BACKGROUND

Congenital Hemophilia

Most commonly, hemophilia is an inherited X-linked recessive congenital disorder that predominantly affects males caused by deficiency of coagulation factor VIII (FVIII; hemophilia A) and factor IX (FIX; hemophilia B). In Hemophilia A, variants in the FVIII gene lead to the associated impairment of the normal coagulation cascade.1, In hemophilia B, variant in the F9 gene results in deficiency or functional defectiveness of FIX.2,3,

Hemophilia affects more than 1.2 million individuals (mostly males) worldwide.4, Hemophilia A is more common than hemophilia B. Typically, the reported incidence of hemophilia A is approximately 1 in 4000 to 1 in 5000 live male births while incidence of hemophilia B has been reported to occur in approximately 1 in 15,000 to 1 in 30,000 live male births. Approximately one-third to half have severe disease (FIX activity <1% of normal).4,5,The exact prevalence of hemophilia in the United States (US) is not known but is estimated to be around 33,000 based on data during the period 2012 to 2018.6,Approximately 77% of all hemophiliacs in the US have hemophilia A, of which 60% may have severe disease. The estimated incidence of hemophilia A in the US is 1:5000 live male births. This translates to approximately 400 infants born each year with hemophilia

A. There is no clear effect of geography itself on incidence or prevalence. All races and ethnic groups are

equally affected.7,8,9,World Federation of Hemophilia (WFH) data from 1998 to 2006 indicate a global trend of increased prevalence of hemophilia A in approximately 80% of surveyed countries.10, Potential contributing factors include increased survival, improved diagnostic capabilities, a broader use of national registries and migration from areas with limited access to healthcare to areas with better access. The estimated number of prevalent cases of hemophilia B in the US is between 6300 and 7600 as of 2018.11, Reported prevalence rate of hemophilia B was estimated at 3.7 per 100,000 male population while the incidence rate was estimated at

5.3 per 100,000 male births, or 1 case per 19,283 live male births. Worldwide, there are approximately 33,000 people living with hemophilia B as of 2020.12,

The severity of hemophilia has generally been defined by factor levels.13, Severity based on factor levels does not perfectly correlate with any individual’s clinical severity, but no other classification system is widely accepted.14, Disease severity using factor level classifications is summarized in Table 1. Individuals with more severe hemophilia are more likely to have spontaneous bleeding, severe bleeding, and an earlier age of first bleeding episode, which can begin as early as birth. Those with severe disease, are at risk for potentially life threatening bleeding episodes and debilitating long-term complications.1, Individuals with severe hemophilia typically experience frequent, spontaneous bleeds (1 to 2 times per week) in their muscles or joints.15, Repeated, spontaneous bleeding in the joints (hemarthrosis) results in joint inflammation and damage to joint cartilage and synovium leading to hemophilic arthropathy.16, According to 1 study, hemophilic arthropathy was observed in >90% of those with severe hemophilia before the age of 30 years.17, Severe hemophilia is almost exclusively a disease of males, although females can be affected in some rare cases (eg, compound heterozygosity; skewed lyonization; X chromosome loss). In contrast, mild hemophilia has been reported in up to one-quarter of female carriers who are heterozygotes. Most commonly, hemophilia is inherited. However, sporadic disease (without a positive family history, presumed due to a new variant) is also common. Studies have demonstrated that sporadic causes account for as much as 55% of cases of severe hemophilia A and 43% of cases of severe hemophilia B.18, In moderate and mild hemophilia A and B, approximately 30% are sporadic cases.

Table 1. Hemophilia Severity, Factor Levels and Symptoms15,

 

Severity of Hemophiliaa	Clotting Factor levels	Symptoms
Mild	5% to 40% of normal	Might bleed for a long time after surgery, dental extraction, or a very bad injury Rarely bleeds unless injured (rarely has spontaneous bleeding)
Moderate	1% to 5% of normal	Might bleed for a long time after surgery, a bad injury, or dental work Might bleed for no clear reason (occasional spontaneous bleeding)
Severe	Below 1% of normal	Bleed often into the joints and sometimes the muscles Can bleed for no obvious reason (spontaneous bleeding)

 

a Severity of hemophilia is measured in percentage of normal factor activity in the blood, or in number of international units (IU) per milliliter (mL) of whole blood. The normal range of clotting factor VIII or IX in the blood is 40% to 150%. People with factor activity levels of less than 40% are considered to have hemophilia. Some people’s bleeding pattern does not match their baseline level. In these cases, the phenotypic severity (bleeding symptoms) is more important than the baseline level of factor in deciding upon treatment options.

