CADTH Reimbursement Review

Fidanacogene Elaparvovec (Beqvez)

Sponsor: Pfizer Canada ULC

Therapeutic area: Hemophilia B

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

AAV = adeno-associated virus; NOC = Notice of Compliance; vg = vector genome.

Sources: Sponsor’s Summary of Clinical Evidence¹ and draft product monograph.²

Introduction

Hemophilia is a serious and lifelong genetic disorder linked to the X chromosome 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 Moderate and severe hemophilia B cases are defined by the World Federation of Hemophilia (WFH) as those with 1% to 5% and less than 1% of normal enzymatic FIX activity, respectively.⁵ However, according to the clinical experts consulted by CADTH for this review, severity in clinical practice is defined by the patients' phenotype (i.e., tendency to bleed) and not simply their coagulation factor activity levels; the decision to initiate prophylaxis with clotting factor concentrates takes into the account both their clinical phenotype and factor activity levels, as well as lifestyle and professional activities. Individuals with moderately severe to severe hemophilia frequently experience bleeding and recurrent spontaneous bleeding into muscle, soft tissue, and joints (hemarthroses) starting from infancy and continuing through adulthood.^4,6 Hemarthrosis is the most common manifestation of moderate and severe hemophilia B.^4,5 As of 2021, there were 704 patients with hemophilia B (with recorded severity) in Canada, 535 of whom were adult males.

The treatment goal for hemophilia, as outlined by WFH guidelines,⁵ is to reduce or prevent bleeding while allowing patients to lead active lives and achieve a quality of life comparable to that of individuals not affected by the condition. Current management strategies for hemophilia B include on-demand treatment to stop bleeds as they occur and/or routine prophylaxis therapy to prevent bleeding, both involving the administration of exogenous FIX coagulation factor concentrates (CFCs) to treat the FIX deficiency.⁵ According to the clinical experts consulted by CADTH, routine FIX prophylaxis involving lifelong regular IV administration of FIX CFCs is currently the standard of care for patients with hemophilia B in Canada. Recombinant coagulation factor IX (rFIX) products are the mainstay of prophylactic treatments for hemophilia B.^5,7,8 The clinical experts consulted by CADTH noted that the frequency of FIX injections varies from individual to individual depending on the type of FIX concentrate and the pharmacokinetics of individual patients. According to the clinical experts consulted by CADTH, plasma-derived FIX, such as factor IX concentrate (human) (Immunine), is also available in Canada but with very limited use.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of fidanacogene elaparvovec (Beqvez) (concentrate solution for infusion, 1 × 10¹³ vector genomes [vg] per millilitre, IV infusion) for the treatment of moderately severe to severe hemophilia B in patients aged 18 years or older.

Stakeholder Perspectives

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

Patient Input

The Canadian Hemophilia Society (CHS) provided input for the review of fidanacogene elaparvovec for the treatment of moderately severe to severe hemophilia B patients aged 18 years or older. Patient input was gathered from an online survey conducted between July 10 and July 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, a CHS online survey of Canadians with severe hemophilia A and B received 39 responses, of which 31 were from patients with hemophilia A, 7 were from those with hemophilia B, and 1 was from a patient whose hemophilia was 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, 4 patients in the 2023 CHS survey reported being very satisfied, 7 were satisfied, 5 were neither satisfied nor dissatisfied, and 1 was very dissatisfied. Patients from this survey noted that treatments greatly complicate their everyday life, travel, and leisure activities. They also mentioned the infusion process was difficult due to vein visibility, poor vein issues, and side effects. Patients also reported facing socioeconomic problems due to the need for regular visits, missing work due to visits, travel and insurance issues, and accessing treatment.

When patients from the 2023 CHS survey were asked how gene therapy could potentially change their lives, all patients provided positive feedback. Patients hoped gene therapy would 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, 63% of the respondents from the 2022 survey indicated they expected gene therapy to be effective in preventing bleeding for at least 10 years. The 2022 survey asked if people would be willing to receive gene therapy knowing that that 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 (likely close to 5) patients in Canada have undergone gene therapy for hemophilia B, but it had no information about their experience outside the preliminary data from the trials.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH noted that FIX prophylaxis requires frequent IV injections performed by the patients themselves, which poses a heavy burden for patients with hemophilia B and significantly undermines their ability to live normal lives. The clinical experts noted that poor adherence to FIX prophylaxis may result in reduced effectiveness and an increased risk of bleeding, and even patients who execute prophylaxis on the prescribed schedule (i.e., are adherent) can experience breakthrough bleeds, particularly in the days before the next infusion. According to the clinical experts consulted by CADTH, the key advantage of fidanacogene elaparvovec over an exogenous FIX prophylaxis regimen, if effective, would be avoiding fluctuations in FIX levels and eliminating the need for repeated CFC infusions. The clinical experts consulted by CADTH noted that fidanacogene elaparvovec could be a curative treatment if a steady high level of FIX is expressed and efficacy is maintained over the long-term. The clinical experts noted that it remains unclear whether the use of fidanacogene elaparvovec will lead to a shift in the treatment paradigm.

The clinical experts noted that all patients with hemophilia B who have a clinically severe phenotype regardless of FIX level are likely to benefit from treatment with fidanacogene elaparvovec in terms of reductions in burden of care, pain, and pain interference as well as improvement in mobility and quality of life. The clinical experts noted that those who would likely benefit the most from the treatment of fidanacogene elaparvovec would be patients without pre-existing joint damage due to hemophilia B, as well as younger patients who are usually more active. The clinical experts consulted by CADTH noted that identifying the patients best suited for treatment should involve clinical assessments and shared decision-making with patients. Based on the study design of the pivotal BeneGene-2 trial, the clinical experts indicated that testing for neutralizing antibodies (nAbs) against variant adeno-associated virus serotype rh74 (AAVrh74var) should be mandatory for patients to receive fidanacogene elaparvovec. The clinical experts noted that patients least suitable for fidanacogene elaparvovec include those with pre-existing nAbs against adeno-associated virus (AAV) and those who conclude that the benefit does not outweigh the risk associated with fidanacogene elaparvovec gene therapy, given that its long-term efficacy and safety remain unclear. In addition, some patients may not want to change their current treatment.

According to the clinical experts consulted by CADTH, the most important assessment of treatment response requires monitoring patients’ bleeding to determine whether fidanacogene elaparvovec prevents bleeding events and allows patients to live the lifestyle they want without concern about the risk of bleeding. The clinical experts agreed that the length of follow-up for hepatic function and FIX activity levels after fidanacogene elaparvovec infusion should be lifelong. The clinical experts noted that monitoring after fidanacogene elaparvovec infusion will be more frequent in the short-term and less frequent over time in the long-term. The clinical experts consulted by CADTH noted that it is reasonable to monitor FIX activity levels and liver function twice a week at the early stage postinfusion, although the production of FIX is unlikely to occur immediately postinfusion. The clinical experts noted that monitoring changes in the Hemophilia Joint Health Score (HJHS) as well as in quality-of-life–related end points following fidanacogene elaparvovec infusion (e.g., improvement in activities associated with daily living, physical activity, and functioning; decrease in development of disability; and improvement in psychosocial health and functioning) are also important. The clinical experts consulted by CADTH noted that treatment failure should be determined by the treating clinician on a case-by-case basis. The clinical experts consulted by CADTH noted that, if treatment with fidanacogene elaparvovec fails, patients may not be eligible for another gene therapy based on AAV vectors because they may present with cross-reactivity against most AAV vectors.

The clinical experts consulted by CADTH noted that fidanacogene elaparvovec should be prescribed based on the judgment of a multidisciplinary team at a comprehensive hemophilia treatment centre. The team may consist of specialists such as a hematologist with experience in treating hemophilia patients, a physiotherapist to assess joint function, a hepatologist for liver-related issues, a pharmacist, and an HIV specialist if the patient is HIV-positive. The clinical experts noted that administration of fidanacogene elaparvovec takes place on an outpatient basis, as do postinfusion follow-ups for most of the patients.

Clinician Group Input

Nine clinicians from the Association of Hemophilia Clinic Directors of Canada (AHCDC) and 3 nurses from Canadian Association of Nurses in Hemophilia Care (CANHC) provided input. Both the AHCDC and CANHC emphasized that currently available treatments in Canada do not modify or alter the underlying disease process, making persons with hemophilia B dependent for life on regular IV infusions of FIX to prevent and treat bleeding. In addition, the AHCDC noted that the frequent venipunctures required for prophylactic CFC replacement can pose challenges for patients with poor venous access. The group emphasized that all these factors lead to the need for persons with hemophilia B and a severe bleeding phenotype to restore coagulation factor levels 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.

Both the AHCDC and the CANHC noted that fidanacogene elaparvovec would provide a 1-time treatment leading to sustained FIX production, which would address the underlying disease process and natural history, rather than provide symptomatic management. This would represent a paradigm shift in the treatment of hemophilia B. The AHCDC indicated that patients eligible for gene therapy include adults with hemophilia B and a clinically severe bleeding phenotype requiring prophylaxis, no history of inhibitory antibodies, no significant comorbidities, and no pre-existing anti-AAV nAbs.

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 affect the implementation of a CADTH recommendation for fidanacogene elaparvovec:

• relevant comparators

• consideration for initiation of therapy

• consideration of continuation or renewal of therapy

• consideration of discontinuation 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 (BeneGene-2, N = 45) was included in the systematic literature review (SLR) conducted by the sponsor. The BeneGene-2 trial involved 45 participants from 27 centres across 13 countries and territories around the globe, including 3 centres in Canada.¹ The BeneGene-2 trial enrolled adult male patients who had moderately severe to severe hemophilia B (defined as circulating coagulation factor IX [FIX:C] ≤ 2%). Patients were excluded if their anti-AAVrh74var nAb titre was equal to or greater than 1:1 or if they had a prior history of FIX inhibitors (i.e., nAbs against FIX) or a positive FIX inhibitor test result equal to greater than 0.6 Bethesda units.

The primary objective of the BeneGene-2 trial was to determine the noninferiority of fidanacogene elaparvovec relative to the standard of care in Canada (FIX prophylaxis), as measured by the annualized bleed rate for treated and untreated bleeds (ABR_total) at week 12 to month 15 (denoted as year 1) following fidanacogene elaparvovec infusion. Other efficacy and safety end points were also examined in the BeneGene-2 trial, including number of patients without bleeds; annualized bleeding rate for treated bleeds (ABR_treat); annualized bleeding rate for treated and untreated joint bleeds (ABR_joint); annualized infusion rate (AIR); annualized FIX consumption; HJHS, Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), and Hemophilia Activities List (HAL) scores; withdrawals due to adverse events (AEs); treatment-emergent adverse events (TEAEs); treatment-emergent serious adverse events (TESAEs); deaths; and notable harms (e.g., increased alanine transaminase [ALT], abnormal hepatic function, increased aspartate aminotransferase [AST], increased hepatic enzyme, and increased transaminases). Tests of both noninferiority and superiority were also conducted, and a gatekeeping process was applied to control for multiplicity of testing multiple end points. For efficacy outcomes such as ABR_total, ABR_treat, ABR_joint, AIR, and annualized FIX consumption, the 45 participants in the pivotal BeneGene-2 trial served as their own controls, using data collected from when they were on FIX prophylaxis during an open-label, noninvestigational, prospective, lead-in study (BeneGene-1, N = 102) for comparison.

Patients in the BeneGene-2 trial had a median age of 29 years, ranging from 18 to 62. The majority of patients were white (73.3%), followed by Asian (15.6%) as well as Black or African American (2.2%).

The BeneGene-2 trial is ongoing and expected to be completed in December 2029. Data gathered before the data cut-off date (November 16, 2022) were used to support the sponsor’s present submission to CADTH.^9,10

Efficacy Results

As of the data cut-off date, the mean duration of follow-up in the BeneGene-2 trial was |||| ||||| (standard deviation [SD] = |||||) with a median of |||| ||||| ||||| ||||. For the lead-in BeneGene-1, the mean duration of follow-up in the lead-in BeneGene-1 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| |||||

Bleeding Outcomes

The model estimate of the difference in the ABR_total between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial versus the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 study was −3.13 (95% CI, −5.44 to −0.81) at year 1 postinfusion, favouring fidanacogene elaparvovec. The difference in the ABR_total from week 12 to the data cut-off date (overall) was ||||| |||||| || ||||||, in favour of fidanacogene elaparvovec. The analysis found that 64.4% (29 of 45) of the patients treated with fidanacogene elaparvovec and 28.9% (13 of 45) of the patients treated with routine FIX prophylaxis had no untreated and treated bleeds at year 1 postinfusion. From week 12 to the data cut-off date postinfusion, ||||| ||||||| of the patients treated with fidanacogene elaparvovec and ||||| ||||||| of the patients treated with routine FIX prophylaxis had no bleeds.

The estimated mean differences in the ABR_treat between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial were −2.62 (95% CI, −4.27 to −0.96) at year 1 postinfusion and ||||| |||||| || |||||| from week 12 to the data cut-off date, ||| ||||||||| fidanacogene elaparvovec. No treated bleeds at year 1 postinfusion were reported in 73.3% (33 of 45) of the patients treated with fidanacogene elaparvovec and 35.6% (16 of 45) of the patients treated with routine FIX prophylaxis. ||||| ||||||| of the patients treated with fidanacogene elaparvovec and ||||| ||||||| of the patients treated with routine FIX prophylaxis had no treated bleeds at year 1 postinfusion.

The estimated difference in the ABR_joint between patients treated with fidanacogene elaparvovec and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial was ||||| |||||| || |||||| at year 1 postinfusion, in favour of fidanacogene elaparvovec. From week 12 to the data cut-off date, the difference was ||||| |||||| || ||||||, |||| ||||||||| fidanacogene elaparvovec. No joint bleeds at year 1 postinfusion were reported in 68.9% (31 of 45) of the patients treated with fidanacogene elaparvovec and 44.4% (20 of 45) of the patients treated with routine FIX prophylaxis ||||| ||||||| of the patients treated with fidanacogene elaparvovec infusion and ||||| ||||||| of the patients treated with routine FIX prophylaxis had no joint bleeds.

Use of FIX Post–Fidanacogene Elaparvovec Infusion

The differences in the AIR between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 study were −54.37 (95% CI, −63.64 to −45.10) at year 1 postinfusion and |||||| ||||||| || ||||||| from week 12 to the data cut-off date, ||| ||||||||| fidanacogene elaparvovec. From week 12 to the data cut-off date, the difference in the annualized FIX consumption between patients treated with fidanacogene elaparvovec and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 study was |||||||| IU/kg ||||||||| || ||||||||), ||||||||| fidanacogene elaparvovec.

Patient-Reported Outcomes

Among patients treated with fidanacogene elaparvovec, change from baseline at week 52 or week 104 postinfusion |||||| |||||||||||| in the HJHS total score, Haem-A-QoL physical health domain, Haem-A-QoL total score, HAL complex lower extremity activities score, and HAL total score.

Harms Results

Treatment-emergent AEs were reported in 84.4% (38/45) of the safety population of the BeneGene-2 trial. The most commonly reported TEAE was increased ALT (26.7%), followed by nasopharyngitis (17.8%) and arthralgia (17.8%). Serious adverse events (SAEs) were reported in 7 patients (15.6%) in the BeneGene-2 trial. The most common SAE was anemia (4.4%). No patients in the BeneGene-2 trial discontinued the study due to AEs or died as of the data cut-off date of November 16, 2022.

In terms of notable harms, increased ALT and abnormal hepatic function occurred in 26.7% (12 of 45) and 13.3% (6 of 45) of the patients in the BeneGene-2 trial, respectively. Increased AST, increased hepatic enzyme, and increased transaminases occurred in 6.7% (3 of 45) of the patients in the BeneGene-2 trial.

