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Indication: For the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital Factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74
CADTH recommends that Beqvez be reimbursed by public drug plans for the treatment of adults with moderately severe to severe hemophilia B (congenital factor IX deficiency) who are negative for neutralizing antibodies to variant adeno-associated virus (AAV) serotype Rh74 , if certain conditions are met.
Beqvez should only be covered to treat adult patients (aged 18 years or older) with circulating coagulation factor IX (FIX:C) activity of 2% or less and bleeding that requires ongoing prophylactic treatment. Beqvez should not be covered if the patient has FIX inhibitors or has previously received gene therapy for hemophilia B.
Beqvez should only be reimbursed if prescribed by specialists who have expertise in treating hemophilia B and if the cost of Beqvez is reduced. Beqvez is a 1-time therapy.
Hemophilia B is a life-long genetic bleeding disorder resulting from a deficiency in FIX that leaves patients at risk for excessive blood loss and organ damage. As of 2021, there were more than 700 patients with hemophilia B in Canada.
There is a need for treatments for hemophilia B that will alter the underlying disease process, restore coagulation factors to clinically effective levels, reduce the need for venipunctures, prevent or reduce bleeds, and improve quality of life.
Treatment with Beqvez is expected to cost $4,773,595 per patient.
The Canadian Drug Expert Committee (CDEC) recommends that fidanacogene elaparvovec be reimbursed for the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital factor IX deficiency) who are negative for neutralizing antibodies (nAbs) to variant adeno-associated virus (AAV) serotype Rh74 (AAVRh74var), only if the conditions listed in Table 1 are met.
CDEC recognized the rarity of hemophilia B and the unmet needs of patients with this disease who require coagulation factor IX (FIX) prophylaxis. Evidence from a phase III, single-arm, open-label clinical trial (the BeneGene-2 trial) demonstrated that treatment with fidanacogene elaparvovec decreased annualized bleeding rates and reduced the use of FIX in adult male patients with moderately severe to severe hemophilia B (circulating coagulation factor IX [FIX:C] ≤ 2%) compared to the same patients treated with routine FIX prophylaxis during a lead-in study (the BeneGene-1 study). After a median duration of follow-up of approximately | |||||, the difference in annualized bleeding rate for treated and untreated bleeds (ABRtotal) between patients was −3.13 (95% confidence interval [CI], −5.44 to −0.81) at week 12 to month 15 (denoted as year 1) after fidanacogene elaparvovec infusion, favouring fidanacogene elaparvovec. Results for other bleeding outcomes (annualized bleeding rate for treated bleeds [ABRtreat] and annualized bleeding rate for treated and untreated joint bleeds [ABRjoint]) and the use of FIX (annualized infusion rate [AIR] and |||||||||| ||| |||||||||||) also showed a benefit with fidanacogene elaparvovec compared to FIX prophylaxis during the follow-up period.
Patients identified a need for treatments that alter the underlying disease process, restore coagulation factors to clinically effective levels, reduce the need for venipunctures, prevent or reduce bleeds, and improve their quality of life (QoL). CDEC concluded that fidanacogene elaparvovec may meet some of these needs because it is a 1-time gene therapy designed to provide an alternative active source of endogenous FIX that improves bleeding outcomes and reduces FIX use after treatment. The evidence from the BeneGene-2 trial is associated with uncertainty because the comparative evidence is nonrandomized and potential sources of bias were identified (e.g., open-label design, self-reported bleeding events, subjective nature of some outcomes, assumptions of the statistical models used for intrapatient comparisons). In addition, while patients are expecting gene therapy to be effective for at least 10 years, the long-term efficacy of fidanacogene elaparvovec is unknown due to the limited duration of follow-up in the available evidence.
Based on the sponsor’s submitted analysis, fidanacogene elaparvovec may improve health outcomes and reduce overall health care costs relative to FIX prophylaxis. However, at the submitted price, it will take at least 12 years for the acquisition cost of fidanacogene elaparvovec to be offset by cost-savings to the health care system and be considered cost-neutral. There are limited data to support the long-term efficacy of fidanacogene elaparvovec. There is also a high degree of clinical uncertainty, and the potential for the scope of clinical practice to change during this period. Jurisdictions may wish to consider price reductions and/or other product listing mechanisms to mitigate the long-term financial risk to public payers.