 

Diagnosis

Hemophilia should be suspected in individuals who present with a history of easy bruising; “spontaneous” bleeding (i.e., bleeding for no apparent/known reason), particularly into the joints, muscles, and soft tissues; excessive bleeding following trauma or surgery. Diagnosis is made by assessing the patient’s personal and family history of bleeding and is confirmed through screening tests, including a complete blood count test and a blood coagulation tests, typically activated partial thromboplastin clotting time (aPTT) and a prothrombin time (PT) test.19, Both tests measure the length of time it takes for blood to clot and are important in identifying the potential cause of bleeding; the aPTT test assesses the clotting ability of factors VIII, IX, XI and XII while the PT assay tests for factors I, II, V, VII and X.20,6, In the event of an abnormal aPTT result, diagnosis of hemophilia A or B is established by the following criteria:

Diagnosis of hemophilia A requires confirmation of a factor VIII activity level below 40% of normal (below 0.40 international units [IU]/mL), or, in some circumstances where the factor VIII activity level is

≥40 percent, a pathogenic variant in the F8 gene. A normal von Willebrand factor antigen (VWF:Ag)

should also be documented to eliminate of the possibility of some forms of von Willebrand disease.

 Diagnosis of hemophilia B requires confirmation of a FIX activity level below 40% of normal, or, in some circumstances where the FIX activity level is ≥40%, a pathogenic variant in the F9 gene. Newborns have a lower normal range of FIX activity; the normal newborn range should be used as a reference when evaluating factor levels in newborns.

Genetic testing is recommended to identify the specific disease-causing gene mutation and evaluate the risk of inhibitor development.19, Diagnosis is usually at a younger age among patients with the severe (≤2 years) or moderate (<5 to 6 years) form of the disorder compared with those with mild disease who are typically diagnosed later in life or in adulthood.8,

Current Treatment

Factor replacement therapy is provided via 1 of 2 modalities: prophylaxis (regular replacement) or on demand (episodic). Prophylaxis is primary (before a bleeding event has occurred) or secondary (a bleeding event has occurred), and continuous or intermittent (eg, for a few months at a time). Individuals with hemophilia, particularly those with severe hemophilia, can be affected by development of inhibitors (antibodies that develop in response to exogenous administration of exogenous factors). In a 13-year US longitudinal study of individuals with hemophilia, 11% to 17% of those with severe hemophilia and 3% of individuals with mild hemophilia developed inhibitors during follow-up.21, The median age of inhibitor development for those with severe hemophilia A was 3 years or less in developed countries, and was approximately 30 years in those with moderate-to-mild hemophilia, often following intensive FVIII exposure with surgery.1, Development of inhibitors is also associated with increased mortality. A retrospective analysis of Centers for Disease Control and Prevention (CDC) surveillance data in individuals with severe hemophilia A reported that odds of death among the subgroup with inhibitors was 70% higher than among the subgroup without inhibitors (p<.01).22, In a retrospective claims analysis conducted in the Netherlands, all-cause mortality rates among individuals with non-severe hemophilia A were 5 times higher in the subgroup with inhibitors when compared with the subgroup without inhibitors.23, Several factor preparations are available for prophylaxis, some prepared from human plasma, some prepared using recombinant technology including some with modifications to extend the half-life of the therapy. An updated table is maintained by the of the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) in the United States (www.hemophilia.org).

Regulatory Status

 

On November 22, 2022, Etranacogene dezaparvovec-drlb (Hemgenix) (Hemgenix; CSL Behring) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with Hemophilia B (congenital FIX deficiency) who currently use FIX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

On June 29, 2023, Valoctocogene roxaparvovec-rvox (Roctavian)(Roctavian; BioMarin Pharmaceutical Inc.) was approved by the U.S. FDA for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.

RATIONALE

This evidence review was created in January 2023 and with a search of the PubMed database through une 27, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Congenital Hemophilia B

 

Clinical Context and Therapy Purpose

 

The purpose of gene therapy in adults who have congenital hemophilia B is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this therapy may include the following:

A novel mechanism of action or approach that may allow successful treatment of many individuals for whom other available treatments are not available or have failed or have yielded sub-optimal response.