Critical Appraisal

The only eligible study identified by the SLR, BeneGene-2, was a phase III, single-arm, open-label clinical trial that enrolled 45 patients. Although interpretation of the study results is limited due to the nonrandomized, open-label, single-arm design, the clinical experts consulted by CADTH for this review considered the discontinuity design appropriate for clinical studies of hemophilia B treatment. Participants in the BeneGene-2 trial were requested to suspend their FIX prophylaxis regimen following fidanacogene elaparvovec infusion but were allowed to resume FIX prophylaxis based on certain conditions. These conditions were considered generally appropriate by the clinical experts consulted by CADTH. Moreover, resumption of a FIX prophylaxis regimen postinfusion in the BeneGene-2 trial was not expected to modify treatment effects. This was supported by the “jump to reference” sensitivity analysis, in which participants who resumed FIX prophylaxis regimens following fidanacogene elaparvovec infusion were excluded and the difference in the ABR_total was similar to that found in the primary analysis. The patients included in the pivotal BeneGene-2 trial were selected from the lead-in BeneGene-1 study. Of the 102 patients in the BeneGene-1 trial, only 45 were enrolled in the pivotal BeneGene-2 trial. CADTH determined that the potential selection bias due to a large number of patients being left out was not a serious concern because the data provided by the sponsor showed that outcomes reported in the majority of the patients who were left out (i.e., the 40 patients who were not enrolled in the BeneGene-2 trial because they had not completed the BeneGene-1 trial), such as the ABR_total, ABR_treat, and AIR, were similar to the those at year 1 postinfusion among the 45 patients enrolled in the BeneGene-2 trial. The documentation of bleeding events in the BeneGene-2 trial relied on the use of an electronic diary by patients, and the determination of whether a bleed needed to be treated relied on physicians’ clinical decisions shared with patients. Despite the risk of bias likely being low, and based on information provided by the sponsor, CADTH determined that the potential risk of bias that may lead to exaggeration of treatment effects of fidanacogene elaparvovec (i.e., annualized bleeding rate [ABR] outcomes) could not be ruled out. Furthermore, due to a lack of comparative data for some end points and the open-label design, reliable assessments of patient-reported outcomes (e.g., health-related quality of life [HRQoL] end points) could not be made. CADTH concluded that the gatekeeping process used to control for multiplicity when testing multiple end points was appropriate. However, some concerns regarding the assumptions of the statistical models used in the BeneGene-2 trial were raised, which may make interpretation of the magnitude of the effect estimates of fidanacogene elaparvovec compared to FIX prophylaxis challenging.

CADTH identified several considerations related to the generalizability of the BeneGene-2 trial. First and most importantly, given the novelty of gene therapy as well as patients’ and clinicians’ expectation of long-lasting effects, it may not be possible to use evidence from the current follow-up period (|||| ||| |||||) in the BeneGene-2 trial to generalize about long-term efficacy and safety. Second, the indication includes patients with “moderately severe to severe” hemophilia B, and defining this description has implementation considerations. Whereas the BeneGene-2 trial defined “moderately severe to severe” as a FIX:C level less than or equal to 2%, the clinical experts consulted by CADTH noted that severity in clinical practice is defined by the patients' phenotype and not simply their factor activity levels. According to the clinical experts consulted by CADTH, hemophilia in some patients will be considered moderately severe to severe due to clinical symptoms despite a FIX level greater than 2%. Furthermore, the BeneGene-2 trial included only patients with an anti-AAVrh74var nAb titre of less than 1:1. According to the clinical experts consulted by CADTH, the efficacy of fidanacogene elaparvovec in patients with an anti-AAVrh74var nAb titre equal to or greater than 1:1 remains uncertain. Nonetheless, the clinical experts consulted by CADTH agreed that, if fidanacogene elaparvovec were to be publicly reimbursed, selection of eligible patients should follow the threshold used in the BeneGene-2 study.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for Grading of Recommendations Assessment, Development and Evaluation (GRADE) was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: ABR_total, ABR_treat, ABR_joint, percentage of patients without bleeds, AIR, annualized FIX consumption, HJHS, Haem-A-QoL (physical health and total scores), HAL (complex lower extremity activities and total scores), and harms. According to 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 Fidanacogene Elaparvovec for Patients with Hemophilia B (Outcomes With Comparative Data)

ABR = annualized bleeding rate; ABR_joint = annualized bleeding rate for treated and untreated joint bleeds; ABR_total = annualized bleeding rate for treated and untreated bleeds; ABR_treat = annualized bleeding rate for treated bleeds; AIR = annualized infusion rate; CI = confidence interval; FIX = coagulation factor IX; SD = standard deviation.

Note: Year 1 refers to the period between week 12 and month 15 following fidanacogene elaparvovec infusion. Overall refers to the period from week 12 following fidanacogene elaparvovec infusion to the data cut-off date of November 16, 2022. As of the data cut-off date, the mean duration of follow-up in the pivotal BeneGene-2 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||. Week 52 and week 104’s baseline was defined as the last nonmissing measurement before the dosing date (day 1) in the pivotal study. The mean duration of follow-up in the lead-in BeneGene-1 study was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||.

^aThe risk of bias was not rated down. According to the clinical experts consulted by CADTH, although not optimal, the study design adopted by the BeneGene-2 trial was considered to be of sufficiently low risk of confounding and sampling bias to not introduce serious risk of bias. Although there were differences between patients in the indication and patients in pivotal trial (e.g., definition of moderately severe to severe disease), the clinical experts consulted by CADTH did not consider them sufficient 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.

Source: BeneGene-2 Clinical Study Report.⁹

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

ALT = alanine transaminase; AST = aspartate transaminase; CI = confidence interval; Haem-A-QoL = Hemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score; HRQoL = health-related quality of life; MID = minimal important difference; SD = standard deviation; TESAE = treatment-emergent serious adverse event.

Note: Year 1 refers to the period between week 12 and month 15 following fidanacogene elaparvovec infusion. Overall refers to the period from week 12 following fidanacogene elaparvovec infusion to the data cut-off date of November 16, 2022. As of the data cut-off date, the mean duration of follow-up in the pivotal BeneGene-2 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||. Week 52 and week 104’s baseline was defined as the last nonmissing measurement before the dosing date (day 1) in the pivotal study. The mean duration of follow-up in the lead-in the BeneGene-1 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||.

^aIn absence of a comparator arm, certainty of evidence started at very low. Although there were differences between patients in the indication and patients in the pivotal trial (e.g., definition of moderately severe to severe disease), the clinical experts consulted by CADTH did not consider them serious enough to result in important differences in the observed effect. No MID was identified. Imprecision was not rated down as the improvement was considered clinically meaningful by the clinical experts consulted by CADTH.

^bIn 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. Although the Patient Reported Outcomes Burdens and Experiences instrument is more commonly used in Canada, this was not considered a serious generalizability issue by the clinical experts consulted by CADTH because all these HRQoL measurement instruments are closely aligned.

^CRated down 1 level for imprecision. The meaningful within-patient change identified in the literature was 10.0 for Haem-A-QoL physical health domain, ||||| ||| ||||||| || ||| ||| ||| ||| ||||| ||| || ||| ||| || ||| ||| ||||| ||| || |||||| ||||.

^dRated down 1 level for imprecision due to the small number of patients involved. The meaningful within-patient change identified in the literature was 7.1 for Haem-A-QoL total score, ||||| ||| ||| ||||||| || ||| ||| ||.

^eRated down 1 level for imprecision. No MID was available, and the upper end of the 95% CI did not cross the no-effect line.

^fIn absence of a comparator arm, certainty of evidence started at very low. Although there were differences between patients in the indication and patients in pivotal trial (e.g., definition of moderately severe to severe disease), the clinical experts consulted by CADTH did not consider them sufficient to result in important differences in the observed effect. Rated down 1 level for imprecision due to the small sample size, although the safety profile was considered acceptable by clinical experts consulted by CADTH.

Source: BeneGene-2 Clinical Study Report.⁹

Studies Addressing Gaps in the Evidence From the Systematic Review

The sponsor submitted 2 additional studies to address gaps in the pivotal trial evidence. Study C0371005 was submitted to address a gap in knowledge of the safety and kinetics of fidanacogene elaparvovec. Study C0371003 was a corresponding extension study submitted to address a gap in knowledge of the longer-term efficacy and safety of fidanacogene elaparvovec. Patients who completed Study C0371005 were encouraged to enrol in Study C0371003 to evaluate fidanacogene elaparvovec for up to an additional 5-year, longer-term follow-up.

Study C0371005

Description of Study

Study C0371005 (N = 15) was a phase I and IIa, open-label, nonrandomized, dose-escalation, multicentre study. The objective was to evaluate the safety, tolerability, and kinetics of a single IV infusion of fidanacogene elaparvovec (dose of 5 × 10¹¹ vg/kg) in hemophilia B participants with endogenous FIX levels of less than of equal to 2%. Patients were followed for 52 weeks. No formal efficacy evaluations were performed. All efficacy analyses were exploratory in nature. The safety analysis set included 15 participants who received the infusion.

All 15 participants enrolled were male with a mean age of 38.6 years, ranging from 18 to 61 years. The majority of participants were white (80.0%). The majority of participants (80.0%) had no family history of FIX inhibitors and 66.7% had hemophilia B with a FIX:C level of less than 1%.

Efficacy Results

Bleeding outcomes: Among 15 treated participants, 12 participants (80.0%) did not experience any on-study bleeds. No traumatic bleeds were observed during the study, and all 3 participants who experienced bleeding episodes had spontaneous bleeds. The median ABR during the 52-week period preceding fidanacogene elaparvovec infusion (historical) was 4.00, ranging from 0.0 to 48.0. The median ABR decreased to 0.00 (range = 0.0 to 4.0) during the 52-week period following fidanacogene elaparvovec infusion (on study). The mean ABR decreased from 8.87 (SD = 14.040) to 0.40 (SD = 1.060).

The overall mean annualized FIX production consumption was |||| |||||||||| IU in all 15 participants, with a mean of |||| |||||||||| IU in the 11 participants previously on prophylaxis treatment and |||| |||||||| IU in the 4 participants previously receiving treatment on demand.

During the 52-week period preceding screening, the mean number of target joint bleeds was |||| ||||||| in 5 participants (4 previously on prophylactic treatment and 1 previously receiving treatment on demand). The mean number of target joint bleeds decreased from |||| ||||||| in 4 participants to ||| |||||| occurring in 2 participants previously on prophylactic treatment from 52 weeks preceding screening to the end of study.

Patient-Reported Outcomes: As the HJHS, HAL, and McGill pain questionnaire assessments were added in a protocol amendment, only the final | participants enrolled were evaluated for these assessments.

Regarding HJHS, || || participants had assessments done at baseline and end of study. In general, a |||||||| ||| |||||||| || ||| ||||||||| |||||||||||| |||| ||||| ||||| |||||| |||||| |||||| |||| |||||| ||||| |||||| |||| |||||| ||||| |||| ||| |||| ||||| |||| ||| |||| |||||| ||| ||| ||||| ||||| || |||| ||||| ||||||| ||||| ||||||| ||| ||||| ||||||.

A |||||||| || ||| ||||| ||| ||||| ||| ||| |||||| |||| |||| ||| |||||||| || |||| || participants who had assessments done at baseline and end of study. A |||||||| was also observed in |||||||||| ||||||| ||||| ||||| |||| ||||, as well as in the |||||| ||||| |||||| |||||| ||||||| ||||| |||||.

Harms Results

Fourteen out of 15 participants (93.3%) had at least 1 reported TEAE. A total of 81 TEAEs were reported in the study. The most commonly reported TEAEs were in the system organ class of infections and infestation (8 participants, or 53.3%), gastrointestinal disorders (7 participants, or 46.7%) and musculoskeletal and connective disorders (6 participants, or 40.0%). The majority of TEAEs (53 out of 81, or 65.4%) were mild in severity, and the other 28 (34.6%) were moderate in severity. No study drug discontinuation, study discontinuation, SAEs, or deaths were reported in the study.

Study C0371003

Description of Study

Study C0371003 (N = 17) is a phase IIa, open-label, nonrandomized, longer-term follow-up study designed to evaluate the safety and efficacy of previously administered fidanacogene elaparvovec at a dose of 5 × 10¹¹ vg/kg for up to 6 years. Participants enrolled in this study either had been dosed with fidanacogene elaparvovec in Study C0371005 (summarized previously; N = 14) or received fidanacogene elaparvovec in a dose-escalation substudy (N = |) within this study. Results presented in this report are for the cohort of 14 patients from Study C0371005 who entered Study C0371003. The dose-escalation substudy is not covered in this report due to the small number of participants and the fact that the dose of fidanacogene elaparvovec used did not align with the recommended dose (patients received a dose of |||||| |||||| |||| || |||||||| |||).

The primary outcome measures for Study C0371003 were related to safety and immunogenicity, while secondary measures were related to efficacy. As the primary objective of this study was safety, no hypothesis testing was planned, and all summaries are descriptive.

At the data cut-off date (November 2, 2022), 2 patients had discontinued from the study, 5 patients had completed the longer-term follow-up, and 7 participants were continuing the study. The duration of follow-up at the data cut-off ranged from || |||||| || || |||||| following fidanacogene elaparvovec infusion.

The mean age of participants was 40.1 years, ranging from 18 to 61 years at the time of fidanacogene elaparvovec infusion. Most participants were aged 35 years or older (71.4%) and white (85.7%). There were 10 participants on FIX prophylaxis and 4 participants using on-demand regimens before fidanacogene elaparvovec infusion. All participants had FIX levels of 2% or lower.

Efficacy Results

Bleeding outcomes: The mean ABR_treat remained lower than 1.0 from year 2 through year 6 postinfusion, with || participants (|||||) having no bleeds during their entire time in the study. The mean treated ABRs were |||| |||||||, |||| |||||||, |||| |||||||, |||| |||||||, and |||| ||||||| during years 2, 3, 4, 5, and 6 postinfusion, respectively. |||| participants had treated bleeds from years 2 through 6.

The AIR generally decreased over the entire follow-up periods, from a mean of |||| in year 2 to |||| in year 6 following fidanacogene elaparvovec infusion. The mean AIRs were |||| |||||||, |||| |||||||, |||| |||||||, |||| |||||||, and |||| ||||||| during years 2, 3, 4, 5, and 6 postinfusion, respectively.

As of the data cut-off date, there were no prophylactic infusions in the study, and no participants had resumed prophylaxis. The median total factor consumption and annualized FIX consumption, excluding consumption required for surgery, was |||| for year 2 through year 6. |||| of the 14 participants have had no nonsurgical FIX consumption over the longer-term follow-up period.

From week 52 to week 130 following fidanacogene elaparvovec infusion, the number of participants with target joint bleeds decreased from || ||||||| to ||||||, based on responses to target joint assessment questionnaires. || ||||||||||| had target joint bleeding reported beyond week 130 as of the data cut-off (from weeks 156 to 312 or end of study).

Patient-Reported Outcomes: The HJHS, an exploratory end point, was added after most participants were dosed, resulting in a low number of assessments at baseline. The baseline HJHS score was the last nonmissing measurement before fidanacogene elaparvovec infusion in Study C0371005. The median HJHS total scores were |||| ||||| at baseline, |||| |||||| at week 156, |||| ||||| at week 208, |||| ||||| at week 260, and |||| ||||| at week 312 or end of study.

Haem-A-QoL total scores and domain scores |||||||| |||||||||| throughout the longer-term follow-up period (years 2 through 6). Median change from baseline in Haem-A-QoL total scores ranged from ||||| || |||||| over the longer-term follow-up (years 2 through 6).

Mean HAL domain scores |||||||| ||||| || and the total score |||||||| ||||| || at all following fidanacogene elaparvovec infusion visits over the longer-term follow-up period (years 2 through 6). HAL scores can range from 0 to 100, with higher scores indicating fewer functional limitations.

Harms Results

Of the 10 TEAEs reported, 5 were mild, 1 was moderate, and 4 were severe. These 10 TEAEs included 9 SAEs and 1 nonserious AE (back pain). The most frequently reported TEAEs regardless of severity were related to musculoskeletal and connective tissue disorders in 2 participants (14.3%).

Four of the 14 participants (28.6%) experienced a total of 9 SAEs. No participants discontinued from the study due to AEs. There were no deaths.

No participants experienced hypersensitivity reactions or another AE of special interest. During the longer-term follow-up period, 8 of 14 participants experienced increased ALT above the upper limit of normal (ULN), 3 of whom had increased AST above the ULN. None of these cases were managed with corticosteroids and, as of the data cut-off, all of these participants had ALT and AST levels back within normal limits, except for 1 patient who completed the study with an ALT level above the ULN. Regarding immunogenicity, all 14 participants remained negative for FIX inhibitors during the study.

Critical Appraisal

Internal Validity

Study C0371005 was an open-label, single-arm, multicentre, phase I and IIa study. All efficacy analyses were exploratory in nature and were presented using descriptive statistics. The absence of a comparator group limited the interpretation of results because causality could not be established. The open-label design may have biased the reporting of some end points because awareness of the study treatment received may have influenced the perception of improvement and/or harms by patients and clinicians, particularly for outcomes that are subjective in measurement and interpretation (e.g., patient-reported outcomes and subjective AEs). The follow-up period was only 1 year, which was insufficient to permit drawing any definite conclusions regarding long-term efficacy and safety outcomes. In addition to the general limitations of the study design, because the HJHS and HAL assessments were added to the study later during a protocol amendment, data were missing for most of the participants (only 4 patients contributed data to the analyses). As such, no conclusions can be drawn for these outcomes with certainty.

Study C0371003 provided a longer-term follow-up for 14 of the patients who had previously received fidanacogene elaparvovec in Study C0371005. As the primary objective of Study C0371003 was to evaluate safety, no hypothesis testing was planned. All efficacy and safety data were summarized descriptively, resulting in no statistical inferences. Data were missing for HJHS and HAL assessments in this study as well, for the reasons discussed for Study C0371005.