Reimbursement Conditions and Reasons.
Hemophilia is a serious, X-linked, life-long genetic disorder that leaves patients at increased risk of blood loss and organ damage due to impaired functioning of the coagulation cascade. Hemophilia B is characterized by an absence or shortage of FIX resulting from a mutation in the F9 gene. Moderate and severe hemophilia B cases are defined by the World Federation of Hemophilia (WFH) as having 1% to 5% and less than 1% of normal enzymatic FIX activity, respectively. However, according to the clinical experts consulted by CADTH, severity in clinical practice is defined by a patient’s phenotype (i.e., tendency to bleed) and not simply their factor activity levels; the decision to initiate prophylaxis with clotting factor concentrates takes into the account 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 events into muscle, soft tissue, and joints (hemarthroses). Hemarthrosis is the most common manifestation of moderate and severe hemophilia B. As of 2021, there were 704 patients with hemophilia B (with recorded severity) in Canada, 535 of whom were adult male patients.
The treatment goal for hemophilia, as outlined by the WFH guidelines, is to reduce or prevent bleeding while allowing patients to lead active lives and experience a QoL comparable to 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.
Fidanacogene elaparvovec is an AAV vector-based gene therapy indicated for the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74. It is available as 1 × 1013 vector genomes (vg)/mL, and the dosage recommended in the product monograph is 5 × 1011 vg/kg of body weight administered as a single-dose IV infusion.
To make its recommendation, the committee considered the following information:
The 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, 2023, 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 people living in Canada with severe hemophilia A and B and received 39 responses; among them, 31 were individuals with hemophilia A, 7 with hemophilia B, and 1 not specified.
Joint damage — primarily to knees, ankles, and elbows, caused by repeated internal hemarthroses — was reported to be the primary physical health impact of hemophilia B. Regarding the currently available treatments, 4 patients reported being very satisfied, 7 satisfied, 5 neither satisfied nor dissatisfied, and 1 very dissatisfied. Patients from this survey noted that treatments greatly complicate their everyday life, travel, and leisure activities. They also mentioned the difficulty with infusion due to vein visibility, poor vein issues, and side effects. Patients also reported socioeconomic problems they face due to regular visits, such as missing work due to visits, travel and insurance issues, and access issues.
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, approximately 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 receive gene therapy knowing that there would be frequent blood draws in the weeks and months following administration, and that 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 that they did not know.
The CHS mentioned that a small number of people living in Canada (likely close to 5) have undergone gene therapy for hemophilia B, but nothing is known to the CHS about their experience outside the preliminary data from the trials.
The clinical experts consulted by CADTH noted that FIX prophylaxis requires frequent IV injections conducted by the patients themselves, which poses a heavy burden for patients with hemophilia B and significantly impacts patients’ ability to live a normal life. The clinical experts consulted by CADTH noted that poor adherence to FIX prophylaxis may result in reduced effectiveness and 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 exogenous FIX prophylaxis regimen, if effective, would be avoiding the fluctuation of 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 long-term. 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 all patients with hemophilia B who have 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 the identification of patients best suited for treatment should be through clinical assessment and shared decision-making with patients. Based on the study design of the pivotal BeneGene-2 trial, the clinical experts indicated that testing for nAb against AAVRh74var capsid should be mandatory to receive fidanacogene elaparvovec. The clinical experts consulted by CADTH noted that patients least suitable for fidanacogene elaparvovec include those with pre-existing antibodies against AAV and those who consider that the benefit does not outweigh the risk associated with fidanacogene elaparvovec gene therapy, in 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 for treatment response is to monitor patients’ bleeding to observe whether fidanacogene elaparvovec prevents bleeding events and allows patients to live the lifestyle they want without concern for risk of bleeding. The clinical experts agreed that the length of follow-up for hepatic function and FIX activity levels after infusion of fidanacogene elaparvovec should be life-long. The clinical experts noted that