) had an associated RR of 0.09 (95% CI, 0.03 to 0.25). When comparing FIX consumption, mean total FIX consumption for etranacogene dezaparvovec was 44.34 IU/kg/year when compared against rIX-FP, where mean consumption was 2,619.49 IU/kg/year with an associated mean difference of −2,575.15 IU/kg/year (95% CI, −2,990.83 IU/kg/year to −2,159.46 IU/kg/year).

Table 19: Comparative Efficacy of Etranacogene Dezaparvovec Versus rIX-FP (Base-Case Analysis)

CI = confidence interval; ESS = effective sample size; FIX = factor IX; IPTW = inverse probability of treatment weighting; NA = not applicable; OR = odds ratio; rIX-FP = recombinant factor IX albumin fusion protein; RR = relative risk.

Source: Sponsor-submitted indirect treatment comparison.⁶³

Etranacogene Dezaparvovec Versus rFIXFc (Alprolix)

For the comparison of etranacogene dezaparvovec versus rFIXFc, the sponsor provided an overview of baseline characteristics among the group 1 population of the B-LONG trial, corresponding to those patients who received prior prophylaxis. The sponsor noted that only 3 covariates could be assessed among this population and, of these, prior ABR was imbalanced (SMD > 0.2) in the unadjusted population. Following MAIC, all 3 covariates were balanced (SMD < 0.2). A summary of differences is provided in Table 20.

Table 20: Baseline Characteristics of Patients in the HOPE-B Study and B-LONG Study (Etranacogene Dezaparvovec Versus rFIXFc, Primary Analysis)

ABR = annualized bleeding rate; ALT = alanine transaminase; AST = aspartate aminotransferase; BMI = body mass index; EHL = extended half-life; ESS = effective sample size; FIX = factor IX; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; NA = not available; NR = not reported; rFIX = recombinant factor IX; rFIXFc = recombinant factor IX Fc fusion protein; rIX-FP = recombinant factor IX albumin fusion protein; SD = standard deviation; SHL = standard half-life; SMD = standardized mean difference.

^aThe data for the covariate were taken at screening for the HOPE-B study and the comparator trial.

^bThe data for the covariate were taken during the lead-in period in the HOPE-B study and at screening in the comparator trial.

^cThe data for the covariate were taken after the lead-in period in the HOPE-B study and at screening in the comparator trial.

Source: Sponsor-submitted ITC.⁶³

In terms of comparative efficacy, results for ABR were available only in the primary analysis population. The sponsor noted that the ABR among the unadjusted etranacogene dezaparvovec population (ABR = 0.38; N = 51) was lower than among patients receiving rFIXFc (ABR = 2.99; N = 32), corresponding to an RR of 0.13 (95% CI, 0.07 to 0.25) for etranacogene dezaparvovec versus rFIXFc. When adjusted for ABR, the sponsor reported a similar trend, with the ABR-adjusted MAIC population of patients receiving etranacogene dezaparvovec having a lower ABR (ABR = 0.43; ESS = 28.2) than patients receiving rFIXFc (ABR = 2.99; N = 32), corresponding to an RR of 0.14 (95% CI, 0.08 to 0.25) for etranacogene dezaparvovec versus rFIXFc.

Etranacogene Dezaparvovec Versus Pegylated Nonacog Beta Pegol

For the comparison of etranacogene dezaparvovec versus pegylated nonacog beta pegol (Rebinyn), the sponsor provided an overview of baseline characteristics among the prior prophylaxis population of the Paradigm 2 trial. The sponsor noted that this population, while otherwise being a closer fit for the HOPE-B ITC analysis population, had limited information with respect to patient baseline characteristics. A summary of the pre- and post-MAIC population characteristics is provided in Table 21. Prior to MAIC, the following covariates were noted to be imbalanced (SMD ≥ 0.2) between trials: prior ABR, prior FIX product class, and prior FIX product use. Following MAIC, 2 characteristics were noted to still be imbalanced (SMD ≥ 0.2): prior FIX product class and prior FIX product use. The ESS following MAIC was 8.5 for the HOPE-B trial’s ITC analysis population.