In Study C0371003, the duration of follow-up at the data cut-off ranged from || |||||| || || |||||| following fidanacogene elaparvovec infusion. Only 5 participants had completed the 6-year longer-term follow-up as of the data cut-off. According to the clinical experts consulted by CADTH, the data provided for up to 6 years of follow-up are limited but reasonable for the purposes of assessing safety and efficacy in the patient population. The clinical experts noted that a longer follow-up (20 to 25 years) involving more patients is warranted to make any definitive determinations on overall long-term safety and efficacy of fidanacogene elaparvovec. Although Study C0371003 provides the longest-term data available on the efficacy of fidanacogene elaparvovec, this evidence is inconclusive.

External Validity

The external validity was similar to that of the pivotal trial and its corresponding lead-in study. The dose of fidanacogene elaparvovec used in Study C0371005 aligns with the recommended dose in the draft product monograph. The majority of the patients enrolled were white (80.0% and 85.7% in Study C0371005 and Study C0371003, respectively), which, according to the clinical experts consulted by CADTH, was higher than what would be expected for the patient population in Canada. Both Study C0371005 and Study C0371003 enrolled only male patients, although the clinical experts noted this is likely not a serious generalizability issue because the treatment effects are not expected to differ between males and females due to the same underlying mechanism of disease, and female patients with moderately severe to severe hemophilia B are rare. One of the eligibility criteria in Study C0371005 was both hemophilia B with FIX activity less than or equal to 2% at screening and historical evidence or a documented genotype known to produce a clinically severe phenotype of hemophilia B. The clinical experts consulted by CADTH noted that severity in clinical practice is defined by the patients' phenotype and not simply their factor activity levels. Hemophilia in some patients will be considered moderately severe to severe due to clinical symptoms even for those with a FIX level greater than 2%, according to the clinical experts consulted by CADTH. Last, generalizability may be limited by the small sample size.

Conclusions

One phase III, single-arm, open-label trial (BeneGene-2) investigated the efficacy and safety of fidanacogene elaparvovec in 45 patients with moderately severe to severe hemophilia B (defined as FIX:C ≤ 2%). For efficacy outcomes regarding bleeding events and use of FIX following fidanacogene elaparvovec infusion, patients in the BeneGene-2 trial served as their own controls, using data collected from when these patients were on FIX prophylaxis during a lead-in study (BeneGene-1). Compared to FIX prophylaxis, fidanacogene elaparvovec may result in a decrease in the ABR_total, ABR_treat, |||||| AIR, and |||||||||| ||| |||||||||||, and the effects observed for all of these outcomes were considered clinically relevant by the clinical experts consulted by CADTH. However, uncertainty associated with interpreting the clinical significance of the magnitude of the treatment differences remains due to limitations such as the nonrandomized comparative design, potential risk of bias in self-reporting bleeding events caused by the open-label design, and potential biases introduced by assumptions of the statistical models used to make the comparisons. The safety profile of fidanacogene elaparvovec during the follow-up period was considered acceptable by the clinical experts consulted by CADTH; however, the safety evidence is uncertain given the lack of comparative data, sample size, and limited duration of follow-up. To address the limited duration of follow-up in the BeneGene-2 study, evidence from a phase I and IIa, single-arm, open-label trial and a corresponding extension study that provided data for up to 6 years of follow-up was examined. However, the limitations of these supportive studies (e.g., a single arm and noncomparative design, descriptive analyses, small sample size, many patients ongoing, and missing data) preclude CADTH from drawing conclusions with certainty about the longer-term efficacy and safety of fidanacogene elaparvovec based on this evidence. Altogether, the long-term efficacy and safety of fidanacogene elaparvovec remains inconclusive.

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 fidanacogene elaparvovec, 1 × 10¹³ vg/mL, supplied as a concentrate solution for IV infusion in the treatment of moderately severe to severe hemophilia B in patients aged 18 years or older.

Disease Background

Contents within this section were informed by materials submitted by the sponsor and clinical expert input. The following summary was 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 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.¹³

• Moderate and severe hemophilia B cases are defined by the WFH as having 1% to 5% and less than 1% of normal enzymatic FIX activity, respectively.⁵ Moderately severe hemophilia has also been defined as factor levels of 1% to no more than 2% in previous clinical trials that have investigated treatment with prophylaxis.¹⁴ However, according to the clinical experts consulted by CADTH, severity in clinical practice is defined by the patients’ phenotype (i.e., tendency to bleed) and not simply their factor activity levels. The decision to initiate prophylaxis with clotting factor concentrates takes into the account both their clinical phenotype and factor activity levels, as well as lifestyle and professional activities.

• Clinically, hemophilia B presents as a susceptibility to bruising and episodes of prolonged bleeding from surgery or trauma.⁴ In patients with moderate or severe hemophilia, spontaneous and internal serious and life-threatening bleeding into joints, muscles, and vital organs may also occur.⁴ The frequency of spontaneous bleeding episodes is variable in severe patients and bleeding may occur up to 20 or 30 times without an apparent cause or after minor trauma, each year.^4,15 The majority of spontaneous bleeds occur in the joints (70% to 80%) and muscles (10% to 20%).⁵ Less than 5% of bleeds occur in the central nervous system (e.g., intracranial hemorrhage), but these can be particularly serious and debilitating, potentially leading to seizures, impaired motor function, or death in up to 20% of cases.^5,16,17 Patients with hemophilia B are prone to prolonged bleeding after injury, surgery, or trauma, as well as nosebleeds and bleeding from the gums.^4,18 Individuals with moderately severe to severe hemophilia frequently experience bleeding and recurrent spontaneous bleeding events into muscle, soft tissue, and joints (hemarthroses) throughout their entire lives.^4,6 However, bleeds can occur in any organ, and other affected organs can include kidneys, stomach, intestines, and the brain.^4,5,19 Hemarthrosis is the most common manifestation of moderate and severe hemophilia B.^4,5

• 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.²⁰ The mean prevalence per 100,000 males in Canada from 1998 to 2006 was 3.23.²¹ The estimated prevalences at birth per 100,000 males in Canada from 1991 to 2015 were 3.9 for all severities of hemophilia B and 1.3 for severe disease only.²²

Standards of Therapy

Contents within this section were informed by materials submitted by the sponsor and clinical expert input. The following summary was validated by the CADTH review team.

The treatment goal for hemophilia, as outlined by WFH guidelines,⁵ is to reduce or prevent bleeding while allowing patients to lead active lives and achieve a quality of life comparable to that of individuals not affected by the condition. Current management strategies of hemophilia B for affected patients include on-demand treatment to stop bleeds as they occur and/or routine prophylaxis therapy to prevent bleeding, both involving the administration of exogenous FIX CFCs to treat a FIX deficiency.⁵

According to the clinical experts consulted by CADTH, routine FIX prophylaxis involving lifelong regular IV administration of FIX CFCs is currently the standard of care for patients with hemophilia B in Canada. The clinical experts consulted by CADTH noted that FIX prophylaxis should be based on clinical phenotype (e.g., presenting clinical bleeds) and not simply laboratory severity (FIX levels).

Prophylaxis aims to maintain hemostasis with the primary goal of preventing bleeds, especially into the joints, to avoid long-term joint damage and enable patients to live a full and active life.^5,8,23 Products based on rFIX are the mainstay prophylactic treatments for hemophilia B.^5,7,8 All rFIX products have either a standard half-life (SHL) and therefore must be administered once weekly at a minimum, and often 2 to 3 times per week, or an extended half-life (EHL), and therefore require administration either once weekly or once every 1 to 2 weeks.^24-26 The clinical experts consulted by CADTH noted that the frequency of FIX injections varies from individual to individual depending on the type of FIX concentrate and the pharmacokinetics of individual patients. Preparations of rFIX CFCs for the treatment of hemophilia B are available in Canadian provinces and territories through Canadian Blood Services, excluding Québec, and include rFIX Fc fusion protein (Alprolix]), pegylated nonacog beta pegol (Rebinyn), and nonacog alfa (BeneFIX).^1,27 According to the clinical experts consulted by CADTH, plasma-derived FIX, such as factor IX concentrate (human) (Immunine), is also available in Canada but with very limited use.

Drug Under Review

Key characteristics of fidanacogene elaparvovec and other treatments available for moderately severe to severe hemophilia B in patients aged 18 years of age and older are summarized in Table 4.

Fidanacogene elaparvovec is a gene therapy designed to introduce a functional copy of a high-activity variant of the F9 gene (FIX-R338L) in the transduced cells to address the monogenic root cause of hemophilia B. By providing an alternative active source of the FIX protein, which is secreted into the plasma, it is expected to restore hemostasis.² Fidanacogene elaparvovec is a nonreplicating recombinant AAV vector that utilizes the AAVrh74var capsid to deliver a stable, fully functional human FIX transgene. The AAVrh74var capsid is derived from AAVrh74, which is not known to cause disease in humans. The AAVrh74var capsid is able to transduce hepatocytes, the natural site of FIX synthesis. The F9 gene present in fidanacogene elaparvovec is designed to reside predominately as episomal DNA within transduced cells. Expression of the transgene is driven by a liver-specific promoter, which results in tissue-specific, continuous, and sustained expression of the FIX protein.²

Table 4: Key Characteristics of Fidanacogene Elaparvovec, rFIXFc, Pegylated Nonacog Beta Pegol, and Nonacog Alfa

AAV = adeno-associated virus; AAVrh74va = adeno-associated virus rh74 variant protein; FIX = coagulation factor IX; rFIXFc = recombinant factor IX Fc fusion protein; vg = vector genome.

^aHealth Canada–approved indication.

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

Source: Pfizer (2023),² Sanofi (2021),²⁶ Novo Nordisk (2022),²⁴ and Pfizer (2017).²⁵

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 inputs received by CADTH are included in the Stakeholder section of this report.

The CHS provided input for the review of fidanacogene elaparvovec for the treatment of moderately severe to severe hemophilia B patients who are 18 years of age and older. Patient input was gathered from an online survey, conducted between July 10 and July 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 patients in Canada with severe hemophilia A and B and received 39 responses, among which 31 were from patients with hemophilia A, 7 were from patients with hemophilia B, and 1 was from a patient whose hemophilia was 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, 4 patients in the 2023 CHS survey reported being very satisfied, 7 were satisfied, 5 were neither satisfied nor dissatisfied, and 1 was very dissatisfied. Patients from this survey noted that treatments greatly complicate their everyday life, travel, and leisure activities. They also mentioned the difficulty associated with infusions due to vein visibility, poor vein issues, and side effects, and reported dealing with socioeconomic problems due to the need for regular visits, missing work to attend visits, and travel and insurance issues, and accessing treatment.

When respondents to the 2023 CHS survey were asked how gene therapy could change their lives, all patients provided positive feedback. Patients hoped gene therapy would 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 expected gene therapy to be effective in preventing bleeding for at least 10 years. The 2022 survey asked if people would be willing to receive gene therapy knowing that that 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 patients in Canada (likely close to 5) have undergone gene therapy for hemophilia B, but it had no information about their experiences beyond the preliminary trial data. The group also noted that, in the absence of peer-reviewed publications describing the results of phase III clinical trials for fidanacogene elaparvovec, it cannot comment on the relative benefits and risks compared to current therapies or other gene therapies for hemophilia B currently under review by Health Canada.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the review of fidanacogene elaparvovec, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, help identify and describe 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 a 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 clinical experts consulted by CADTH noted several important goals of treatment for patients with hemophilia B, including allowing patients to have a normal life expectancy, improve their quality of life, and decrease the burden of disease by reducing or eliminating pain as well as preventing or reducing functional impairment; preventing or reducing bleeding such as joint bleeds and spontaneous bleeds; and preventing the development of chronic musculoskeletal complications due to recurrent bleeding, particularly chronic hemophilic arthropathy, and the resulting health system resource consumption of joint replacement.

The clinical experts consulted by CADTH noted that FIX prophylaxis requires frequent IV injections performed by the patients themselves. Patients who are on prophylactic therapy have to inject themselves at home, usually about 2 times per week (if on an SHL product) or once every 2 weeks (if on an EHL product). This poses a heavy burden for patients with hemophilia B and significantly affects patients’ ability to live a normal life. The clinical experts consulted by CADTH noted that poor adherence to FIX prophylaxis, which may result in reduced effectiveness of prophylaxis and increased risk of bleeding, has been a significant problem for patients with hemophilia B due to the frequency and difficulty associated with self-injections.

After infusion, the plasma FIX level varies over time. Patients must adapt their lifestyle to these continuous waves of FIX levels, limiting their freedom to enjoy activities (and productivity) to specific temporal windows. Furthermore, the decline in plasma FIX concentrations in the period between infusions is such that patients may have little or no protection from bleeding for variable periods of time. This is accentuated if an infusion is missed or delayed because of difficulty or misadventure in carrying out the infusion, or depletion of the home inventory (FIX concentrates are not delivered to the patient’s home but must be picked up at a designated hospital blood bank). Even patients who administer prophylaxis on the prescribed schedule (i.e., are adherent) can experience breakthrough bleeds, particularly in the days before the next infusion.

Place in Therapy

The clinical experts consulted by CADTH noted that the key advantage of fidanacogene elaparvovec over an exogenous FIX prophylaxis regimen is avoiding the fluctuations in FIX levels and eliminating the need for repeated CFC infusions. A stable level of FIX via a single infusion of fidanacogene elaparvovec is expected, while current FIX prophylaxis requires frequent self-injections of FIX to sustain what is still a fluctuating FIX activity level characterized by peaks and troughs. The clinical experts consulted by CADTH noted that fidanacogene elaparvovec could be a curative treatment if a steady and high level of FIX is expressed.

The clinical experts consulted by CADTH noted that a first or later line of treatment is not an appropriate framework to describe the relationship between fidanacogene elaparvovec and FIX prophylaxis. The adoption of fidanacogene elaparvovec or FIX prophylaxis depends on the situation. For instance, fidanacogene elaparvovec is unlikely to be offered to newborn patients with hemophilia B, and newborn patients may need FIX prophylaxis for years before they are considered for gene therapy such as fidanacogene elaparvovec. Additionally, fidanacogene elaparvovec can be offered to not only patients who respond to FIX prophylaxis but also those who cannot or will not perform the injections of FIX due to reasons such as unreliable venous access, elbow arthropathy limiting self-infusion, needle phobia, or unwillingness. The clinical experts consulted by CADTH noted that it remains uncertain whether the use of fidanacogene elaparvovec will cause a shift in treatment paradigm.

The clinical experts noted that patients who qualify for fidanacogene elaparvovec would have been exposed to FIX concentrates since early childhood and that there are potential situations in which clinicians may discuss other options with patients before initiating fidanacogene elaparvovec. For instance, prophylaxis with an available EHL FIX product may not have been attempted, or nonfactor therapies may become available in the future (currently no nonfactor therapies are licensed for the indicated population). However, the clinical experts consulted by CADTH noted that these situations do not necessarily mean that patients must try other options before fidanacogene elaparvovec. The clinical experts indicated that the selection of treatment options will involve a shared decision-making process between clinicians and patients.

Patient Population

The clinical experts consulted by CADTH noted that all patients with hemophilia B who have a clinically severe phenotype (regardless of FIX level) are likely to benefit from treatment with fidanacogene elaparvovec in terms of reductions in burden of care, pain, and pain interference as well as improvement in mobility and quality of life. The clinical experts noted that those who would gain the most from fidanacogene elaparvovec treatment would be patients without pre-existing joint damage due to hemophilia B in terms of preserving joint function, as well as younger patients who are usually more active and would enjoy physical activity and being able to practise sports in a safer way.

The clinical experts noted that other patients with hemophilia B who would also benefit from fidanacogene elaparvovec include those on FIX prophylaxis with an ABR of 0 as the burden of care would be reduced, those not on prophylaxis who experience bleeding (ABR > 0) as they are likely to achieve an ABR of 0, those who are unable to adhere to prophylactic therapy, those with pre-existing joint damage as fidanacogene elaparvovec may reduce the progression to arthropathy and eliminate daily pain and aches, and those with recurrent bleeding despite prophylactic therapy.

The clinical experts noted that the patients who would be best suited for treatment with fidanacogene elaparvovec will be identified primarily by clinical assessment and shared decision-making with patients. A misdiagnosis (a false-positive due to diagnosis of hemophilia B in a patient with another bleeding disorder) is unlikely to occur in practice, as the laboratory measurement of plasma factor IX is a relatively sensitive and specific test, and because it is standard practice in Canada to confirm the phenotypic diagnosis of hemophilia B with genotyping. Testing for nAbs against AAVrh74var should be mandatory as a companion diagnostic test.

The clinical experts consulted by CADTH noted that the patients least suitable for fidanacogene elaparvovec include those with pre-existing anti-AAV antibodies and those who conclude that the benefit does not outweigh the risk associated with fidanacogene elaparvovec gene therapy, given that its long-term efficacy and safety remain unclear. In addition, some patients may not want to change their current treatment.