the postinfusion monitoring of fidanacogene elaparvovec will be more frequent for the short term, and less frequent over time for the long term. The clinical experts consulted by CADTH noted that it is reasonable to monitor FIX activity level and liver function tests twice a week at the early stages after infusion, although the production of FIX is unlikely to happen immediately after infusion. The clinical experts noted that monitoring changes in HJHS as well as in QoL–related end points after infusion of fidanacogene elaparvovec (e.g., improvement in activities of 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 the determination of treatment failure should be case-by-case, based on the judgment of the treating clinician. The clinical experts consulted by CADTH noted that if fidanacogene elaparvovec fails, patients may not be eligible for another gene therapy developed based on AAV vectors because they may present 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 that is composed by a hemophilia comprehensive treatment centre, and may consist of specialists such as a hematologist with experience in treating patients with hemophilia, a physiotherapist to assess joint function, a hepatologist for liver-related issues, pharmacy support, and an HIV specialist (if the patient is HIV-positive). The clinical experts noted that the administration of fidanacogene elaparvovec is on an outpatient basis, as is follow-up after fidanacogene elaparvovec infusion for most patients.
A total of 9 clinicians from AHCDC and 3 nurses from CANHC provided input. Both AHCDC and CANHC highlighted that the currently available treatments in Canada do not modify or alter the underlying disease process, hence making persons with hemophilia B dependent, life-long, on regular IV infusions of FIX to prevent and treat bleeding. In addition, AHCDC noted that the frequent venipuncture required for prophylactic CFC replacement can pose challenges for patients with poor venous access. The group emphasized that all of these factors lead to the need for persons with hemophilia B and a severe bleeding phenotype to restore coagulation factor to clinically effective levels without the need for frequent venipunctures on a regular basis throughout one’s lifespan. AHCDC also mentioned the variability of the efficacy of prophylaxis with CFCs across individuals, which poses some patients susceptible to breakthrough bleeds into joints and muscles.
Both AHCDC and CANHC noted that fidanacogene elaparvovec would provide a 1-time treatment leading to sustained FIX production, thus addressing the underlying disease process and natural history, rather than symptomatic management. This would represent a paradigm shift in the treatment of hemophilia B. AHCDC indicated that eligible candidates for gene therapy include adults with hemophilia B with clinically severe bleeding phenotype requiring prophylaxis, no history of inhibitory antibodies, no significant comorbidities, and no pre-existing anti-AAV nAbs.
Input was obtained from the drug programs that participate in the CADTH Reimbursement Review process. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One phase III, single-arm, open-label clinical trial (the BeneGene-2 trial; N = 45) was included in the systematic literature review conducted by the sponsor. The BeneGene-2 trial was conducted with 45 participants from 27 centres across 13 countries and territories worldwide, including 3 centres in Canada. The BeneGene-2 trial enrolled adult male patients who had moderately severe to severe hemophilia B (defined as FIX:C ≤ 2%). Patients were excluded if their anti-AAVRh74var nAb titre was greater than or equal to 1:1 or if they had a prior history of FIX inhibitors (i.e., nAbs against FIX), or positive FIX inhibitor testing greater than or equal to 0.6 BU.
The primary objective of the BeneGene-2 trial was to determine the noninferiority of fidanacogene elaparvovec relative to the standard of care in Canada, which is FIX prophylaxis, as measured by ABRtotal at week 12 to month 15 (denoted as year 1) after infusion of fidanacogene elaparvovec. Other efficacy and safety end points were also examined in the BeneGene-2 trial, including the number of patients without bleeds, ABRtreat, ABRjoint, AIR, annualized FIX consumption, HJHS, Haem-A-QoL, HAL, treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), deaths, withdrawals due to adverse events (AEs), and notable harms (e.g., increased alanine transaminase [ALT], abnormal hepatic function, increased aspartate aminotransferase [AST], increased hepatic enzyme, and increased transaminases). In addition to noninferiority, tests of superiority were also conducted, and a gatekeeping process was applied to control multiplicity of testing multiple end points. For efficacy outcomes such as ABRtotal, ABRtreat, ABRjoint, AIR, and annualized FIX consumption, the 45 participants in the pivotal BeneGene-2 trial served as their own controls, using data collected from when these patients were on FIX prophylaxis during an open-label, noninvestigational, prospective, lead-in study (the BeneGene-1 study, N = 102) for comparison.