Table 21: Baseline Characteristics of Patients in the HOPE-B Study and Paradigm 2 Study (Etranacogene Dezaparvovec Versus Pegylated Nonacog Beta Pegol, Base-Case Analysis)

ABR = annualized bleeding rate; ALT = alanine transaminase; AST = aspartate aminotransferase; BMI = body mass index; EHL = extended half-life; ESS = effective sample size; FIX = factor IX; IPTW = inverse probability of treatment weighting; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; NA = not applicable; NR = not reported; pdFIX = plasma-derived factor IX; rFIX = recombinant factor IX; rFIXFc = recombinant factor IX Fc fusion protein; rIX-FP = recombinant factor IX albumin fusion protein; SD = standard deviation; SHL = standard half-life; SMD = standardized mean difference.

^aThe data for the covariate were taken at screening in the HOPE-B study and the comparator trial.

^bThe data for the for covariate were taken during the lead-in period in the HOPE-B study and at screening in the comparator trial.

^cThe data for the for covariate were taken after the lead-in period in the HOPE-B study and at screening in the comparator trial.

^dSD imputed from variance of ABR outcome to facilitate adjustment.

Source: Sponsor-submitted ITC.⁶³

Among the population that had received prior prophylaxis treatment, data were available only for the comparison of ABR; data on ABR for spontaneous bleeds and ABR for joint bleeds were not available. The unadjusted ABR was lower for etranacogene dezaparvovec (0.36; N = 51) than for pegylated nonacog beta pegol (3.33; N = 17). The RR for etranacogene dezaparvovec relative to pegylated nonacog beta pegol was 0.11 (95% CI, 0.06 to 0.22). A similar trend was seen following univariable adjustment for prior ABR: the RR for etranacogene dezaparvovec (ESS = 8.5) relative to pegylated nonacog beta pegol (N = 17) was 0.24 (95% CI, 0.07 to 0.82); following univariable adjustment for prior FIX product class, the RR for etranacogene dezaparvovec (ESS = 21) relative to pegylated nonacog beta pegol (N = 17) was 0.10 (95% CI, 0.03 to 0.27).

Critical Appraisal of the ITC

A key limitation shared among the sponsor-submitted ITC is the absence of a common comparator, which requires methods that accommodate for unanchored comparisons. The use of unanchored MAIC as well as IPTW analyses generally requires an assumption that the propensity score model includes all treatment-effect modifiers and prognostic factors. This assumption cannot be tested and is often dependent on the completeness of the included covariates.⁶⁶ In several of these analyses, this assumption is unlikely to hold due to the lack of available data from the covariates that were considered to be of the highest relevance. Failing to adjust for all relevant covariates introduces an unknown amount of bias in the reported effect estimates. In the analyses relative to rIX-FP, the sponsor noted that between-population differences (defined as an SMD threshold > 0.2) remained following inverse weighting of the HOPE-B patient population, which is an indication that the propensity score models did not include sufficient complexity to remove the potential bias.

The sponsor noted heterogeneity in the outcome definitions relating to bleeding events. The lack of a common comparator across the evidence base means that the impact of outcome definition differences cannot be assessed. Despite this, the clinical experts consulted by CADTH for this analysis did not feel that the definitions were substantially different and may be sufficient to explain the differences in observed effect sizes.

For comparisons of etranacogene dezaparvovec relative to rFIXFc and pegylated nonacog beta pegol, the interpretation of the primary analysis is hindered by the number of nonevaluable covariates among the study population receiving prophylaxis. This is further compounded by the lack of outcome reporting from these trials; the prophylaxis-receiving population had a limited number of outcomes reported; therefore, clinically relevant outcomes such as ABR for spontaneous bleeds and ABR for joint bleeds cannot be assessed. The sponsor did provide an exploratory sensitivity analysis of the mixed prophylaxis and on-demand populations, for which greater information was available on covariates and outcomes of interest. However, these comparisons are confounded by the use of a mixed-eligibility population, which cannot be accounted for in these analyses.

A significant limitation of the included ITC is the lack of comparative harms data. Accordingly, there is a gap in the indirect evidence with respect to the estimated harms of etranacogene dezaparvovec relative to other products.