Assessing the Response Treatment

The clinical experts consulted by CADTH noted that the most important assessment of treatment response is monitoring patients’ bleeding to determine whether fidanacogene elaparvovec prevents bleeding events and allows patients to live the lifestyle they want without concerns about the risk of bleeding. The clinical experts noted that FIX activity levels may also be monitored to assess response to treatment; this can allow clinicians to determine the degree to which the deficiency in FIX has been corrected by fidanacogene elaparvovec. The clinical experts consulted by CADTH noted that a higher FIX activity level is in general associated with better bleeding outcomes (e.g., no bleeding). However, in some cases, there can be a discrepancy between FIX activity levels and bleeding outcomes.

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

The clinical experts consulted by CADTH noted that monitoring changes in the HJHS as well as in quality-of-life–related end points following fidanacogene elaparvovec infusion (e.g., improvement in activities associated with daily living, physical activity, and functioning; decrease in development of disability; and improvement in psychosocial health and functioning) are also important. The clinical experts added that the PROBE tool is typically used to measure quality of life in patients with hemophilia B in the Canadian setting instead of Haem-A-QoL and HAL, although these latter instruments are closely aligned in measuring quality of life, and PROBE includes questions covering activities of daily life.

Discontinuing Treatment

The “discontinuation of treatment” concept is not applicable to gene therapy, which is a 1-time treatment. The clinical experts consulted by CADTH noted that determination of treatment failure should be made by the treating clinician on a case-by-case basis. Although the pivotal trial has provided some definitions of treatment failure, the clinical experts consulted by CADTH noted that determining treatment failure is more complicated in clinical practice than in the clinical trial setting. The clinical experts noted that, if fidanacogene elaparvovec fails, patients may not be eligible for another gene therapy based on AAV vectors because they may present cross-reactivity against most AAV vectors. However, the clinical experts added that patients may in the future try alternative approaches to a gene therapy based on other viral vectors or even nonviral vectors, although this is hypothetical because no such gene therapy is currently available.

Prescribing Considerations

The clinical experts consulted by CADTH noted that fidanacogene elaparvovec should be prescribed based on the judgment of a multidisciplinary team organized by a comprehensive hemophilia treatment centre, and the team may consist of specialists such as a hematologist with experience in treating hemophilia patients, a physiotherapist to assess joint function, a hepatologist for liver-related issues, a pharmacist, and an HIV specialist if the patient is HIV-positive. The clinical experts consulted by CADTH noted that the administration of fidanacogene elaparvovec is on an outpatient basis, as are follow-ups following fidanacogene elaparvovec infusion for most patients (some may occasionally need to be admitted for follow-up).

Clinician Group Input

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

Nine clinicians from the AHCDC and 3 nurses from the CANHC provided input. Both the AHCDC and CANHC highlighted unmet needs for persons with hemophilia and a severe bleeding phenotype, and specifically hemophilia B. Both the AHCDC and CANHC mentioned that the treatment currently available in Canada does not modify or alter the underlying disease process, making persons with hemophilia B dependent for life on regular IV infusions of FIX to prevent and treat bleeding. In addition, the AHCDC emphasized the frequency of venipuncture required for prophylactic CFC replacement. The group noted that routine prophylaxis can be challenging for patients with poor venous access and the placement of a central venous catheter can lead to long-term complications, including risks of infection, bleeding, thromboembolism, and loss of function requiring removal. The group emphasized that all these factors lead to the need for persons with hemophilia B and a severe bleeding phenotype to restore coagulation factor levels to clinically effective levels without the need for frequent venipunctures on a regular basis throughout their lifespans. The AHCDC also discussed the variability of the efficacy of prophylaxis with CFCs across individuals, with some patients susceptible to breakthrough bleeding into joints and muscles. The group noted that these breakthrough bleeds result in pain, loss of function, absenteeism from work or school, reduced quality of life, and, more importantly, disability from progressive joint damage. Last, the AHCDC noted that the FIX trough levels associated with prophylaxis regimens are often insufficient to allow for safe anticoagulation or dual antiplatelet therapy.

Both the AHCDC and CANHC noted that fidanacogene elaparvovec would provide a 1-time treatment leading to sustained FIX production, addressing the underlying disease process and natural history rather than symptomatic management. This would 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 CFCs outside of clinical trials, making the need for gene therapy greater for hemophilia B patients.

The AHCDC noted that candidates for gene therapy include adults with hemophilia B and a clinically severe bleeding phenotype requiring prophylaxis, no history of inhibitory antibodies, no significant comorbidities, and no pre-existing anti-AAV nAbs. The group also highlighted the difficulty involved in estimating 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, detailed liver assessment, and 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 affect 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

AAV = adeno-associated virus vector; AAVrh74var = adeno-associated virus rh74 variant protein; ALT = alanine transaminase; AST = aspartate transaminase; CBS = Canadian Blood Services; FIX = coagulation factor IX; FIX:C = circulating coagulation factor IX; nAb = neutralizing antibody; rFIX = recombinant coagulation factor IX; rFIXFc = recombinant factor IX Fc fusion protein; vg = vector genome.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of fidanacogene elaparvovec, 1 × 10¹³ vg/mL, supplied as a concentrate solution for IV infusion in the treatment of moderately severe to severe hemophilia B in patients aged 18 years or older. The focus is on comparing fidanacogene elaparvovec to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of fidanacogene elaparvovec 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 additional studies that were considered by the sponsor to address important gaps in the systematic review evidence. No long-term extensions studies or indirect treatment comparisons were submitted by the sponsor.

Included Studies

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

• One pivotal phase III, open-label, single-arm study (along with a lead-in study conducted before the pivotal study to provide a comparator) identified in the systematic review

• One additional study (along with a lead-in study) addressing gaps in evidence.

Systematic Review

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the CADTH review team.

Description of Studies

One study (BeneGene-2),^1,9 which was conducted by the sponsor, met the inclusion criteria of the sponsor submitted SLR. Characteristics of BeneGene-2 are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

AAVrh74var = adeno-associated virus rh74 variant protein; ABR_l = annualized bleeding rate for treated and untreated bleeds; ABR_treat = annualized bleeding rate for treated bleeds; AIR = annualized infusion rate; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; BU = Bethesda units; FIX = coagulation factor IX; FIX:C = circulating coagulation factor IX; Haem-A-QoL = Hemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HJHS = Hemophilia Joint Health Score; nAb = neutralizing antibody; ULN = upper limit of normal.

Sources: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

BeneGene-2 is a phase III, open-label, single-arm study investigating the use of fidanacogene elaparvovec for the treatment of adult male patients with moderately severe to severe hemophilia B (defined as FIX:C ≤ 2%). BeneGene-2 was conducted in 45 participants from 27 centres across 13 countries or territories around the globe, including 3 centres in Canada.¹ The primary objective was to demonstrate the noninferiority of fidanacogene elaparvovec as opposed to FIX prophylaxis replacement therapy via ABR_total from week 12 to month 15 postinfusion.^1,10 Superiority of fidanacogene elaparvovec via ABR_total was a secondary objective if noninferiority was established. BeneGene-2 is ongoing and expected to be completed in December 2029. Data from the data cut-off date (November 16, 2022) were used to support the sponsor’s present submission to CADTH.^9,10 As of the data cut-off date, the mean duration of follow-up in the BeneGene-2 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||.

The 45 participants enrolled in the pivotal BeneGene-2 phase III trial were selected from patients who had completed at least 6 months of FIX prophylaxis during the BeneGene-1 study.²⁸ The Bene-Gene-1 study was an open-label, noninvestigational-product, prospective, multicentre, lead-in study conducted before the BeneGene-2 trial to prospectively collect efficacy and safety data of current FIX prophylaxis replacement therapy in the usual care setting of adult male participants with moderately severe to severe hemophilia B (FIX:C ≤ 2%) (Figure 1). FIX prophylaxis replacement therapy was continued during the patient screening stage in the BeneGene-2 trial until the infusion of fidanacogene elaparvovec. The outcome data of the FIX prophylaxis replacement therapy during the BeneGene-1 trial as well as the stage of patient screening were used by the sponsor to serve as a comparator to the fidanacogene elaparvovec arm in the BeneGene-2 trial.

The duration of follow-up for participants in the lead-in BeneGene-1 trial was at least 6 months until the completion of the trial for patients with hemophilia B, which was determined when the number of treated participants required for the pivotal BeneGene-2 trial were met. The mean duration of follow-up in the lead-in BeneGene-1 trial was |||| ||||| ||||||| with a median of |||| |||||||||| ||||| Based on number of infusions, ||||| ||||||| of the patients in the BeneGene-1 trial were ≥ 80% compliant and |||| |||||| were < 70% compliant.

Figure 1: BeneGene-1 and BeneGene-2 Study Design

Source: Sponsor’s Summary of Clinical Evidence.¹

Populations

Inclusion and Exclusion Criteria

BeneGene-2 included male participants (≥ 18 years old) with moderately severe to severe hemophilia B (defined as FIX:C ≤ 2%), who must have completed 6 months or more of routine FIX prophylaxis therapy during the lead-in BeneGene-1 trial and agreed to suspend prophylactic FIX therapy following fidanacogene elaparvovec infusion. Patients with nAbs or a history of or presence of FIX inhibitors or with elevated LFTs or bilirubin, relevant unstable or significant liver disease, infection, or clinically relevant disease were excluded.

Interventions

In the pivotal BeneGene-2, fidanacogene elaparvovec was administered as a single IV infusion over 1 hour on day 1 at a dose of 5 × 10¹¹ vg/kg of body weight. For participants with a body mass index greater than 30 kg/m², the dose was calculated using a maximum permissible body mass index of 30 kg/m².

Participants in the Benegene-2 trial were asked to suspend their FIX prophylaxis regimen following fidanacogene elaparvovec infusion. However, FIX replacement therapy was allowed as needed:

• For a bleeding event, the trial investigator recommended an appropriate dose of FIX to treat the bleed because the dose of factor concentrate should include the recent steady-state fidanacogene elaparvovec–induced FIX activity levels to avoid overdosing resulting in a potential thrombotic event.

• A participant might resume prophylaxis if fidanacogene elaparvovec was considered inefficacious, defined as FIX activity after 12 weeks of 2% or lower (in the absence of a confirmed FIX inhibitor) as determined by the central laboratory on 2 consecutive samples collected within a 2-week period, and/or over a 4-week period (in the absence of a confirmed FIX inhibitor) of 2 or more spontaneous bleeds into a major joint and/or target joint, or over a 4-week period (in the absence of a confirmed FIX inhibitor) of 3 or more spontaneous bleeds (consisting of joint bleeds and/or significant soft tissue/muscle or other site bleeds).

A tapering course of oral corticosteroids (i.e., prednisone or prednisolone) was the first consideration for the suppression of apparent immune hepatitis. Due to the importance of timely intervention of corticosteroids, decisions to begin treatment were based on local laboratory values. Approximately 60 mg to 100 mg of oral corticosteroids once a day for the first week was recommended as the starting dosage unless the investigator determined that a different regimen was preferable based on the patient’s medical history. The first-week dose could be extended for another week, according to the judgment of the investigator, if the patient experienced no adverse effects. Guidance given was that the subsequent prednisolone or prednisone taper should not be started until the ALT and/or AST levels had declined for at least 2 consecutive lab draws or returned to approximately baseline (pre-administration) levels and any decline in FIX:C activity had plateaued. Combined oral corticosteroids and IV corticosteroids (methylprednisolone) was recommended if there was no evidence of resolution of transaminase elevation while on oral corticosteroid treatment alone.

Outcomes

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

Descriptions of efficacy and safety outcomes presented in the BeneGene-2 trial and appraised in the CADTH Clinical Reviews are as described in the following section.^10,29

Table 7: Outcomes Summarized from BeneGene-2

ABR_joint = annualized bleeding rate for untreated and treated joint bleeds; ABR_total = annualized bleeding rate for treated and untreated bleeds; ABR_treat = annualized bleeding rate for treated bleeds; AIR = annualized infusion rate; FIX = coagulation factor IX; Haem-A-QoL = Hemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score.

^aYear 1 refers to the period between week 12 and month 15 following fidanacogene elaparvovec infusion.

^bOverall refers to the period between week 12 and the data cut-off date of November 16, 2022. The mean duration of follow-up in the pivotal BeneGene-2 was |||| ||||| ||||||| with a median of |||| ||||| ||||| |||||

Source: BeneGene-2 study protocol incorporating Amendment 3.¹⁰

Efficacy Outcomes

Annualized Bleeding Rate for Treated and Untreated Bleeds

The ABR_total included treated bleeds (defined as an event that required FIX infusion within 72 hours of signs or symptoms of bleeding) and untreated bleeds (defined as a bleeding event that did not require FIX infusion within 72 hours of signs or symptoms of bleeding). Every occurrence of bleed events was counted as a separate bleed if occurring more than 72 hours after the previous bleed at the same site or more than 72 hours after stopping treatment.

The ABR_total for each participant was calculated using the following formula:

The ABR_total excluded surgical or procedural bleeds (defined as a bleed related to a procedure or surgery such as hematomas or bruising resulting from any surgery or invasive procedure or invasive diagnostic procedure, and bleeds related to procedures or surgery not associated with any trauma except procedure- or surgery-induced trauma). If a prophylaxis FIX regimen was resumed for a participant after fidanacogene elaparvovec infusion, the time period following the resumption of the prophylaxis regimen was excluded from the ABR end point calculation, which means the bleeding events would be excluded and the time period of observation would be deducted as well.

To calculate the ABR_total from the lead-in BeneGene-1 trial, the denominator of the formula presented earlier was the date of fidanacogene elaparvovec infusion minus the date of enrolment in the BeneGene-1 trial in the comparison between ABR_total at year 1 following fidanacogene elaparvovec infusion versus the lead-in period. The same comparator group of the lead-in period was utilized in the comparison of ABR_total (overall) versus the lead-in period. The time periods were the same across outcomes for the ABR, AIR, and annualized FIX consumption, except that the postresumption period for the ABR was not counted in the follow-up duration and bleeds occurring postresumption were excluded from the ABR calculation as well. However, the postresumption period was included for the AIR calculation.

In addition, a hand-held electronic diary was provided to all participants. The participants were required to enter any occurrence of hemophilic bleeding episodes (including date, time, location, and etiology) and any exogenous FIX replacement (including date, time, reason, and dose) required to treat the bleeds in the diary. If bleeding episodes or treatments were not entered in the diary during the appropriate time window, data were to be entered by the investigator (or appropriate site staff member) according to the process in place with appropriate source documentation in the participant’s medical record.

Annualized Bleeding Rate for Treated Bleeds and Annualized Bleeding Rate for Treated and Untreated Joint Bleeds

The ABR_treat involved treated bleeds only, while the ABR_joint involved joint bleeds only, which were defined as a bleeding episode characterized by rapid loss of range of motion compared with baseline that was associated with any combination of the following: pain or an unusual sensation in the joint, palpable swelling, and warmth of the skin over the joint. The calculation of an ABR_treat or ABR_joint used the same methods as for the ABR_total, except only treated bleeds or joint bleeds were included.

Annualized Infusion Rate

The AIR included all FIX infusions during the observation period for any purpose, including treating bleeding, preventive purposes, perioperative purposes, or if a prophylaxis FIX regimen was resumed.

The AIR for each participant was calculated using the following formula:

Descriptions of HJHS, Haem-A-QoL, and HAL are shown in Table 8.

Table 8: Summary of Outcome Measures and Their Measurement Properties

Haem-A-QoL = Hemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score; HJHS 2.1 = Hemophilia Joint Health Score version 2.1; ICC = intraclass correlation coefficient; MID = minimal important difference; SDC = smallest detectable change; SEM = standard error of measurement; WFH = World Federation of Hemophilia.

Harms Outcomes

The harms outcomes assessed in the BeneGene-2 trial included TEAEs, TESAEs, withdrawals due to AEs, mortality, and notable harms (e.g., increased ALT, increased AST, and abnormal hepatic function). AEs were coded using the Medical Dictionary for Regulatory Activities. TEAEs included any AEs that occurred on or after the infusion of fidanacogene elaparvovec.

Statistical Analysis

In the pivotal BeneGene-2 trial, all hypothesis testing was 2-sided, unless specified otherwise. The primary objective was to determine the efficacy of fidanacogene elaparvovec in adult males with moderately severe to severe hemophilia B (FIX:C ≤ 2%), quantified by the primary end point of an ABR_total. The primary hypothesis was noninferiority pre- and posttreatment with fidanacogene elaparvovec on the ABR_total. If noninferiority was demonstrated on the ABR_total outcome, subsequent testing for superiority would be conducted. The test of superiority via an ABR_total was considered a secondary analysis.