Patients in the BeneGene-2 trial had a median age of 29 years, ranging from 18 years to 62 years. The majority of patients were white (73.3%), followed by patients identifying as Asian (15.6%), Black or African American (2.2%), American Indian or Alaska Native (0), and Native Hawaiian or other Pacific Islander (0) [all wording for these categories from original source].
The BeneGene-2 trial is ongoing and expected to be completed in December 2029. Data from before the data cut-off date (November 16, 2022) were used to support the sponsor’s present submission to CADTH.
As of the data cut-off date, the mean (standard deviation [SD]) duration of follow-up in the BeneGene-2 trial was |||| ||||| ||||||| with a median (minimum, maximum) of |||| ||||| ||||| ||||. For the lead-in BeneGene-1 study, the mean (SD) duration of follow-up was |||| ||||| ||||||| with a median (minimum, maximum) of |||| ||||| ||||| ||||.
The model estimate of the difference in ABRtotal 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 after fidanacogene elaparvovec infusion, favouring fidanacogene elaparvovec. The difference in ABRtotal from week 12 to the data cut-off date (overall) was −3.37 (95% CI, −5.80 to −0.95), in favour of fidanacogene elaparvovec. Overall, 64.4% (29 out of 45) of the patients treated with fidanacogene elaparvovec and 28.9% (13 out of 45) of the patients treated with routine FIX prophylaxis had no untreated or treated bleeds at year 1 after fidanacogene elaparvovec infusion. From week 12 to the data cut-off date after infusion, ||||| ||||||| of the patients treated with fidanacogene elaparvovec and ||||| ||||||| of the patients treated with routine FIX prophylaxis had no bleeds.
The estimated mean difference in ABRtreat 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 was −2.62 (95% CI, −4.27 to −0.96) at year 1 after fidanacogene elaparvovec infusion and ||||| |||||| || |||||| from week 12 to the data cut-off date, all favouring fidanacogene elaparvovec. In total, 73.3% (33 out of 45) of the patients treated with fidanacogene elaparvovec and 35.6% (16 out of 45) of the patients treated with routine FIX prophylaxis had no treated bleeds at year 1 after fidanacogene elaparvovec infusion. From week 12 to the data cut-off date after infusion, ||||| ||||||| of the patients treated with fidanacogene elaparvovec and ||||| ||||||| of the patients treated with routine FIX prophylaxis had no treated bleeds.
The estimated difference in ABRjoint between patients treated with fidanacogene elaparvovec and the same patients treated with routine FIX prophylaxis was ||||| |||||| || |||||| at year 1 after fidanacogene elaparvovec infusion, in favour of fidanacogene elaparvovec. From week 12 to the data cut-off date, the difference was ||||| |||||| || ||||||| |||| ||||||||| |||||||||||| |||||||||||. Overall, 68.9% (31 out of 45) of the patients treated with fidanacogene elaparvovec and 44.4% (20 out of 45) of the patients treated with routine FIX prophylaxis had no joint bleeds at year 1 after fidanacogene elaparvovec infusion. From week 12 to the data cut-off date after infusion, ||||| ||||||| of the patients treated with fidanacogene elaparvovec infusion and ||||| ||||||| of the patients treated with routine FIX prophylaxis had no joint bleeds.
The difference in 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 was −54.37 (95% CI, −63.64 to −45.10) at year 1 after fidanacogene elaparvovec infusion and |||||| ||||||| || ||||||| from week 12 to the data cut-off date, all favouring fidanacogene elaparvovec. From week 12 to the data cut-off date, the difference (95% CI) in the annualized FIX consumption between patients treated with fidanacogene elaparvovec and the same patients treated with routine FIX prophylaxis was |||||||| IU/kg ||||||||| || ||||||||), ||||||||| |||||||||||| |||||||||||.