 

 Reduced treatment complexity such as avoidance of repeated intravenous infusion or subcutaneous injections.

The following PICO was used to select literature to inform this review.

Populations

 

The relevant population of interest is individuals who are adults with congenital hemophilia B who currently use factor IX (FIX) prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

Interventions

 

The therapy being considered is Etranacogene dezaparvovec-drlb (Hemgenix) and fidanacogene elaparvovec-dzkt. Etranacogene dezaparvovec-drlb (Hemgenix) is an adeno-associated virus (AAV) based gene therapy using a non- replicating recombinant AAV5 containing a codon-optimized DNA sequence of the gain-of-function Padua variant of human FIX (variant R338L), under control of a liver-specific promotor 1 (LP1).

Comparators

 

Life-long prophylaxis with exogenous factor replacement therapy is currently being used to manage individuals with congenital hemophilia B.

Outcomes

 

The general outcomes of interest are disease-specific survival, change in disease status, health status measures, quality of life, resource utilization, treatment-related mortality and treatment-related morbidity. Relevant outcome measures in alphabetical order are summarized in Table 2.

Table 2. Health Outcome Measures Relevant to Hemophilia B

 

Outcome	Description	Relevance
Annualized bleeding rate	Applicants of other FDA approved products have relied on ABR to demonstrate clinical benefit.8,	Although it is a direct assessment of clinical benefit, it has limitations in that it is a relatively infrequent event in patients on prophylactic factor regimens and the decision by a patient to treat a possible bleeding episode is usually somewhat subjective.8,
Factor activity levels	Factor activity levels is an objective endpoint. For gene therapies, functional and structural differences between the transgene and normal factor protein may present a challenge in understanding the relationship between numerically identical factor activity levels or levels that are within the normal range for the transgene protein and normal factor protein.8,	To consider factor activity level as a validated surrogate endpoint, clinical data to assess and quantitate the relationship between steady-state factor activity levels and bleeding outcomes in patients with severe hemophilia are critical.8,
Haem-A-QoL	Patient-reported outcome questionnaire validated for hemophilia; contains 6 domains: Consequences of Bleeding, Emotional Impact, Physical Functioning, Role Functioning, Treatment Concern, and Worry.24, Subscale and total scores range from 0 to 100. 41 total items scored from 0 to 5 with higher scores indicating better health-related quality of life or less impairment for a particular subscale.	The Haem-A-QoL has been validated for this population and trials.25,
Joint Activity/Bleeding	Joint examination using imaging measures such as x-rays, MRI, and ultrasound.	No validated scales or instruments that quantify joint damage have been identified. As per ISTH, target joints are major joints with ≥3 bleeding events within 6 months; bleeding in target joints is considered to be resolved if there are ≤2 bleeding events within 12 months.13,
Resource Utilization	Repeat intravenous infusions are burdensome and can results in non- adherence.	It is estimated that more than 94% of direct healthcare costs for patients with severe hemophilia A are attributable to the cost of FVIII replacement

 

 

therapy.26,27, Reduction in quantity as well as frequency of exogenous factor FVIII replacement is desirable.

ABR: annualized bleeding rate; FDA: Food and Drug Administration; FVII: factor VIII; ISTH: International Society on Thrombosis and Hemostasis; MRI: magnetic resonance imaging; QoL: quality of life.

 

Study Selection Criteria

 

Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

 Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

 Studies with duplicative or overlapping populations were excluded.

Etranacogene dezaparvovec-drlb (Hemgenix) Review of Evidence

The clinical development program is summarized in Table 3 and consists of 3 interventional studies (AMT-060- 01, AMT-061-01 and AMT-061-021). All 3 interventional studies are single-arm, open-label trials. Of these, the first 2 studies, AMT-060-01 and AMT-061-01 were phase I/II studies and are not reviewed in detail. The key trial for Etranacogene dezaparvovec-drlb (Hemgenix) is the phase III Hope-B trial (AMT-061-021) that includes 54 participants and is reviewed in detail.