A gatekeeping process was applied to control for multiplicity when testing multiple end points at the primary analysis. The subsequent hypothesis testing was performed only after success on a previous hypothesis test, with each test performed at the type I error rate defined for the primary analysis (0.05). The analyses would cease when a failure occurred. The sequence of gatekeeping process of multiple hypothesis tests in the BeneGene-2 trial is shown below in the following order:

1. ABR_total noninferior to FIX prophylaxis regimen (The upper bound of the confidence interval of the difference in ABR_total and ABR_treat between pre– and post–fidanacogene elaparvovec infusion was compared to the noninferiority margin. All other hypothesis tests were 2-sided.).

2. ABR_treat noninferior to FIX prophylaxis regimen.

3. AIR superior to FIX prophylaxis regimen.

4. Steady state FIX:C > 5% (Steady-state FIX:C was analyzed using a 1-sided, 1-sample t test.).

5. FIX consumption superior to FIX prophylaxis regimen.

6. ABR_treat superior to FIX prophylaxis regimen.

7. ABR_total superior to FIX prophylaxis regimen.

8. Haem-A-QoL Physical Health domain significantly improved from baseline.

9. HAL Complex Lower Extremity component significantly improved from baseline.

10. ABR_total of specific bleed type noninferior to FIX prophylaxis regimen, and HJHS.

Participants who completed the lead-in BeneGene-1 study were screened into the BeneGene-2 trial to achieve a desired sample size of 40 eligible participants assigned to fidanacogene elaparvovec. The sample size could have exceeded 40 participants because all participants who completed the lead-in study and met other eligibility criteria were allowed to participate in this study. When all 40 participants had completed at least 15 months of follow-up after fidanacogene elaparvovec infusion, the number of observed ABR_total events would provide at least 90% power (1-sided test with an alpha of 0.025) to demonstrate noninferiority of fidanacogene elaparvovec compared to prophylaxis treatment against a noninferiority margin of 3.0 bleeds per year under an assumed negative binomial regression with repeated measures.

The noninferiority margin for the ABR_total was determined by the sponsor using the constancy assumption and the “95% to 95%” methods.^51,52 The noninferiority margin was based on previously reported effects of prophylaxis over on-demand treatment and was expressed as the mean difference in the ABR in a single-arm trial, with a switch from on-demand to prophylaxis using a paired comparison. Based on the lower bound of the CI of an estimate for the ABR for treated bleeds (defined as an event that required FIX infusion within 72 hours of signs or symptoms of bleeding) in on-demand participants, the ABR for treated bleeds was assumed to be higher by at least 24.5 and was considered M1 in the noninferiority test setting for the ABR for treated bleeds. It was assumed that the treatment difference (on-demand – prophylaxis) in the ABR_total was proportional to that in the ABR for treated bleeds. The ratio of the treatment difference (ABR_total over ABR_treat) was estimated to be 1.17. The M1 for ABR_total was therefore estimated to be 28.7 (1.17 × 24.5). Given the large effect size of prophylaxis treatment (over on-demand therapy), an appropriate value for M2 was considered to preserve a sufficiently large proportion of this effect. Simulations were conducted to assess preservation levels of 80%, 85%, and 90% of M1. These percentages corresponded to noninferiority margin values of 5.7, 4.3, and 2.9 bleeding events per year respectively, on an absolute scale. A value of 3.0 for M2 (approximately 89.5% of the M1 effect preserved) was proposed to be both clinically meaningful and yielded a reasonable sample size for establishing efficacy. In addition, the noninferiority margin of 3.0 was in line with differences observed in the ABR for treated bleeds in the real-world and clinical-trial settings. A superiority margin of 0 was used for the ABR_total to demonstrate a better response for fidanacogene elaparvovec.

Details of the statistical analysis of efficacy end points in the BeneGene-2 trial are presented in Table 9.

Table 9: Statistical Analysis of Efficacy End Points in BeneGene-2

ABR_joint = annualized bleeding rate for treated and untreated joint bleeds; ABR_total = annualized bleeding rate for treated and untreated bleeds; ABR_treat = annualized bleeding rate for treated bleeds; AIR = annualized infusion rate; CI = confidence interval; FIX = coagulation factor IX; Haem-A-QoL = Hemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score. NA = not applicable.

Sources: BeneGene-2 Study Protocol Incorporating Amendment 3,¹⁰ BeneGene-2 Statistical Analysis Plan version 6²⁹ and the sponsor’s Summary of Clinical Evidence.¹

Analysis Populations

Analysis populations of the BeneGene-2 trial are summarized in Table 10.

Table 10: Analysis Populations of BeneGene-2

^aSignificant interruption was determined after discussion between the investigator and the medical monitor, e.g., if a participant required a major surgery, this would be a significant interruption of measurement.

Sources: BeneGene-2 study protocol incorporating Amendment 3¹⁰ and the sponsor’s Summary of Clinical Evidence.¹

Protocol Amendments and Deviations

Three amendments were made to the protocol. The original protocol and the protocol with Amendment 3 were issued on December 13, 2018, and June 29, 2022, respectively. In protocol Amendment 3, the primary end point was revised from the ABR_treat to the ABR_total. In protocol amendments 2 and 3, the start point for outcome analysis was revised from day 1 following fidanacogene elaparvovec infusion to week 12 postinfusion to correspond with the estimated FIX:C steady-state onset.¹⁰

Common protocol deviations were related to specimens that could not be analyzed, lab work not done, procedures and or tests not done, procedures and/or tests not performed following protocol, procedures and or tests performed out of window, and electronic diary not completed.⁹

Results

Patient Disposition

The lead-in BeneGene-1 study enrolled 102 participants, of whom 59 (57.8%) completed the study and 3 (2.9%) discontinued. As of the data cut-off on November 2, 2022, 40 participants (39.2%) were continuing the study. Among 59 patients who completed the BeneGene-1 study, 8 decided not to continue onto the BeneGene-2 trial; as a result, 51 patients from the lead-in BeneGene-1 study entered the screening phase of the BeneGene-2 trial.

A summary of patient disposition in the BeneGene-2 trial is presented in Table 11. Of the 51 patients from the BeneGene-1 study, 5 (9.8%) discontinued due to screen failures, reasons for which included an nAb titre above the established threshold; the patient did not complete 6 months of routine FIX prophylaxis therapy during the lead-in study and had 50 or more lifetime exposure days to a FIX protein product; the patient was unable to comply with scheduled visits, treatment plans and laboratory tests and other study procedures for up to 6 years postinfusion; the patient had current unstable liver or biliary disease; and screening laboratory values for hemoglobin, platelets and creatinine were outside of acceptable range.²⁸ In addition, 1 patient withdrew from screening due to the COVID-19 pandemic and hepatocellular carcinoma risk (classified under “Other” by the sponsor).

All 45 participants completed the 1-time fidanacogene elaparvovec IV infusion. Forty-three (84.3%) of the participants had completed follow-ups up to and including 52 weeks following fidanacogene elaparvovec IV infusion as of the data cut-off on November 16, 2022. During the long-term follow-up, 1 patient discontinued after losing motivation due to a self-reported “lack of efficacy.”²⁸

Table 11: Summary of Patient Disposition from BeneGene-2

FIX = coagulation factor IX.

Note: As of the data cut-off date of November 16, 2022.

^aThe participant resumed FIX prophylaxis on day 365 following fidanacogene elaparvovec infusion and withdrew on day 910.

Sources: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Baseline Characteristics

The baseline characteristics listed in Table 12 are limited to those most relevant to this review or assumed to affect the outcomes or interpretation of the study results. Patients who completed the lead-in BeneGene-1 study and enrolled in the BeneGene-2 trial were aged between 18 and 62 years with a median of 29 years. The majority of patients were white (73.3%). All participants had a factor mutation, including 7 (15.6%) with a nonsense mutation, 20 (44.4%) with a missense mutation, 0 with an insertion, 9 (20%) with a deletion, 0 with an inversion, and 9 (20%) with other mutations. Thirteen participants (28.9%) had at least 1 target joint at baseline, which was defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and ankle) into which repeated bleeds occur (3 or more spontaneous bleeds into a single joint within a consecutive 6-month period). Moreover, 84.4% of the 45 patients had a FIX level below 1%, while the remaining patients’ FIX levels were between 1% and 2% (inclusive). In addition, 53.3% of the patients had a family history of hemophilia.

Exposure to Study Treatments

Details on the extent of exposure to fidanacogene elaparvovec in the BeneGene-2 trial are summarized in Table 13. In the 45 participants, the median total dose of fidanacogene elaparvovec infusion was ||||||||||||||||||||||||||||||||||||||||||||||||||||| vg.

Prior and Concomitant Treatments

Prior or concomitant medications were reported in || ||||||| of the safety population of BeneGene-2 (N = 45).⁹ The most commonly reported prior medications included paracetamol in 7 participants (15.6%) and celecoxib in 6 participants (13.3%). The most commonly used concomitant medications included prednisone in || ||||||| participants, prednisolone in || ||||||| participants, and paracetamol in || ||||||| participants.

Table 12: Summary of Baseline Characteristics From BeneGene-2 (Safety Population)

BMI = body mass index; FIX = coagulation factor IX; SD = standard deviation.

Note: As of the data cut-off date of November 16, 2022.

^aCounts and percentages of subjects with positive laboratory results for the corresponding parameter.

^bA target joint was defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and ankle) into which repeated bleeds occur (3 or more spontaneous bleeds into a single joint within a consecutive 6-month period). A target joint is considered resolved when there are no more than 2 bleeds into the joint within a 12-month period.

Sources: BeneGene-2 Clinical Study Report^9,53 and the sponsor’s Summary of Clinical Evidence.¹

Table 13: Summary of Patient Exposure From BeneGene-2 (Dosed Population)

SD = standard deviation; vg = vector genome.

Note: As of data cut-off date November 16, 2022.

^aThe actual dose was adjusted from the planned dose when a participant’s body mass index was greater than 30 kg/m².

Source: BeneGene-2 Clinical Study Report.⁹

Use of FIX Prophylaxis Post–Fidanacogene Elaparvovec Infusion

The summary of participants resuming FIX prophylaxis regimen after fidanacogene elaparvovec infusion in the BeneGene-2 trial is presented in Table 14. In total, 6 out of 45 (13.3%) participants had resumed prophylaxis therapy, with time to resumption ranging from 5.1 months to 20.5 months. All of the patients resumed FIX prophylaxis within 15 months after fidanacogene elaparvovec infusion except 1 patient who resumed after 15 months postinfusion.

Table 14: Summary of Participants Resuming FIX Prophylaxis Post–Fidanacogene Elaparvovec Infusion (Dosed Population)

FIX = coagulation factor IX.

Note: As of the data cut-off date of November 16, 2022. Overall includes from day 1 to data cut-off date.

^aThe percentage was calculated using the number of participants who were in follow-up at the start of the interval as the denominator.

Source: BeneGene-2 Clinical Study Report.⁹

Efficacy

Key efficacy results in the dosed population of the BeneGene-2 trial are presented in Table 15. The data cut-off date was November 16, 2022.

Annualized Bleeding Rate for Treated and Untreated Bleeds

The model estimates of the mean difference in the ABR_total between patients who were treated with fidanacogene elaparvovec during the BeneGene-2 trial and the ABR_total from the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial was −3.13 (95% CI, −5.44 to −0.81) at year 1 following fidanacogene elaparvovec infusion, favouring fidanacogene elaparvovec, which met the noninferiority margin (3.0 bleeds per year) as well as the criteria for subsequent hierarchical testing for superiority. The difference in the ABR_total from week 12 to data cut-off date (overall) was ||||| |||||| || ||||||, in favour of fidanacogene elaparvovec.

Totals of 29 of 45 (64.4%) of the patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and 13 of 45 (28.9%) of the patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial had no bleeds (untreated and treated) at year 1 following fidanacogene elaparvovec infusion. From week 12 to the data cut-off date postinfusion, ||||| ||||||| of the patients treated with fidanacogene elaparvovec infusion during BeneGene-2 and ||||| ||||||| of the patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial had no bleeds.

A “jump to reference” sensitivity analysis was conducted to assess the impact of participants who discontinued or resumed FIX prophylaxis before completing the 15 months of follow-up after fidanacogene elaparvovec infusion. In total, 5 patients were included in the sensitivity analysis, among them 4 who resumed FIX prophylaxis within 15 months after fidanacogene elaparvovec infusion as well as 1 who resumed FIX prophylaxis within 15 months after fidanacogene elaparvovec infusion but who withdrew on ||| ||| postinfusion. One other patient also resumed FIX prophylaxis but only after 15 months postinfusion, and was therefore excluded from the sensitivity analysis. Results |||| |||||||||| with the primary analyses: The difference in the ABR_total was ||||| |||||| || ||||||, favouring fidanacogene elaparvovec, and the percentages of patients who had no treated and untreated bleeds were ||||| in patients who were treated with fidanacogene elaparvovec infusion during the BeneGene-2 trial versus ||||| the same patients who were treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial (Appendix 1, Table 19).

Annualized Bleeding Rate for Treated Bleeds

The estimated mean differences in the ABR_treat between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial were −2.62 (−4.27 to −0.96) at year 1 following fidanacogene elaparvovec infusion and ||||| |||||| || |||||| from week 12 to the data cut-off date, all in favour of fidanacogene elaparvovec.

A comparison of the 2 studies found that 73.3% (33 of 45) of the patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and 35.6% (16 of 45) of the patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial had no treated bleeds at year 1 following fidanacogene elaparvovec infusion. ||||| ||||||| of the patients treated with fidanacogene elaparvovec infusion during the BeneGene-2 trial and ||||| ||||||| of the patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial had no treated bleeds.

Annualized Bleeding Rate for Treated and Untreated Joint Bleeds

The estimated mean difference in the ABR_joint between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial was ||||| |||||| || |||||| at year 1 following fidanacogene elaparvovec infusion, ||||||||| fidanacogene elaparvovec. From week 12 to the data cut-off date, the difference was ||||| |||||| || ||||||| ||||||||| fidanacogene elaparvovec.

Comparing the 2 studies, 68.9% (31 of 45) of the patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and 44.4% (20 of 45) of the patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial had no joint bleeds at year 1 following fidanacogene elaparvovec infusion. ||||| ||||||| of the patients treated with fidanacogene elaparvovec infusion during BeneGene-2 and ||||| ||||||| of the patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial had no joint bleeds.

Annualized Infusion Rate

The differences in the AIR between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial was −54.37 (−63.64 to −45.10) at year 1 following fidanacogene elaparvovec infusion and |||||| ||||||| || ||||||| from week 12 to data cut-off date, all favouring fidanacogene elaparvovec.

Annualized FIX Consumption

Overall (from week 12 to the data cut-off date following fidanacogene elaparvovec infusion), the difference in the annualized FIX consumption between patients treated with fidanacogene elaparvovec during the BeneGene-2 trial and the same patients treated with routine FIX prophylaxis during the lead-in BeneGene-1 trial was |||||||| ||||| ||||||||| || |||||||||| ||||||||| fidanacogene elaparvovec.

Hemophilia Joint Health Score

Change from baseline at week 52 or week 104 following fidanacogene elaparvovec infusion |||||| |||||||||||| in the HJHS total score in patients treated with fidanacogene elaparvovec.

Hemophilia Quality of Life Questionnaire for Adults

At week 52 or week 104 following fidanacogene elaparvovec infusion, the Haem-A-QoL physical health score and total score |||| ||||||||.

Hemophilia Activities List

|||||||||, at week 52 or week 104 following fidanacogene elaparvovec infusion, the score of HAL complex lower extremity activities and the HAL score |||||||||

Table 15: Summary of Key Efficacy Results From the Pivotal BeneGene-2 and Lead-in BeneGene-1 Trials (Dosed Population)

ABR = annualized bleeding rate; ABR_joint = annualized bleeding rate for treated and untreated joint bleeds; ABR_total = annualized bleeding rate for treated and untreated bleeds; ABRtreat = annualized bleeding rate for treated bleeds; AIR = annualized infusion rate; CI = confidence interval; FIX = coagulation factor IX; Haem-A-QoL = Hemophilia Quality of Life Questionnaire for Adults; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score; SD = standard deviation.

Note: Year 1 refers to the period between week 12 and month 15 following fidanacogene elaparvovec infusion. Overall refers to the period from week 12 following fidanacogene elaparvovec infusion to the data cut-off date of November 16, 2022. As of the data cut-off date, the mean duration of follow-up in the pivotal BeneGene-2 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||| Week 52 and week 104’s baseline was defined as the last nonmissing measurement before the dosing date (day 1) in the pivotal study. The mean duration of follow-up in the lead-in BeneGene-1 trial was |||| ||||| ||||||| with a median of |||| ||||| ||||| ||||.

^aNumber of patients who were in follow-up at the start of the period interval.

^bDerived from a repeated measures generalized linear model with negative binomial distribution.