Among patients treated with fidanacogene elaparvovec, change from baseline at week 52 or week 104 after infusion of fidanacogene elaparvovec |||||| |||||||||||| 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.
TEAEs were reported in 84.4% (38 out of 45) of the patients in 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 out of 45) and 13.3% (6 out of 45) of the patients in the BeneGene-2 trial, respectively. Increased AST, increased hepatic enzyme, and increased transaminases each occurred in 6.7% (3 out of 45) of the patients in the BeneGene-2 trial.
The BeneGene-2 trial, the only eligible study identified from the sponsor-conducted systematic literature review, was a phase III, single-arm, open-label clinical trial that enrolled 45 patients. Although the 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 asked to suspend their FIX prophylaxis regimen after infusion of fidanacogene elaparvovec, but could resume FIX prophylaxis based on the judgment of the investigator and the trial protocol–outlined guidance to the treating physician on when to consider resuming FIX prophylaxis. These conditions in the guidance were considered generally appropriate by the clinical experts consulted by CADTH. Moreover, the resumption of a FIX prophylaxis regimen after infusion in the BeneGene-2 trial was not expected to modify treatment effects, supported by the “jump to reference” sensitivity analysis in which participants who resumed FIX prophylaxis regimens after infusion of fidanacogene elaparvovec were excluded and the difference in ABRtotal was similar to that of the primary analysis. The patients included in the pivotal BeneGene-2 trial were selected from the lead-in BeneGene-1 study. Out of 102 patients in the BeneGene-1 study, 45 were enrolled in the pivotal BeneGene-2 trial. 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 majority of the patients who were left out (i.e., 40 patients were not enrolled in the BeneGene-2 trial because they had not completed the BeneGene-1 study), such as ABRtotal, ABRtreat, and AIR, were similar to the those at year 1 after infusion 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 a physician’s clinical decisions shared with patients. Despite the risk of bias likely being low, CADTH determined, based on information provided by the sponsor, that the potential risk of bias that may lead to exaggeration of treatment effects of fidanacogene elaparvovec (i.e., 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., HRQoL end points) could not be made. It was determined by CADTH that the gatekeeping process applied to control multiplicity of testing multiple end points was appropriate. However, there were some concerns regarding the assumptions used in the statistical models in the BeneGene-2 trial, which may make the 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’ expectations of long-lasting effects, evidence from the current follow-up period (|||| ||| |||||) in the BeneGene-2 trial may not be able to be generalized to long-term efficacy and safety. Second, the proposed indication includes patients with “moderately severe to severe” hemophilia B, and defining this has implementation considerations. Whereas the BeneGene-2 trial defined “moderately severe to severe” as FIX:C less than or equal to 2%, the clinical experts consulted by CADTH noted that severity in clinical practice is defined by a patient’s phenotype and not simply their factor activity levels. Some patients’ disease be considered moderately severe to severe due to clinical symptoms although their FIX level is greater than 2%, according to the clinical experts consulted by CADTH. In addition, the proposed indication does not specify sex, while the BeneGene-2 trial limited enrolment to male patients. However, the clinical experts consulted by CADTH noted that this is not a serious generalizability issue because they did not expect treatment effects to differ by sex, and female patients with moderately severe to severe hemophilia B are very rare. Furthermore, the BeneGene-2 trial only included patients with anti-AAVRh74var nAb titre less than 1:1. According to the clinical experts consulted by CADTH, the efficacy of fidanacogene elaparvovec in patients with anti-AAVRh74var nAb titre greater than or equal to 1:1 remains uncertain. Nonetheless, the clinical experts consulted by CADTH agreed that selection of eligible patients, if fidanacogene elaparvovec were to be publicly reimbursed, should follow the threshold used in the BeneGene-2 study. Lastly, most patients (73.3%) in the BeneGene-2 trial were white, which — according to the clinical experts consulted by CADTH — was a higher proportion than would be expected in the population of patients in Canada.