As the sponsor did not provide full details of the SLR used to populate data for the report, uncertainty exists with respect to the potential for selection and reporting bias. Further, no information was provided on the extraction process for the included studies. Finally, the SLR that was used was published 4 years ago; therefore, uncertainty exists with respect to whether new relevant evidence, such as longer-term follow-up or subgroup analyses, may be available. As such, substantial uncertainty exists with respect to the totality of the evidence and the potential for missing data or subgroup data of relevance to this review.

In many analyses, the ESS of the comparison was particularly low. For example, the comparison of ABR for etranacogene dezaparvovec relative to pegylated nonacog beta pegol utilized an ESS of 8.5 for the RR for the etranacogene dezaparvovec population. A small ESS increases the uncertainty of the reported results, and the significance of the findings may be imprecise.

Discussion

Summary of Available Evidence

One ongoing phase III, single-arm, open-label clinical trial, HOPE-B (N = 54), was identified in the sponsor’s SLR. The primary objective of the HOPE-B trial was to demonstrate the noninferiority of etranacogene dezaparvovec in reducing ABR for all bleeding events between month 7 and month 18 post infusion compared with continuous routine FIX prophylaxis treatment. Other efficacy end points included proportion of patients with no bleeds, ABR for spontaneous bleeds, ABR for joint bleeds, AIR for FIX replacement therapy, annualized consumption of FIX replacement therapy, HJHS, and PROBE score. Safety outcomes such as TEAEs, TESAEs, withdrawals due to AEs, mortality, and notable harms (e.g., ALT increased, AST increased) were also reported. The HOPE-B study included a lead-in phase before the infusion of etranacogene dezaparvovec. Data collected during the lead-in phase served as a comparison against etranacogene dezaparvovec for some safety and efficacy outcomes (e.g., ABR for all bleeding events, ABR for spontaneous bleeds, ABR for joint bleeds, AIR, and annualized FIX consumption). The HOPE-B trial enrolled male patients who had moderately severe or severe hemophilia B (defined as a normal circulation FIX ≤ 2%) and were on continuous routine FIX prophylaxis treatment. Patients were excluded from the study if they had a history of FIX inhibitors or tested positive for FIX inhibitors at the last visit of the lead-in period and during the screening period of the HOPE-B trial. Pre-existing nAbs against AAV5 was not used as an exclusion criterion in the HOPE-B trial. Of the 54 patients who received etranacogene dezaparvovec, the majority were white (74.1%), with a mean age of 41.5 years (SD = 15.8 years); 21 patients (38.9%) had pre-existing nAbs against AAV5 before infusion of etranacogene dezaparvovec.

To evaluate the comparative efficacy of etranacogene dezaparvovec against other products, the sponsor submitted an ITC that included data from the rIX-FP (Idelvion), rFIXFc (Alprolix), pegylated nonacog beta pegol (Rebinyn), and nonacog alfa (BeneFIX) trials. Owing to a lack of connected evidence, the sponsor evaluated the feasibility of unanchored approaches using individual patient data to construct an IPTW estimator for comparisons against rIX-FP, and summary statistics for an unanchored MAIC estimator for rFIXFc, pegylated nonacog beta pegol, and BeneFIX. Owing to limitations in reporting, the sponsor determined that comparisons against BeneFIX may be inappropriate and considered its inclusion as a sensitivity analysis. Comparisons against rIX-FP were in favour of etranacogene dezaparvovec with respect to ABR, ABR for joint bleeds, ABR for spontaneous bleeds, proportion of patients with 0 bleeding events, and FIX utilization. Comparisons against rFIXFc demonstrated results in favour of etranacogene dezaparvovec for ABR; other efficacy end points were not available for the prophylaxis-receiving (primary analysis) population. Comparisons against pegylated nonacog beta pegol demonstrated results in favour of etranacogene dezaparvovec for ABR; other efficacy end points were not available for the prophylaxis-receiving (primary analysis) population. No safety data were presented. As no common comparator is available, the MAIC specifications required an assumption that all potentially relevant prognostic factors and treatment-effect modifiers had been included in the propensity score model. Particularly for comparisons against the rFIXFc and pegylated nonacog beta pegol prophylaxis-receiving populations, this was not possible owing to a lack of reporting baseline covariates for the prophylaxis-receiving (primary analysis) population. When using the individual patient data to compare the efficacy of etranacogene dezaparvovec against rIX-FP, all possible confounding variables should have been included.