^cThe treatment difference and P value were obtained from a repeated measures generalized linear model with negative binomial distribution and identity link function.

^dThe percentage reduction and P value were obtained from a repeated measures generalized linear model with a negative binomial distribution and log link function.

^eThe treatment difference estimate (95% CI) and P value were obtained from a paired t test.

^fPercentage reduction in mean the AIR was calculated as (1 − mean AIR for FIX from week 12 to month 15 following fidanacogene elaparvovec infusion / mean AIR during standard of care FIX replacement regimen) × 100%.

^gPercent reduction in mean annualized FIX consumption was calculated as (1 − mean annualized FIX consumption for FIX during the respective year interval following fidanacogene elaparvovec infusion / mean annualized FIX consumption during standard of care FIX replacement regimen) × 100%.

^hThe change from baseline, 95% CI, and P value were obtained from a paired t test.

Source: BeneGene-2 Clinical Study Report.⁹

Harms

A summary of harms in the BeneGene-2 trial is shown in Table 16. The data cut-off date for the harms data was November 16, 2022.

Adverse Events

Treatment-emergent AEs were reported in 84.4% (38 of 45) of the safety population in the BeneGene-2 trial. The most commonly reported TEAE was increased ALT (26.7%), followed by nasopharyngitis (17.8%) and arthralgia (17.8%).

Serious Adverse Events

Serious adverse events were reported in 7 patients (15.6%) in the BeneGene-2 trial. The most common SAE was anemia (4.4%).

Withdrawal due to Adverse Events

No patients in the BeneGene-2 trial continued the study due to AEs as of the data cut-off date of November 16, 2022.

Mortality

No patients in the BeneGene-2 trial died as of the data cut-off date of November 16, 2022.

Notable Harms

Increased ALT and abnormal hepatic function occurred in 26.7% (12 of 45) and 13.3% (6 of 45) of the patients in the BeneGene-2 trial, respectively. Increased AST, increased hepatic enzyme, and increased transaminases occurred in 6.7% (3 of 45) of the patients in the BeneGene-2 trial, respectively.

Table 16: Summary of Harms Results from BeneGene-2 (Safety Population)

ALT = alanine transaminase; AST = aspartate transaminase; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event

Note: Data cut-off date: November 16, 2022.

Source: BeneGene-2 Clinical Study Report.⁹

The harms data were reported in the 102 patients who participated in the lead-in to BeneGene-1 trial.¹ Among them, a total of 16 (15.7%) participants had AEs, of whom 5 (4.9%) experienced injury, poisoning and procedural complications and 5 (4.9%) experienced musculoskeletal and connective tissue disorders. In terms of SAEs, out of 102 participants, 6 (5.9%) had SAEs, of whom 3 (2.9%) had gastrointestinal hemorrhage, joint injury, and arthropathy. No participants discontinued from the BeneGene-1 trial due to AEs, and no deaths occurred. In terms of notable harms, 2 patients (2.0%) reported hypersensitivity.

Critical Appraisal

Internal Validity

The BeneGene-2 trial, the only eligible study identified by the sponsor-conducted SLR, was a phase III, single-arm, open-label clinical trial that enrolled 45 patients. To determine the relative efficacy of fidanacogene elaparvovec and FIX prophylaxis on patient outcomes (i.e., the standard of care in Canada), patients in the BeneGene-2 trial served as their own controls for efficacy outcomes (e.g., ABR_total, ABR_treat, ABR_joint, AIR, and annualized FIX consumption). Specifically, data collected from the same patients who were on FIX prophylaxis for at least 6 months during the lead-in phase (the BeneGene-1 trial) before the pivotal BeneGene-2 trial were used for comparison. Although interpretation of the study results is limited due to the nonrandomized, open-label, single-arm design, the discontinuity design was considered appropriate in the field of hemophilia B by the clinical experts consulted by CADTH for this review.

Participants in the BeneGene-2 trial were requested to suspend their FIX prophylaxis regimen after fidanacogene elaparvovec infusion but were allowed to resume FIX prophylaxis based on certain conditions. These conditions were considered generally appropriate by the clinical experts consulted by CADTH. Moreover, the resumption of FIX prophylaxis regimen postinfusion in the BeneGene-2 trial was not expected to modify treatment effects, ||||||||| || ||| ||||| || |||||||||| ||||||||||| |||||||| || ||||| |||||||||||| ||| ||||||| ||| ||||||||||| |||||||| |||| |||||||| || |||||||||||| ||||||||||| |||| |||||||| ||| ||| |||||||||| || || ||||||| || |||| |||| ||| ||||||| ||||||||.

To suppress immune hepatitis, patients can be treated with corticosteroids following fidanacogene elaparvovec infusion under certain circumstances, which the clinical experts consulted by CADTH determined were appropriate. Still, a relatively large proportion of patients (28 of 45) were given corticosteroids following fidanacogene elaparvovec infusion. Although a subgroup analysis based on corticosteroid use was carried out by the sponsor (data not shown), the effect of corticosteroid use following fidanacogene elaparvovec treatment remains unclear because the subgroup analysis was unadjusted for confounding variables, and the BeneGene-2 trial was not powered to perform a comparison based on corticosteroid use.

The clinical experts consulted by CADTH for this review noted that the inclusion and exclusion criteria in the BeneGene-2 trial were appropriate and reflective of patients they would have expected to experience in clinical practice. The patients included in the BeneGene-2 trial were selected from the lead-in BeneGene-1 trial according to an additional set of criteria on top of those specified in the BeneGene-1 trial. CADTH found that the purpose of the additional criteria specified in the BeneGene-2 trial was mainly to ensure that patients had acceptable conditions to receive the gene therapy of interest (fidanacogene elaparvovec). Of the 102 patients in the lead-in BeneGene-1 study, only 45 were enrolled in the pivotal BeneGene-2 trial, while 57 were not. Other than 8 who chose not to continue into the BeneGene-2 trial and 9 who failed the BeneGene-2 screening, the remaining and majority (40 patients) of the 57 patients did not enter the BeneGene-2 trial because they had not completed the BeneGene-1 study. It was determined by CADTH that the potential selection bias due to a large number of patients being left out was not a serious concern because the data provided by the sponsor showed that outcomes of the 40 patients, such as the ABR_total, ABR_treat, and AIR, were similar to the those at year 1 postinfusion among the 45 patients enrolled in the BeneGene-2 trial.

No major concerns were associated with patient compliance to FIX prophylaxis in the BeneGene-1 trial, with ||| |||||||| || |||||||| |||||| |||||||| in the BeneGene-1 trial being 80% or more compliant based on number of infusions. The documentation of bleeding events in the BeneGene-2 trial relied on the use of electronic diaries by patients, and the determination of whether a bleed needs to be treated relied on physicians’ clinical decisions shared with patients. Despite the risk of bias likely being low, and based on information provided by the sponsor, CADTH determined that the possibility of bias that may exaggerate the treatment effects of fidanacogene elaparvovec (i.e., ABR outcomes) could not be ruled out. Furthermore, due to the single-arm, open-label design, reliable assessments of patient-reported outcomes (e.g., HRQoL end points) could not be made.

According to the clinical experts consulted by CADTH, the definitions of the efficacy outcomes such as the ABR_total and AIR, the start point for outcome analysis (week 12 after fidanacogene elaparvovec infusion instead of immediately postinfusion), as well as the noninferiority margin for the ABR_total were acceptable. In addition, CADTH determined that the gatekeeping process applied to control for multiplicity of testing multiple end points was appropriate. However, there were some concerns about the statistical models (assumptions) used to inform the comparative efficacy of fidanacogene elaparvovec relative to FIX prophylaxis. The first assumption, which was considered reasonable by the experts consulted by CADTH, was that rate of bleeding during FIX prophylaxis in the BeneGene-1 trial would be comparable to the bleeding rate during the BeneGene-2 trial if FIX prophylaxis had not been discontinued and fidanacogene elaparvovec not been given as an intervention. This assumption is required to interpret observed differences in bleeding rates pre– and post–fidanacogene elaparvovec treatment intervention in the BeneGene-2 trial. The second assumption of the negative binomial mixed model is that the cohort bleed rates were constant during the entire period of study. The challenge lies in interpreting the magnitude of the effect estimates of fidanacogene elaparvovec compared to FIX prophylaxis as the model describes a weighted average of the rate of bleeding over time that is dependent on the observed censoring mechanism.

External Validity

CADTH identified several considerations related to the generalizability of the BeneGene-2 trial. First and most importantly, given the novelty of gene therapy and the expectation of long-lasting effects, evidence from current follow-up period (|||| ||| |||||) in the BeneGene-2 trial may not be adequate to inform long-term efficacy and safety.

Second, the indication includes patients with “moderately severe to severe” hemophilia B. The BeneGene-2 trial defined “moderately severe to severe” as a FIX:C level less than or equal to 2%. However, the clinical experts consulted by CADTH noted that severity in clinical practice is defined by the patients’ phenotype and not simply their factor activity levels. In some patients, the disease will be considered moderately severe to severe due to clinical symptoms although the FIX level is greater than 2%, according to the clinical experts consulted by CADTH.

Third, the BeneGene-2 trial only included patients with an anti-AAVrh74var nAb titre of less than 1:1. According to the clinical experts consulted by CADTH, the efficacy of fidanacogene elaparvovec in patients with an anti-AAVrh74var nAb titre greater than or equal to 1:1 remains uncertain. However, the clinical experts consulted by CADTH agreed that selection of eligible patients should follow the threshold used in the BeneGene-2 trial.

Fourth, the indication does not specify sex (i.e., it includes both men and women) but the product monograph states that fidanacogene elaparvovec is not intended for administration in women. Following the protocol, BeneGene-2 only enrolled male patients.

Fifth, 73.3% (33 of 45) of the patients in the BeneGene-2 trial were white, which, according to the clinical experts consulted by CADTH, was higher than would be expected in the patient population in Canada.

Sixth, the clinical experts consulted by CADTH noted that PROBE is more commonly used in the Canadian settings to measure HRQoL, rather than Haem-A-QoL and HAL, which were used in the BeneGene-2 trial. However, this was not considered a serious generalizability issue because all these HRQoL measurement instruments are aligned.

Last, results from the lead-in BeneGene-1 trial were from patients treated with EHL FIX or SHL FIX. No supplemental analyses were submitted comparing fidanacogene elaparvovec with FIX prophylaxis based on the type of FIX concentrate (e.g., EHL versus SHL) used in prophylaxis. According to the clinical experts consulted by CADTH, the key difference between EHL and SHL FIX in treating patients is the frequency of infusion. Due to its half-life, EHL FIX may be associated with a lower ABR. However, the clinical experts consulted by CADTH raised no concerns about applying the mixed results to EHL FIX or SHL FIX.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For 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:^54,55

• 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 the 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 potential for unmeasured confounding of the pivotal intrapatient single-arm trial comparing bleeding pre- and postintervention. The GRADE report captures the study limitations (which refer 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 the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for the ABR_total and ABR_treat was set according to the presence or absence of an important effect based on thresholds informed by the sponsor and agreed upon by clinical experts consulted by CADTH for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the AIR and annualized FIX consumption due to the lack of a formal estimate of a minimally importance difference. The certainty of evidence was summarized narratively for the HJHS, Haem-A-QoL (physical health score and total score), and HAL (complex lower extremity activities score and total score), as well as harms outcomes due to lack of comparators.

Results of GRADE Assessments

Table 2 and Table 3 presents the GRADE summary of findings for fidanacogene elaparvovec versus FIX prophylaxis in adult patients (18 years and older) with moderately severe to severe hemophilia B.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the CADTH review team.

Two studies (C0371005 and C0371003) submitted by the sponsor to address gaps in the systematic review evidence are summarized in this section. Study C0371005 was submitted to address a gap in knowledge of the safety and kinetics of fidanacogene elaparvovec. Its corresponding extension study, C0371003, was submitted to address a gap in knowledge of the long-term efficacy and safety of fidanacogene elaparvovec.

Study C0371005

Study C0371005⁵⁶ was a phase I and IIa, open-label, single-arm, dose-escalation, multicentre study. The objective of this study was to evaluate the safety, tolerability, and kinetics of a single IV infusion of fidanacogene elaparvovec in hemophilia B participants with endogenous FIX levels less than or equal to 2%. Initially 5 participants were given an initial dose of 5 × 10¹¹ vg/kg. Based on observed safety and efficacy data in the first 5 participants, an additional 10 participants were enrolled at the same dose level. A total of 15 participants completed the study. All dosed participants underwent safety observation for a total of 52 (± 2) weeks after infusion. At the end of study, all participants were encouraged to enrol in an extension study (Study C0371003) evaluating the long-term safety of fidanacogene elaparvovec for up to an additional 5-year long-term follow-up.

The objectives for Study C0371005 were:

• to evaluate the safety and tolerability of a single IV infusion of fidanacogene elaparvovec in hemophilia B participants (primary)

• to characterize the kinetics of fidanacogene elaparvovec. (secondary).

Key inclusion criteria of the participants were:^56,57

• male participants aged 18 years or older

• have hemophilia B with a FIX activity of 2% or less of the normal value at screening, historical evidence, or a documented genotype known to produce a clinically severe phenotype of hemophilia B

• nAbs to fidanacogene elaparvovec of less than 1:5 as determined by an in vitro transduction assay

• have had 50 or more exposure days to any recombinant or plasma-derived FIX product

• patients on prophylaxis treatment must have had documented bleeding events or FIX infusions in the previous 12 weeks

• patients using on-demand treatment must have had 4 or more bleeding events in the previous 52 weeks and/or chronic hemophilic arthropathy in 1 or more joints

• no prior history of hypersensitivity or anaphylaxis associated with FIX or IV immunoglobulin infusion

• acceptable laboratory values for hemoglobin, platelets, AST, ALT, alkaline phosphatase, bilirubin, and creatinine

• agree to use acceptable methods of contraception for the time required for 3 ejaculate samples negative for vector shedding.

Key exclusion criteria were:^56,57

• active hepatitis B or C; hepatitis B surface antigen, hepatitis B virus DNA positivity, or hepatitis C virus RNA positivity

• currently on antiviral therapy for hepatitis B or C

• a pre-existing diagnoses of significant liver disease including portal hypertension, splenomegaly, or hepatic encephalopathy

• serological evidence of HIV-1 or HIV-2 with a CD4+ cell count less than or equal to 200 mm³

• a history of chronic infection or other chronic disease deemed an unacceptable risk by the investigator

• any concurrent clinically significant major disease or condition deemed unsuitable for participation by the investigator

• previously dosed in a gene therapy trial within the last 52 weeks or in a clinical study with an investigational drug in the last 12 weeks.

The median duration of fidanacogene elaparvovec infusion was |||| minutes, ranging from || || || minutes. The median total dose of fidanacogene elaparvovec infused was |||||||| vg, ranging from |||||||| vg.