Table 3. Clinical Development Program for Etranacogene dezaparvovec-drlb (Hemgenix)

 

Study	NCT No	Status	Study Dates	Objective	Sample Size	Follow-Up
CT-AMT- 060-01	NCT02396342	Completed and published28,	2015 to 2021	To evaluate the long-term safety and efficacy of AMT-060 comprising an AAV5 vector carrying a codon- optimized wild-type F9 transgene	10	5 years
CT-AMT- 061-01	NCT03489291	Ongoing and interim results published29,30,	2018 to 2023	To confirm the safety and preliminary efficacy endpoints of AMT-061 (Etranacogene dezaparvovec-drlb (Hemgenix)), with a modified F9 transgene encoding the naturally occurring hyperactive mutation, FIX-Padua, in place of wild- type F9	3	5 years
CT-AMT- 061-02 (HOPE- B)	NCT03569891	Ongoing	2018 to 2025	To evaluate the efficacy, and confirm the safety, of Etranacogene dezaparvovec-drlb (Hemgenix) (as a progression of AMT-060).	54	5 years

 

AAV5: adeno-associated virus serotype 5; FIX-Padua: Padua variant of coagulation Factor IX; NCT: national clinical trial.

 

Nonrandomized Studies

 

Study characteristics and baseline patient characteristics and results are summarized in Table 4 and 5, respectively. The prospective, open-label, single-dose, single arm, multi-national study enrolled adult males aged 19 to 75 years, with severe or moderately severe Hemophilia B. Study design involved a prospective lead-in period of at least 6 months with the intent to receive standard of care routine FIX prophylaxis. Study participants then received a single intravenous dose of Etranacogene dezaparvovec-drlb (Hemgenix) and were then followed up monthly until month 12, and then at 6-month intervals until year 5. The study is on-going. For the efficacy evaluation for the U.S. Food and Drug Administration (FDA) approval, data up to 18 months post- treatment were used.31, Of the 54 study participants, 53 completed at least 18 months of follow-up. One participant, aged 75 with numerous cardiovascular and urologic risk factors, died of urosepsis and cardiogenic shock at month 15 post-dose (at age 77 years) unrelated to treatment. Another participant received around 10% of the intended dose due to an infusion-related hypersensitivity reaction.

The primary efficacy outcome was a non-inferiority test of annualized bleeding rate (ABR) during months 7 to

18 after treatment compared with ABR during the lead-in period. All bleeding episodes, regardless of investigator assessment, were counted. Participants were allowed to continue prophylaxis during months 0 to

6. Results are summarized in Table 6. The ABR ratio (months 7 to 18 post-treatment/lead-in) was 0.46 [95% confidence interval [CI], 0.26 to 0.81] and meets the success criterion where the upper bound of the CI is less than 1.8 demonstrating non-inferiority of ABR during months 7 to 18 compared to the lead-in period. Two study participants were not able to stop routine prophylaxis after treatment with Etranacogene dezaparvovec-drlb (Hemgenix). During months 7 to 18, an additional participant received prophylaxis from days 396 to 534 [approximately 20 weeks].32,

In AAV vector–based gene therapies such as Etranacogene dezaparvovec-drlb (Hemgenix), pre-existing anti-AAV neutralizing antibodies may impede transgene expression at desired therapeutic levels. In the clinical studies, an unvalidated clinical trial assay was utilized to assess pre-existing anti-AAV5 neutralizing antibodies. There were 21 participants with positive neutralizing antibodies to AAV5. These neutralizing antibody titers were measured at baseline prior to infusion of the gene therapy product. The neutralizing antibody titers were in the range of 1:8.5 to 3212. According to the FDA reviewer, overall, there is limited data for participants with positive neutralizing antibody (NAb) titers. One participant with the highest titer of 1:3212, failed treatment, continued on routine prophylaxis with multiple bleeding episodes. The FDA reviewers observed no clear correlation of positive neutralizing antibodies titers and efficacy.31, Nine participants with higher ABRs post treatment compared to baseline included participants with and without neutralizing antibodies. The FDA reviewers noted that 4 participants with positive neutralizing antibodies had much higher ABRs compared to those with negative neutralizing antibodies. According to the prescribing label, individuals who intend to receive treatment with Etranacogene dezaparvovec-drlb (Hemgenix) are encouraged to enroll in a study that evaluates the effect of pre-existing anti-AAV5 neutralizing antibodies on the risk of bleeding.