The selection of outcomes for Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: ABRtotal, ABRtreat, ABRjoint, 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 the GRADE guidance, nonrandomized comparative evidence starts at low certainty and noncomparative evidence starts at very low certainty. The GRADE summary of findings is presented in Table 3 and Table 4.
Summary of Findings for Fidanacogene Elaparvovec for Patients With Hemophilia B (Outcomes With Comparative Data).
Summary of Findings for Fidanacogene Elaparvovec for Patients With Hemophilia B (Outcomes without Comparative Data).
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 the gap in knowledge of the longer-term efficacy and safety of fidanacogene elaparvovec. Patients who completed Study C0371005 were encouraged to enrol into Study C0371003 to evaluate fidanacogene elaparvovec for up to an additional 5-year longer-term follow-up.
Study C0371005 (N = 15) was a phase I/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 participants with hemophilia B with endogenous FIX levels less than or 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 years to 61 years. The majority of participants were white or “Caucasian” (80.0%) [wording from original source]. The majority of participants had no family history of FIX inhibitor (80.0%) and had hemophilia B with a FIX:C level less than 1% (66.7%).
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 (SD) annualized FIX production consumption was |||| |||||||||| IU in all 15 participants, with a mean (SD) of |||| |||||||||| IU in the 11 participants previously on prophylaxis treatment and |||| |||||||| IU in the 4 participants previously on on-demand treatment.
During the 52-week period preceding screening, the mean (SD) number of target joint bleeds was |||| ||||||| in a total of 5 participants (4 participants previously on prophylactic treatment and 1 participant previously on on-demand treatment). The mean (SD) 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 end of study.
The assessments of HJHS, HAL, and the McGill pain questionnaire were added in a protocol amendment; therefore, only the final ||| |||||| participants enrolled were evaluated for these assessments.
Regarding HJHS, ||| | participants had assessments done at baseline and at the end of the study. In general, a |||||||| ||| |||||||| || ||| ||||||||| |||||||||||| |||| ||||| ||||| |||||||| |||||| |||||| |||| |||||| ||||| |||||| |||| |||||| ||||| |||| ||| |||| ||||| |||| ||| |||| |||||| ||| ||| ||||| ||||| || |||| ||||| ||||||| ||||| |||||||| ||| ||||| ||||||.
A |||||||| || ||| ||||| ||| ||||| ||| ||| |||||| |||| |||| ||| |||||||| || ||| | participants who had assessments done at baseline and at the end of the study. A |||||||| was also observed in |||||||||| ||||||| ||||| ||||| |||| ||||, as well as in the |||||| ||||| |||||| |||||| ||||||| ||||| |||||.
Fourteen out of 15 participants (93.3%) reported at least 1 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, 53.3%), gastrointestinal disorders (7 participants, 46.7%), and musculoskeletal and connective disorders (6 participants, 40.0%). The majority of TEAEs (53 out of 81, 65.4%) were mild in severity, and the other 28 (34.6%) were moderate in severity. There were no study drug discontinuations, study discontinuations, SAEs, or deaths reported in the 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 has not been covered in this report due to the small number of participants and because 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 participants had completed the longer-term follow-up, and 7 participants are ongoing. The duration of follow-up at data cut-off ranged from || |||||| || || |||||| after fidanacogene elaparvovec infusion.
The mean age of participants was 40.1 years, ranging from 18 years to 61 years at the time of fidanacogene elaparvovec infusion. Most participants were aged 35 years or older (71.4%) and were 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 less than or equal to 2%.
Mean ABRtreat remained lower than 1.0 from year 2 through year 6 after infusion with |||| participants (|||||) having no bleeds during their entire time in the study. The mean (SD) treated ABR was |||| |||||||, |||| |||||||, |||| |||||||, |||| ||||||| and |||| ||||||| during years 2, 3, 4, 5, and 6 after infusion, respectively. |||| participants had treated bleeds during years 2 through 6.