Results

Baseline Characteristics

A total of 22 participants signed the informed consent form: 15 of these participants received treatment and 7 did not participate due to screening failure. All 15 participants completed the study and were male, with a mean age of 38.6 years, ranging from 18 to 61 years. The majority of participants were aged 35 years or younger (66.7%) and white (80.0%). Among the 15 treated patients, 11 (73.3%) were prophylaxis participants and 4 (26.7%) were on-demand participants at baseline. The majority of participants had no family history of FIX inhibitors (80.0%) and had hemophilia B with a FIX:C level of less than 1% (66.7%). Among 15 participants, 14 (93.3%) had a medical or surgical history related to hemophilia. All 15 participants received at least 1 concomitant medication. The most commonly used concomitant medications included paracetamol in 10 participants (66.7%).⁵⁶

Efficacy Outcomes

No formal efficacy evaluations were performed, and all analyses were exploratory in nature. The ABR (spontaneous and traumatic), annualized FIX consumption, number of target joints, changes in level of activity, HRQoL, and health-economic parameters were collected for exploratory efficacy evaluations. Vector-derived FIX:C levels were used as important indicators of efficacy for dose selection. The safety analysis set included 15 participants who received the infusion. The assessments of the HJHS, HAL and McGill pain questionnaire were added in protocol Amendment 5.1 (January 13, 2017). For this reason, only the final | participants enrolled under this amendment and subsequent versions of the protocol were evaluated for these assessments. All 15 participants were included for other efficacy, pharmacokinetic and vector shedding analyses.⁵⁶

Annualized Bleeding Rate

Among the 15 treated participants, 12 (80.0%) experienced no on-study bleeds. No traumatic bleeds were observed during the study, and all 3 participants experiencing bleeding episodes had spontaneous bleeds. The total number of infusions ranged from 0 to 10 during the study. The median ABR during the 52-week period preceding fidanacogene elaparvovec infusion (historical) was 4.00, ranging from 0.0 to 48.0. The median ABR decreased to 0.00 (range = 0.0 to 4.0) during the 52-week period following fidanacogene elaparvovec infusion (on study). The mean ABR decreased from 8.87 (SD = 14.040) to 0.40 (SD = 1.060).⁵⁶

Annualized FIX Consumption

The overall mean annualized FIX production consumption was |||| ||||||||| IU in all 15 participants, with a mean of |||| ||||||||| IU in the 11 participants previously on prophylaxis treatment and |||| |||||||| IU in the 4 participants previously receiving on-demand treatment.⁵⁶

Target Joints Assessments

During the 52-week period preceding screening, the mean number of target joint bleeds was |||| ||||||| in a total of 5 participants (4 participants previously on prophylactic treatment and 1 participant previously receiving on-demand treatment). The mean number of target joint bleeds decreased from |||| ||||||| in 4 participants to ||| |||||| in 2 participants who were previously receiving prophylactic treatment.⁵⁶

Hemophilia Joint Health Score

Regarding the HJHS, | participants were assessed at baseline and end of study. In general, a |||||||| ||| |||||||| || ||| ||||||||| |||||||||||| |||| ||||| ||||| |||||||| |||||| |||||| |||| |||||| ||||| |||||| |||| |||||| ||||| |||| ||| |||| ||||| |||| ||| |||| |||||| ||| ||| ||||| ||||| || |||| ||||| ||||||| ||||| |||||||| ||| ||||| ||||||.⁵⁶

Hemophilia Activities List and Hemophilia Quality of Life Questionnaire for Adults

A |||||||| in HAL total sum scores and subscores over time was observed in the | participants who had assessments done at baseline and end of study. A |||||||| ||| |||| |||||||| in Haem-A-QoL overall total score over time, || |||| || in the domain total scores except dealing total score.⁵⁶

Adverse Events

Fourteen of 15 participants (93.3%) reported 1 or more TEAE. No study drug discontinuation, study discontinuation, SAEs or deaths were reported in the study.⁵⁶

A total of 81 TEAEs were reported in the study. The most commonly reported TEAEs were in the system organ class of infections and infestation (8 participants, or 53.3%), gastrointestinal disorders (7 participants, or 46.7%) and musculoskeletal and connective disorders (6 participants, or 40.0%). The most frequently reported TEAEs were upper respiratory tract infection (5 participants, or 33.3%), nasopharyngitis (3 participants, or 20.0%), back pain (3 participants, or 20.0%) and muscle strain (3 participants, or 20.0%). One participant (6.7%) reported experiencing arthralgia as a TEAE. Two drug-related TEAEs of increased transaminases (13.3%) were reported. The majority of TEAEs (53 of 81, or 65.4%) were mild in severity, and the other 28 TEAEs (34.6%) were moderate in severity. There were no severe or life-threatening TEAEs, or deaths.⁵⁶

Study C0371003

Description of Studies

Study C0371003⁵⁸ (N = 17) is a phase IIa, open-label, nonrandomized, longer-term follow-up study designed to evaluate the safety and efficacy of previously administered fidanacogene elaparvovec at a dose of 5 × 10¹¹ vg/kg for up to 6 years. Participants enrolled in this study either had been dosed with fidanacogene elaparvovec in Study C0371005 (summarized previously) (N = 14) or received fidanacogene elaparvovec in the dose-escalation substudy (N = |) within this study. Among the 15 participants who completed Study C0371005, a single participant did not provide informed consent for Study C0371003, resulting in 14 participants continuing to Study C0371003. Results presented in this report are for the cohort of 14 patients from Study C0371005 who entered Study C0371003.

The dose-escalation substudy is not summarized in this report because the dose of fidanacogene elaparvovec did not align with the recommended dose in the draft product monograph and the substudy’s small sample size. In the dose-escalation substudy, patients received a dose of |||||| |||||| |||| || ||||||| || ||. The original design of Study C0371003 included only the continuation of the patients previously dosed in Study C0371005; the dose-escalation study was added as a protocol amendment.

The objectives for Study C0371003 were:

• to evaluate the long-term safety of a single fidanacogene elaparvovec infusion administered to participants in Study C0371005 (primary safety and immunogenicity)

• to determine the durability of transgene expression of fidanacogene elaparvovec and to assess the effect of fidanacogene elaparvovec on clinical outcomes of FIX:C, ABR, AIR, FIX consumption, number of spontaneous or traumatic bleeding events, and HRQoL (secondary efficacy)

• to evaluate and provide a descriptive analysis of other relevant outcomes including number of FIX infusions, joint assessments, activities and functioning, health care resource use, and productivity (tertiary/exploratory efficacy).

Study C0371003 included adult males with moderately severe to severe hemophilia B who received a 5 × 10¹¹ vg/kg dose of fidanacogene elaparvovec in Study C0371005 and completed 1 year of follow-up.^57,58 Patients were monitored for safety and efficacy outcomes from year 2 to year 6 in Figure 2.

Figure 2: Study C0371003 Study Design

Source: Pfizer (2023).⁵⁸

Populations

The longer-term follow-up study was conducted in the US and Australia; of the 15 participants dosed in C0371005, | were in Canada (||||| || ||| ||).⁵⁸ Study C0371003 enrolled participants who had received a dose of 5 × 10¹¹ vg/kg of fidanacogene elaparvovec and completed 1 year of follow-up in Study C0371005. The inclusion and exclusion criteria for Study C0371003 are the same as those for Study C0371005.

Interventions

There was no intervention in Study C0371003. Study participants were dosed in Study C0371005.

Outcomes

The primary outcome measures for Study C0371003 were related to safety and immunogenicity, while secondary measures were related to efficacy. The primary end point was the incidence of fidanacogene elaparvovec-related AEs. The secondary end points were efficacy and patient-reported outcome end points, including the ABR for treated bleeds, AIR, annualized FIX consumption, target joint assessments, HJHS, total number of bleeding events, and quality-of-life assessments.

Statistical Analysis

The primary analysis of Study C0371003 is planned to occur when the last patient completes 6 years of post–fidanacogene elaparvovec infusion follow-up or withdraws from the study.⁵⁹ The results described here were part of an interim analysis based on the data available as of a data cut-off that occurred on November 2, 2022. No hypothesis testing was planned and all summaries are descriptive.⁵⁹

The analyses of safety and efficacy in Study C0371003 were performed on the safety analysis set (i.e., all participants who received a single administration of fidanacogene elaparvovec in Study C0371005).⁵⁹ Baseline data from Study C0371005 were used where possible.⁵⁹ In general, descriptive statistics were reported each yearly period and for the duration of the study for the end points of FIX:C, AIR, annualized FIX consumption, number of target joints, HJHS, Haem-A-QoL, HAL, EQ-5D-5L, and safety.⁵⁹ Missing data were not imputed for Study C0371003 unless specified for an individual end point.⁵⁹

An exploratory analysis compared the mean ABR_treat by year to a historical ABR_total obtained from Study C0371005 during the 52 weeks before screening.⁵⁹ The historical ABR included spontaneous and traumatic bleeds, and excluded surgical and perioperative bleeds, but did not distinguish between treated and untreated bleeds; therefore, only the ABR_total was available for the historical ABR.⁵⁹

The ABR_treat and percentage reduction in ABR_treat by year were estimated using a negative binomial mixed model with repeated measures and a log link function.⁵⁹ Treatment (pre- or postinfusion) was included as a factor, duration (elapsed time in years of each yearly treatment period) as numeric, and participants as a random effect.

Results

Patient Disposition

Fourteen of the 15 participants dosed in C0371005 entered into Study C0371003. Of these 14 patients, 2 discontinued from the longer-term follow-up (1 participant was lost to follow-up and 1 withdrew) and neither discontinuation was considered to be related to an AE. At the data cut-off on November 2, 2022, 5 participants had completed the longer-term follow-up and 7 were continuing the study. The duration of follow-up at the data cut-off ranged from || |||||| || || |||||| following fidanacogene elaparvovec infusion.⁵⁸

Baseline Characteristics

The mean age of participants was 40.1 years, ranging from 18 to 61 years, at the time of fidanacogene elaparvovec infusion. Most participants were aged 35 years or older (71.4%) and white (85.7%). Ten participants were on FIX prophylaxis and 4 were using on-demand regimens before fidanacogene elaparvovec infusion. All participants had FIX levels below or equal to 2%.⁵⁸

Concomitant Treatments

||||| ||||||| participants received at least 1 concomitant medication during the study period and 7 participants (50.0%) underwent at least 1 nondrug therapeutic procedure or diagnostic assessment. The most common concomitant medications included ||||||||||| (||| participants [|||||]), ||||||||||||||||||||||| (||| participants [|||||]). ||||| ||||||) participants underwent investigations including |||||||||||| ||||||| ||| |||||||||||| ||||||||||. ||||| ||||| participants underwent surgical procedures such as ||||||||||||||| |||||||||||| |||||| |||||| |||||||||||||| |||||||||||||||||||| |||||| ||||||| ||| ||||||||||||| |||||||||||||| |||| |||||||||| |||| |||||||||| |||||||||||| |||||| |||||| ||||||||| ||||| ||||||||||| ||| ||||||||||||.⁵⁸

Efficacy

Annualized Bleeding Rate for Treated Bleeds

The ABR_treat by year and over time (year 2 to year 6), and the comparison with the historical ABR are presented in Table 17. The mean ABR |||||||| ||||| |||| ||| |||||| |||| year 2 through year 6 postinfusion with || participants (|||||) having 0 bleeds during their entire time in the study. The mean ABRs_treat were |||| |||||||, |||| |||||||, |||| |||||||, |||| |||||||, and |||| ||||||| during years 2, 3, 4, 5, and 6 postinfusion, respectively. |||| participants had treated bleeds during years 2 through 6.⁵⁸

Table 17: Summary of ABR_treat by Year Postinfusion, Safety Analysis Set

ABR = annualized bleeding rate; ABR_treat = annualized bleeding rate for treated bleeds; CI = confidence interval; SD = standard deviation.

Notes: Traumatic and spontaneous bleedings are included. The historical ABR did not distinguish between treated and untreated bleeds; following fidanacogene elaparvovec infusion, only treated bleeding episodes were collected. Data cut-off was on November 2, 2022.

^aThe reported number of bleeds in the 52 weeks before screening in Study C0371005 is used as a historical ABR.

^bTreatment difference and P value were obtained from a repeated measures generalized linear model with negative binomial distribution and log link function comparing to a historical ABR_total obtained from Study C0371005 during the 52 weeks before screening

Source: Pfizer (2023).⁵⁸

Annualized Infusion Rate

The AIR by year and over time (year 2 to year 6) is presented in Table 18. The AIR generally decreased over the entire follow-up periods from a mean of |||| in year 2 to |||| in year 6 following fidanacogene elaparvovec infusion. The mean AIR was |||| |||||||, |||| |||||||, |||| |||||||, |||| ||||||| and |||| ||||||| during years 2, 3, 4, 5, and 6 postinfusion, respectively.⁵⁸

Table 18: Summary of AIR by Year Postinfusion, Safety Analysis Set

AIR = annualized infusion rate; SD = standard deviation.

Note: Data cut-off on November 2, 2022.

Source: Pfizer (2023).⁵⁸

Annualized FIX Consumption

As of the data cut-off date, there were no prophylactic infusions in the study, and no participants had resumed prophylaxis. Median total factor consumption and annualized FIX consumption, excluding consumption required for surgery, was |||| for year 2 through year 6. |||| of the 14 participants have had no nonsurgical FIX consumption over the longer-term follow-up period.⁵⁸

Target Joints Assessments

From week 52 to week 130 following fidanacogene elaparvovec infusion, the number of participants with target joint bleeds ||||||||| from || ||||||| to ||||||, based on target joint assessment questionnaire results. || ||||||||||| had target joint bleeding reported beyond week 130 as of the data cut-off (from weeks 156 to 312 or end of study).⁵⁸

Hemophilia Joint Health Score

The HJHS, an exploratory end point, was added after most participants were dosed, resulting in a low number of assessments at baseline. The median HJHS total scores were |||| ||||| at baseline, |||| |||||| at week 156, |||| ||||| at week 208, |||| ||||| at week 260, and |||| ||||| at week 312 or end of study. The baseline HJHS score was the last nonmissing measurement before fidanacogene elaparvovec infusion in Study C0371005.⁵⁸

Hemophilia Quality of Life Questionnaire for Adults

Haem-A-QoL total scores and domain scores remained consistent throughout the longer-term follow-up period (years 2 through 6) in the 4 patients contributing to the analysis. Decreases from baseline (indicating a higher quality of life) were observed in the domains of physical health, feeling, view of yourself, sport and leisure, work and school, treatment, future, family planning, partnership and sexuality, as well as the total score, at all visits over the longer-term follow-up (years 2 through 6). Median change from baseline in Haem-A-QoL total scores ranged from ||||| || |||||| over the longer-term follow-up (years 2 through 6).⁵⁸

Hemophilia Activities List

Mean HAL domain scores |||||||| ||||| || and the total score |||||||| ||||| || at all visits after fidanacogene elaparvovec infusion over the longer-term follow-up period (years 2 through 6) in the 4 patients contributing to the analysis.⁵⁸

Harms

Four of the 14 participants (28.6%) experienced a total of 9 SAEs. No participants discontinued from the study due to AEs. No participants experienced hypersensitivity reactions or other AEs of special interest and there were no deaths.⁵⁸

Of the 10 TEAEs reported, 5 were mild, 1 was moderate, and 4 were severe. These 10 TEAEs included 9 SAEs and 1 nonserious AE (back pain). The most frequently reported TEAEs regardless of severity were related to musculoskeletal and connective tissue disorders in 2 participants (14.3%).⁵⁸

During the longer-term follow-up period, 8 of 14 participants experienced increased ALT levels above the ULN, 3 of whom had increased AST levels above the ULN. None of these cases were managed with corticosteroids and, as of the data cut-off, the ALT and AST levels of all 3 participants had returned to normal limits, except for 1 patient who completed the study with an ALT level above the ULN. Regarding immunogenicity, all 14 participants remained negative for FIX inhibitors during the study.⁵⁸

Critical Appraisal

Internal Validity

Study C0371005

Study C0371005 is an open-label, single-arm, multicentre, phase I and IIa study. All efficacy analyses were exploratory in nature and were presented using descriptive statistics. The absence of a comparator group limited the interpretation of results because causality cannot be established. The open-label design may have biased the reporting of some end points because awareness of the study treatment received may have influenced patient and clinician perceptions of improvement and/or harms, particularly for outcomes that are subjective in measurement and interpretation (e.g., patient-reported outcomes and subjective AEs). Furthermore, the follow-up period was only 1 year, which is insufficient to draw any definitive conclusions regarding long-term efficacy and safety. In addition to the general limitations of the study design, data were missing for most of the participants (only 4 patients contributed to the analyses) because the HJHS and HAL were added later during a protocol amendment. No conclusions can be drawn for these outcomes with certainty.

Study C0371003

Study C0371003 provided a longer-term follow-up for the 14 patients previously given fidanacogene elaparvovec in Study C0371005. As the primary objective of C0371003 was safety, no hypothesis testing was planned, and all summaries were descriptive, resulting in no statistical inferences. Data were also missing for HJHS and HAL assessments for the reasons previously described.

The duration of follow-up at the data cut-off ranged from || |||||| || || |||||| following fidanacogene elaparvovec infusion, and only 5 participants had completed the 6-year longer-term follow-up as of the data cut-off date. According to the clinical experts consulted by CADTH, the data provided for the 6 years of follow-up are limited but reasonable for the purposes of assessing safety and efficacy in the patient population. The clinical experts consulted by CADTH noted that a longer follow-up period (20 to 25 years) involving more patients is warranted to make any definite determination about the overall long-term safety and efficacy of fidanacogene elaparvovec and may not be feasible in the clinical trial setting. The experts further noted that lifelong monitoring of liver health and carcinogenicity will be necessary as discussed previously. Altogether, the evidence with respect to the long-term efficacy and safety in C0371003 is inconclusive.

External Validity

The external validity of these supportive studies was similar to that of the pivotal trial and its corresponding lead-in study. The majority of the patients were white (80.0% and 85.7% in Study C0371005 and Study C0371003, respectively), which, according to the clinical experts consulted by CADTH, was higher than would be expected for a patient population in Canada. Both Study C0371005 and Study C0371003 enrolled only male patients, although the clinical experts noted this is likely not a serious generalizability issue because the treatment effects are not expected to differ between males and females due to the same underlying mechanism of disease, and female patients with moderately severe to severe hemophilia B are rare. One of the eligibility criteria in Study C0371005 was hemophilia B with FIX activity less than equal to 2% at screening and historical evidence or a documented genotype known to produce a clinically severe phenotype of hemophilia B. The clinical experts consulted by CADTH noted that severity in clinical practice is defined by the patient’s phenotype and not simply factor activity levels. According to the clinical experts consulted by CADTH, the disease will be considered moderately severe to severe in some patients due to clinical symptoms even with a FIX level greater than 2%. Last, generalizability may be limited by the small sample sizes of these studies.