Interpretation of Results

Efficacy

Overall, the efficacy evidence in the pivotal HOPE-B trial was in favour of etranacogene dezaparvovec over FIX prophylaxis in adult male patients who had moderately severe or severe hemophilia B (defined as normal circulation FIX ≤ 2%) and were on stable prophylaxis for at least 2 months before screening. This conclusion was based on the results from several efficacy end points, including bleeding-related end points (e.g., ABR for all bleeds, number of patients without any bleeds, ABR for spontaneous bleeds, ABR for joints bleeds), end points related to the use of FIX post infusion of etranacogene dezaparvovec (e.g., AIR), joint health–related end points (e.g., HJHS), as well as patient-reported outcomes (e.g., PROBE score). These efficacy end points were selected as areas of focus in the CADTH Clinical Review Report based on input from the clinical experts consulted by CADTH, patient and clinician groups, and expert committee members.

In the HOPE-B trial, the overall results for bleeding-related end points indicated that treatment with etranacogene dezaparvovec may result in a decrease in bleeding when compared with FIX prophylaxis treatment. For instance, between months 7 and 18 as well as months 7 and 36 post infusion, etranacogene dezaparvovec led to a decrease in ABR for all bleeding events compared with FIX prophylaxis received during the lead-in phase. The magnitude of the effect size, according to the clinical experts consulted by CADTH, was a clinically relevant improvement. Results from other bleeding outcomes (i.e., ABR for spontaneous bleeds, ABR for joint bleeds, ABR for traumatic bleeds) (Appendix 1) or the sensitivity analyses were generally consistent with ABR for all bleeding events, favouring etranacogene dezaparvovec over FIX prophylaxis. Moreover, along with the improvement in ABR for all bleeding events, there was a sustained increase in the FIX activity level percentage, as measured by 1 one-stage assay and 1 chromogenic assay (Appendix 1).

However, there is uncertainty associated with the interpretation of the efficacy findings due to the nonrandomized, open-label study design which, according to the GRADE guidance used by the CADTH review team, starts at low certainty. There was a potential risk of bias that may have resulted in the underestimation of ABR estimates or overestimation of the percentage of patients with no bleeds in patients treated with etranacogene dezaparvovec because of the open-label design and because bleeding events were self-reported. The risk of bias, although relatively low, could not be ruled out despite the sponsor implementing several measures to ensure patients’ correct use of the e-diary and compliance with its requirements in the HOPE-B trial. Another source of potential risk of bias in determining the magnitude of treatment effect might come from the assumptions of the models used to compare observations between the postinfusion phase and the lead-in phase in the HOPE-B study. Specifically, the probability of no bleeds did not account for the differences in follow-up time during the 2 phases and might bias results, although the direction is unknown.

In addition, there is uncertainty regarding the long-term efficacy of etranacogene dezaparvovec due to the relatively short duration of follow-up (i.e., 36 months), given that more than 60% of the respondents from the patient group input indicated they would expect a gene therapy to be effective in preventing bleeding for at least 10 years. To make any definite determinations on the overall long-term efficacy of etranacogene dezaparvovec, it was noted by the clinical experts consulted by CADTH that a longer follow-up of 20 to 25 years may be warranted.

The patient group input also reported that patients hope gene therapy would lead to fewer FIX infusions and minimal needle injections. Based on the results of the HOPE-B trial, etranacogene dezaparvovec may result in a decrease in AIR and FIX consumption when compared with FIX prophylaxis. The patient input also highlighted the importance of having a treatment for hemophilia B that maintains QoL (e.g., less stress, fewer restrictions on activities, easier to travel). According to the clinical experts consulted by CADTH, PROBE is a tool that is a commonly used in Canada to measure HRQoL outcomes in patients with hemophilia B. The changes from baseline at month 12 and month 24 post infusion of etranacogene dezaparvovec both showed improvements in the PROBE summary score in patients treated with etranacogene dezaparvovec. Improvements from baseline were also seen in other HRQoL outcomes in the HOPE-B study, such as in Haem-A-QoL scores, and the Haem-A-QoL instrument was considered by the clinical experts consulted by CADTH as generally aligned with PROBE. However, given the open-label design of the HOPE-B trial, the subjective nature of outcomes, and the lack of a comparator group, no valid inferences can be made on HRQoL outcomes. Similarly, no conclusion could be drawn with certainty on the HJHS results due to these limitations, despite improvements from baseline being observed.