AIR generally decreased over the entire follow-up periods, from a mean of |||| in year 2 to |||| in year 6 after fidanacogene elaparvovec infusion. The mean (SD) AIR was |||| |||||||, |||| |||||||, |||| |||||||, |||| ||||||| and |||| ||||||| during years 2, 3, 4, 5, and 6 after infusion, respectively.
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.
From week 52 to week 130 after fidanacogene elaparvovec infusion, the number of participants with target joint bleeds decreased from || ||||||| to ||||||, based on target joint assessment questionnaire results. || ||||||||||| had target joint bleeding reported beyond week 130 as of the data cut-off (from week 156 to week 312 or end of study).
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 longer-term follow-up (years 2 through 6).
Mean HAL domain scores |||||||| ||||| || and the total score |||||||| ||||| || at all after 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.
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 (28.6%) of the 14 participants 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 AESI. During the longer-term follow-up period, 8 of 14 participants experienced ALT increase above ULN, 3 of which had AST increase above 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 ALT level above ULN. Regarding immunogenicity, all 14 participants remained negative for FIX inhibitor during the study.
Study C0371005 was an open-label, single-arm, multicentre, phase I to 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 influence 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, subjective AEs). The follow-up period was only 1 year, making it insufficient to draw any definite conclusions regarding long-term efficacy and safety outcomes. In addition to the general limitations of the study design, the HJHS and HAL assessments were added to the study later, during a protocol amendment; hence, 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 longer-term follow-up for 14 of the patients previously administered fidanacogene elaparvovec in Study C0371005. The primary objective of Study C0371003 was to evaluate safety, so no hypothesis testing was planned. All efficacy and safety data were summarized descriptively, resulting in no statistical inferences. Data were missing for the assessments of HJHS and HAL in this study as well, for the reasons previously noted for Study C0371005.
In Study C0371003, the duration of follow-up at data cut-off ranged from || |||||| || || |||||| after 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 assessing safety and efficacy in the patient population. The clinical experts consulted by CADTH noted that longer follow-up (for 20 to 25 years) involving more patients is warranted, to make any definite 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.
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 would be expected in the population of patients in Canada. Both Study C0371005 and Study C0371003 only enrolled male patients, although the clinical experts noted that this is likely not a serious generalizability issue because the treatment effects are not expected to differ by sex 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 of less than or equal to 2% at screening, and historical evidence or being from 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 a patient’s phenotype and not simply by their factor activity levels. Some patients’ disease could be considered moderately severe to severe due to clinical symptoms although their FIX level is greater than 2%, according to the clinical experts consulted by CADTH. Lastly, generalizability may also be limited by the small sample size.
Patient group, clinician group, clinical expert, and drug program input gathered during this CADTH review, as well as the relevant literature, were reviewed to identify ethical considerations relevant to the use of fidanacogene elaparvovec for the treatment of moderately severe to severe hemophilia B in patients aged 18 years or older.
Ethical considerations identified in this review included those related to the following:
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis: the number of patients with moderately severe to severe hemophilia B in Canada is uncertain, the uptake of fidanacogene elaparvovec is uncertain and may be underestimated, market share estimates for FIX prophylaxis treatments are not aligned with Canadian clinical practice, the cost of FIX treatments paid by CBS is confidential and uncertain, and it is unclear whether costs associated with testing for nABs will be covered by the sponsor. The CADTH reanalysis was conducted from the perspective of the CADTH participating drug plans. CADTH reanalysis suggests that the reimbursement of fidanacogene elaparvovec for the treatment of moderately severe to severe hemophilia B in patients aged 18 years and older would be associated with a budgetary increase of $127,503,945 over the first 3 years (year 1: $40,579,580; year 2: $58,746,280; year 3: $28,178,085). The estimated budget impact is highly sensitive to the number of patients who receive fidanacogene elaparvovec.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Edward Xie, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Peter Jamieson, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Trudy Huyghebaert, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: December 20, 2023
Regrets: None
Conflicts of interest: None
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Indication: For the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital Factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74
Sponsor: Pfizer Canada ULC
Final recommendation: Reimburse with conditions
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