Discussion

Summary of Available Evidence

One ongoing phase III, single-arm, open-label clinical trial (BeneGene-2, N = 45) was included in the SLR conducted by the sponsor. The primary objective of BeneGene-2 was to determine the noninferiority of fidanacogene elaparvovec relative to the standard of care FIX prophylaxis, as measured by the ABR_total at year 1 following fidanacogene elaparvovec infusion. Other efficacy and safety end points were also examined, including the number of patients without bleeds, ABR_treat, ABR_joint, AIR, annualized FIX consumption, HJHS, Haem-A-QoL, HAL, and harms. For efficacy outcomes such as the ABR_total, ABR_treat, ABR_joint, AIR, and annualized FIX consumption, the 45 participants in the pivotal BeneGene-2 trial served as their own controls, using data collected when these patients were on FIX prophylaxis during an open-label, noninvestigational, prospective, lead-in study (BeneGene-1, N = 102) for comparison. In addition to noninferiority, tests of superiority were also conducted, and a gatekeeping process was applied to control for multiplicity of testing multiple end points. The BeneGene-2 trial enrolled adult patients who had moderately severe to severe hemophilia B (defined as FIX:C ≤ 2%). Patients were excluded if their anti-AAVrh74var nAb titre was 1:1 or greater or if they had a prior history of FIX inhibitors or a positive FIX inhibitor test result of 0.6 Bethesda units or greater. Patients in the BeneGene-2 trial had a median age of 29 years, ranging from 18 to 62. The majority of patients were white (73.3%), followed by Black or African American (2.2%), Asian (15.6%), American Indian or Alaska Native (0), and Native Hawaiian or Other Pacific Islander (0). All of the participants had a factor mutation, of which 7 (15.6%) were nonsense, 20 (44.4%) were missense, 0 were insertions, 9 (20%) were deletions, 0 were inversions, and 9 (20%) were classified as “other.”

Two additional studies were submitted by the sponsor to address gaps in the pivotal trial evidence. Study C0371005 was a phase I and IIa, open-label, single-arm, dose-escalation, multicentre study that followed patients for 1 year. The objective was to evaluate the safety, tolerability, and pharmacokinetics of a single IV infusion of fidanacogene elaparvovec in male patients with hemophilia B and endogenous FIX levels less than or equal to 2%. Participants who completed Study C037105 were encouraged to enrol in an extension study (C0371003) evaluating the longer-term safety of fidanacogene elaparvovec for up to an additional 5-year follow-up.

Interpretation of Results

Efficacy

Overall, efficacy evidence from the pivotal BeneGene-2 trial favoured fidanacogene elaparvovec over FIX prophylaxis for the treatment of adult male patients with moderately severe to severe hemophilia B (FIX:C ≤ 2%) at the time of the interim analysis (median follow-up time was |||| |||||), although this evidence is associated with uncertainty. This conclusion was drawn after considering bleeding end points (e.g., ABR_total, ABR_treat, ABR_joint, both mean reduction of bleeds and percentage of patients without bleeds) and end points relating to the use of FIX following fidanacogene elaparvovec infusion (e.g., AIR), as well as patient-reported outcomes (e.g., HJHS, Haem-A-QoL, HAL) examined in the CADTH report. These efficacy end points were selected based on input from stakeholders, including the clinical experts consulted by CADTH and patient and clinician groups. These efficacy end points were generally aligned with patients’ expectations of important outcomes. Patients placed importance on controlling bleeding (and joint bleeding caused by repeated internal hemarthroses in particular) and maintaining quality of life.

Patient group input reported that patients hoped gene therapy would lead to fewer FIX infusions, minimal needle injections, and less bleeding. Based on results of the BeneGene-2 trial, fidanacogene elaparvovec may result in a decrease in AIRs and total FIX consumption when compared with FIX prophylaxis. Furthermore, the BeneGene-2 trial results for bleeding end points overall indicated that treatment with fidanacogene elaparvovec may result in decreased bleeds when compared to FIX prophylaxis. Fidanacogene elaparvovec resulted in a decrease in the ABR_total at both year 1 and from week 12 to the data cut-off date when compared with FIX prophylaxis received during the lead-in study, and the clinical experts consulted by CADTH determined that the magnitude of the effect size was a clinically relevant improvement. The improvement in the ABR_total FIX activity levels measured by 2 single-stage assays and 1 chromogenic assay suggest that the steady-state FIX:C level of the majority of the patients was higher than the prespecified fixed threshold of 5% and remained stable (Appendix 1). Results from other bleeding outcomes (i.e., the ABR_treat, | |||||||||||| |||| ||| ||||||||| [Appendix 1]) were consistent with the ABR_total, favouring fidanacogene elaparvovec compared to FIX prophylaxis during the lead-in study. The clinical experts consulted by CADTH considered the percentage of patients with no bleeds to be an efficacy end point that is more clinically relevant and informative compared with the ABR. Results at year 1 following fidanacogene elaparvovec infusion (i.e., 64.4% of patients treated with fidanacogene elaparvovec versus 28.9% of the patients treated with FIX prophylaxis during the lead-in period) suggest that there is a clinically meaningful improvement favouring fidanacogene elaparvovec, according to the clinical experts.

However, there was uncertainty in interpreting the positive findings in the bleeding outcomes. The comparative evidence is nonrandomized, which, according to GRADE guidance used by the CADTH review team, starts at low certainty. Furthermore, CADTH identified potential sources of bias. The magnitude of the observed effect may be biased due to assumptions of the models used to compare observations in the BeneGene-2 study to those in the lead-in BeneGene-1 study. In particular, the probability of no bleeds did not account for differences in follow-up times during the 2 studies, and this is expected to bias results, although the direction is unknown. The open-label design and self-reporting of bleeding events may also have led to an overestimate of the effect size. There was a potential risk of bias in the underestimation of the ABR or overestimation of percentage of patients with no bleeds among those treated with fidanacogene elaparvovec, given that the BeneGene-2 trial was open-label and the bleeding events were recorded by the patients themselves. Furthermore, according to the clinical experts consulted by CADTH, the ABR_treat can be misleading because the determination of whether a bleed needed treatment was a decision made by both clinicians and patients. The risk of bias could not be ruled out despite the sponsor’s decision to implement several measures to ensure patients correctly used electronic diaries. Similarly, given the open-label design of the BeneGene-2 trial, the subjective nature of outcomes and the lack of a comparator group, no valid inferences can be made on HRQoL outcomes despite improvement in change from baseline across all HRQoL outcomes examined in the CADTH report.

According to patient group input, more than 60% of the respondents expect a gene therapy to be effective in preventing bleeding for at least 10 years. In addition, the clinical experts consulted by CADTH noted that a longer follow-up period of 20 to 25 years is warranted to make any definite determinations on the overall long-term efficacy of fidanacogene elaparvovec. An important limitation in the efficacy results in the pivotal BeneGene-2 trial is the relatively short duration of follow-up (median: |||| ||||| with a minimum of ||| and a maximum of ||| |||||). To help address this gap in the pivotal trial evidence, the sponsor submitted results from a phase I and IIa trial (Study C0371005) and its corresponding extension study (Study C0371003), which provided evidence on the safety and efficacy of fidanacogene elaparvovec in 15 patients who were followed for up to 6 years. However, the limitations of these studies (e.g., a single-arm and noncomparative design, descriptive analyses, a small sample size, many patients ongoing, and missing data for some outcomes) preclude CADTH from using this evidence to draw conclusions about the longer-term efficacy of fidanacogene elaparvovec. Furthermore, 6 years of follow-up may not be considered sufficiently long-term, as patients and clinicians expect longer efficacy from a gene therapy.

Patient input emphasized that current treatments for hemophilia B can greatly complicate their everyday life, travel, and leisure activities. Patients indicated that they hoped gene therapy would lead to less stress and fewer restrictions on activities and make it easier to travel. Similarly, the clinical experts consulted by CADTH noted that monitoring changes in the HJHS as well as HRQoL end points following fidanacogene elaparvovec infusion (e.g., improvement in activity of daily living, physical activity and functioning, decrease in development of disability, and improvement in psychosocial health and functioning) are important for assessing treatment response. Although HRQoL was assessed in the BeneGene-2 trial using the Haem-A-QoL instrument, this evidence was noncomparative and therefore provided very low certainty according to GRADE guidance used by the CADTH review team. Similarly, effects on activities were assessed by the HAL tool, but the data were noncomparative. Although the Haem-A-QoL and HAL tools were also assessed in Study C0371005 and C0371003, both of which had only a single arm, data were available for only | patients, and the missing data further limits the interpretation of those results. As such, CADTH could draw no conclusions with certainty regarding the effect of fidanacogene elaparvovec on HRQoL and patient activities.

Harms

The safety profiles of patients treated with fidanacogene elaparvovec in the pivotal BeneGene-2 trial, were considered acceptable by the clinical experts consulted by CADTH. No deaths or study discontinuations due to AEs were reported in the trial. The most common SAE was anemia, and the most common notable harm was increased ALT (26.7%) followed by abnormal hepatic function (13.3%). As the available safety data are noncomparative, the evidence about the effect of fidanacogene elaparvovec on harms overall compared to current treatments (i.e., FIX prophylaxis) is uncertain. In addition, the evidence on safety was considered limited due to the small number of patients involved and the relatively short duration of the follow-up. Although Study C0371005 and C0371003 provide longer-term safety data, with up to 6 years of follow-up, the long-term safety of fidanacogene elaparvovec remains uncertain. Similar to the assessment of efficacy, the clinical experts consulted by CADTH noted that a longer follow-up period of 20 to 25 years involving more patients is warranted to make any definite determinations on the overall long-term safety of fidanacogene elaparvovec.

Conclusion

One phase III, single-arm, open-label trial (BeneGene-2) investigated the efficacy and safety of fidanacogene elaparvovec in 45 patients with moderately severe to severe hemophilia B (defined as FIX:C ≤ 2%). For efficacy outcomes regarding bleeding events and the use of FIX following fidanacogene elaparvovec infusion, patients in the BeneGene-2 trial served as their own controls, using data collected from when these patients were on FIX prophylaxis during a lead-in study (BeneGene-1). Compared to FIX prophylaxis, fidanacogene elaparvovec may result in a decrease in the ABR_total, ABR_treat, ||||||||| AIR, and |||||||||| ||| |||||||||||| and the effects observed for all of these outcomes were considered clinically relevant by the clinical experts consulted by CADTH. However, uncertainty associated with interpreting the clinical significance of the magnitude of the treatment differences remains due to study limitations, such as the nonrandomized comparative design, potential risk of bias in self-reporting of bleeding events caused by the open-label design, and potential biases introduced by the assumptions of the statistical models used to make the comparisons. The safety profile of fidanacogene elaparvovec during the follow-up period was considered acceptable by the clinical experts consulted by CADTH; however, the safety evidence is also uncertain given the lack of comparative data, small sample size, and limited duration of follow-up. To address the limited duration of follow-up in the BeneGene-2 study, evidence from a phase I and IIa, single-arm, open-label trial and a corresponding extension study that provided data for up to 6 years of follow-up was examined. However, the limitations of these supportive studies (e.g., a single arm and noncomparative design, descriptive analyses, small sample size, many patients ongoing, and missing data) preclude CADTH from using this evidence to draw conclusions with certainty about the longer-term efficacy and safety of fidanacogene elaparvovec. Altogether, the long-term efficacy and safety of fidanacogene elaparvovec remains inconclusive.

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Appendix 1: Detailed Outcome Data

Note this appendix has not been copy-edited.

Table 19: Sensitivity Analysis — Jump to Reference of ABR_total to Assess Impact of Discontinuation From BeneGene-2 Prior to Reaching 15 Months of Follow-Up (Dosed Population)

ABR_total = annualized bleeding rate for treated and untreated bleeds; CI = confidence interval; SD = standard deviation.

Note: Year 1 referred to the period between week 12 and month 15 following infusion of fidanacogene elaparvovec.

^aNumber of patients who were in follow-up at the start of the period interval.

Source: BeneGene-2 Clinical Study Report.⁹

Table 20: Mean Steady-State FIX:C Between Week 12 and Month 15 Postinfusion of Fidanacogene Elaparvovec (Dosed Population)

FIX:C = circulating factor IX; SD = standard deviation.

Note: Data cut-off date November 16, 2022.

^aBased on central laboratory data from 12 weeks to 15 months. Any samples taken within 7 days (14 days if EHL product is used) of exogenous FIX replacement therapy are not included in the assessment of steady-state FIX:C postinfusion.

^bSignificantly higher than the fixed threshold of 5%

Sources: BeneGene-2 Clinical Study Report9 and the sponsor’s Summary of Clinical Evidence.1

Table 21: Results for the Analysis of Sustained FIX:C (Dosed Population)

FIX:C = circulating factor IX; SD = standard deviation.

Note: Data cut-off date November 16, 2022

^aBased on central laboratory data from 12 weeks to 15 months. Any samples taken within 7 days (14 days if EHL product is used) of exogenous FIX replacement therapy are not included in the assessment of steady-state FIX:C postinfusion.

Sources: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Figure 3: Stacked Bar Plot for Proportions of Participants Within the FIX:C Category Over Time With Imputation by Assay (Dosed Population) [Redacted]

FIX:C = circulating coagulation factor IX; SD = standard deviation.

Notes: Analyses are based on central laboratory data and any samples taken within 7 days of exogenous FIX replacement therapy (or 14 days if EHL product used) are excluded; If a patient withdrew consent, discontinued or resumed FIX prophylaxis, then assessments for visits following withdrawal/discontinuation/FIX prophylaxis resumption were imputed as 1.9%

Source: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Figure 4: Box-Whisker Plot of FIX:C Over Time With Imputation by One-Stage Assay With Actin-FSL Reagent (Dosed Population) [Redacted]

EHL = extended half-life; FIX = coagulation factor IX; FIX:C = circulating factor IX; IQR = interquartile range.

Notes: Analyses are based on central laboratory data and any samples taken within 7 days of exogenous FIX replacement therapy (or 14 days if EHL product used) are excluded; If a patient withdrew consent, discontinued or resumed FIX prophylaxis, then assessments for visits following withdrawal/discontinuation/FIX prophylaxis resumption were imputed as 1.9%.

Box contains the 25th (Q1) and 75th (Q3) percentiles; median is denoted by the line inside the box; whiskers mark the 1.5*IQR; values beyond 1.5*IQR range are considered outliers and are denoted by open circles; mean values are denoted by filled diamonds.

Source: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Figure 5: Box-Whisker Plot of FIX:C Over Time with Imputation by One-Stage Assay with SynthASil Reagent (Dosed Population) [Redacted]

EHL = extended half-life; FIX = coagulation factor IX; FIX:C = circulating factor IX; IQR = interquartile range

Notes: Analyses are based on central laboratory data and any samples taken within 7 days of exogenous FIX replacement therapy (or 14 days if EHL product used) are excluded; If a patient withdrew consent, discontinued or resumed FIX prophylaxis, then assessments for visits following withdrawal/discontinuation/FIX prophylaxis resumption were imputed as 1.9% The box contains the 25th (Q1) and 75th (Q3) percentiles; median is denoted by the line inside the box; whiskers mark the 1.5*IQR; values beyond 1.5 × IQR range are considered outliers and are denoted by open circles; mean values are denoted by filled diamonds.

Sources: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Table 22: Analysis of Target Joints in the BeneGene-2 Trial (Dosed Population)

Note: Data cut-off date November 16, 2022.

^aTarget joint was defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and ankle) into which repeated bleeds occur (≥ 3 spontaneous bleeds into a single joint within a consecutive 6-month period). A target joint is considered resolved when there are ≤ 2 bleeds into the joint within a 12-month period.

^bOverall includes from day 1 to data cut-off date.

Sources: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Figure 6: Box-Whisker Plot of FIX:C Over Time With Imputation by Chromogenic Assay (Dosed Population) [Redacted]

EHL = extended half-life; FIX = coagulation factor IX; FIX:C = circulating factor IX; IQR = interquartile range.

Notes: Analyses are based on central laboratory data and any samples taken within 7 days of exogenous FIX replacement therapy (or 14 days if EHL product used) are excluded; If a patient withdrew consent, discontinued or resumed FIX prophylaxis, then assessments for visits following withdrawal/discontinuation/FIX prophylaxis resumption were imputed as 1.9% The box contains the 25th (Q1) and 75th (Q3) percentiles; median is denoted by the line inside the box; whiskers mark the 1.5*IQR; values beyond 1.5*IQR range are considered outliers and are denoted by open circles; mean values are denoted by filled diamonds.

Sources: BeneGene-2 Clinical Study Report⁹ and the sponsor’s Summary of Clinical Evidence.¹

Table 23: ABR for Spontaneous Bleeding and Traumatic Bleeding in the BeneGene-2 Trial (Dosed Population)