In addition to the pivotal HOPE-B trial, the sponsor provided 1 ITC, which provided efficacy data on the estimated indirect effect of etranacogene dezaparvovec relative to rIX-FP, rFIXFc, and pegylated nonacog beta pegol. Owing to the lack of a common comparator, estimates required strong assumptions on the completeness of prognostic factors, treatment-effect modifiers, and potential confounders. In particular, comparisons relative to rFIXFc and pegylated nonacog beta pegol in the primary analysis are subject to further uncertainty owing to the lack of covariates to be adjusted and restricted to a limited subset of outcomes. The sponsor also noted differences that could not be adjusted for, such as in the definition of bleeding events between trials. As such, significant uncertainty remains with respect to the conclusions of ITC efficacy. Conversely, with these limitations in mind, the submitted evidence does show etranacogene dezaparvovec to have a consistent pattern of favourable efficacy, regardless of comparator.

Harms

According to the clinical experts consulted by CADTH, in the pivotal HOPE-B trial, the safety profiles of the patients treated with etranacogene dezaparvovec were considered acceptable overall, despite that more harms events occurred post infusion of etranacogene dezaparvovec than occurred when patients were receiving FIX prophylaxis treatment during the lead-in period. There was 1 death due to cardiogenic shock (according to the product monograph,² this event was not treatment related) and 1 withdrawal due to hypersensitivity post infusion of etranacogene dezaparvovec. The evidence on harms in the HOPE-B study was limited due to the small number of patients involved and the relatively short duration of follow-up. No comparative assessment was made with respect to harms in the sponsor-submitted ITC and, as such, an evidence gap exists for the safety of etranacogene dezaparvovec relative to other prophylactic treatments.

Conclusion

One phase III, single-arm, open-label trial (HOPE-B) investigated the efficacy and safety of etranacogene dezaparvovec in 54 male patients who had moderately severe or severe hemophilia B (defined as normal circulation FIX ≤ 2%) and who had been on continuous routine FIX prophylaxis treatment. Compared with the lead-in period when patients received FIX prophylaxis, etranacogene dezaparvovec may result in a decrease in ABR for all bleeding events, ABR for spontaneous bleeds, ABR for joint bleeds, AIR, and annualized FIX consumption post infusion of the gene therapy. The effects observed for all of these outcomes were considered clinically relevant by the clinical experts consulted by CADTH. However, there is uncertainty associated with interpretating the clinical significance of the magnitude of the treatment differences due to limitations such as the nonrandomized comparative design, potential risk of bias in the self-recording of bleeding events caused by the open-label design, multiplicity was not controlled for in the analyses using the months 24 and 36 data cut-offs, and potential biases introduced by assumptions in the statistical models used to make the comparisons. The harms profile for etranacogene dezaparvovec during the follow-up period was considered acceptable by the clinical experts consulted by CADTH, despite that more harms events occurred post infusion of etranacogene dezaparvovec than when patients were receiving FIX prophylaxis during the lead-in period. The harms evidence is limited, given the relatively short follow-up period and small sample size. A key gap in the pivotal trial evidence is that results remain unknown with respect to the long-term efficacy and safety of etranacogene dezaparvovec relative to FIX prophylaxis due to the current duration of follow-up (i.e., 36 months). One ITC provided efficacy data on the estimated effect of etranacogene dezaparvovec relative to rIX-FP (Idelvion), rFIXFc (Alprolix), and pegylated nonacog beta pegol (Rebinyn). No conclusions could be drawn on relative efficacy from the ITC. Interpretation of the effect magnitude is uncertain and hindered by the lack of connected evidence available, and potential confounding due to the lack of reporting of potentially influential prognostic and predictive factors. No safety data were reported in the sponsor-submitted ITC; therefore, no conclusions could be drawn on the comparative safety of etranacogene dezaparvovec versus other products, based on this evidence.

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Appendix 1: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 22: FIX Activity by Visit in the Posttreatment Period in the HOPE-B Trial (Full Analysis Set)