The most common adverse reactions (incidence ≥5%) were elevated alanine aminotransferase (ALT), headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise and elevated aspartate aminotransferase (AST). One death was reported due to cardiogenic shock and was deemed unrelated to treatment.32, Nine participants were treated with corticosteroids for ALT elevation of either >2 times upper limit of normal (ULN; n=8) or >2 x baseline value (n=1). Participants with ALT elevation had approximately 44% lower mean FIX activity at month 18 compared to those that did not have ALT elevation. Study participants (17% or 9/53) that were treated with corticosteroid for ALT elevations exhibited approximately 63% lower mean FIX activity at month 18 compared to those who did not receive corticosteroid coadministration. Participants were treated for 51 to 130 days. ALT elevation is likely the result of T-cell response toward capsid proteins and may cause the lower FIX activity as noted. All participants discontinued steroid use prior to week 26, and no other form of immunosuppression was used in this study.33, As per the prescribing label, integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. As per the label, for individuals with preexisting risk factors (e.g., cirrhosis, advanced hepatic fibrosis, hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol

 

consumption, non-alcoholic steatohepatitis, and advanced age), regular (e.g., annual) liver ultrasound and alpha-fetoprotein testing should be performed following treatment.32,

Table 4. Summary of Key Nonrandomized Trial

 

Study	Study Type	Country	Dates	Participants	Treatment	Follow-Up
HOPE- B32,33,	Open- label, single- arm	US, UK and EU	2018- 2025	Inclusion Adult males with severe (FIX <1%) or moderately severe (FIX 1% to 2%) hemophilia Received continuous FIX protein prophylaxis for ≥2 months >150 previous exposure days of treatment with FIX protein Exclusion   History of FIX inhibitors or positive FIX inhibitor test at screening Positive HIV test at screening, not controlled with anti- viral therapy Active infection with hepatitis B or C virus at screening History of hepatitis B or C exposure, currently controlled by antiviral therapy at the end of the lead-in phase Previous gene therapy treatment	Screening period of approximately 4 weeks, followed by a ≥26-week lead- in phase with FIX prophylaxis, during which they were evaluated for bleeding events. After the lead-in period, patients received a single dose of 2 x 1013 gc/kg of etranacogene dezaparvovec- drlb.	78 weeks (intended duration of study 5 years)

EU: European Union; FIX: factor IX; US: United States; UK: United Kingdom.

 

 

Table 5. Summary of Baseline Demographics and Disease Characteristics

 

Patient Characteristics in (HOPE-B)32,33,	N=54
Age, mean (SD, min to max), years	41.5 (15.8, 19 to 75)
Race, n (%)
White	40 (74.1)
Black	1 (1.9)
Asian	2 (3.7)
Other	6 (11.1)
Severity of hemophilia B at diagnosis, n (%)
Severe (FIX <1%)	44 (81.5)
Moderately severe (FIX ≥1% and ≤2%)	10 (18.5)
Positive HIV status, n (%)	3 (5.6)
Prior hepatitis B infection, n (%)	9 (16.7)
Prior hepatitis C infection, n (%)	31 (57.4)
Pre-screening FIX treatment (n, %)
Extended half-life	31 (57.4)
Standard half-life	23 (42.6)
Detectable NAbs at baseline, n (%)	21 (38.8)
Participants with zero bleeds at lead-in, n (%)	14 (25.9%)

 

FIX: factor IX; NAbs: neutralizing antibodies; SD: standard deviation.

 

 

Table 6. Summary of Results

 

Outcomes (HOPE-B)32,	Pre-Study Perioda	Post-Study Period (months 7 to 18b after Etranacogene dezaparvovec-drlb (Hemgenix) treatment)
Bleeding Related Outcome (Primary)
All Bleeds	136	96c
Follow-up time (person-year)	33	52
Mean adjusted ABR (95% CI)d	4.1 (3.2 to 5.4)	1.9 (1.0 to 3.4)
Individuals with bleeds	40 (74%)	20 (37%)
Individuals with zero bleeds	14 (26%)	34 (63%)
Observed spontaneous bleed count (proportion of total bleeds)e	50 (37%)	14 (26%)
Observed joint bleed count (proportion of total bleeds)e	77 (57%)	19 (35%)
Mean spontaneous ABR	1.52	0.44
Mean traumatic ABR	2.09	0.62
Number of bleeding episodes	136 (including 118 treated episodes)	54 (including 30 bleeding episodes)
Secondary Outcomes33,
FIX Activity (One-stage activated partial thromboplastin time-based assay), mean (±SD)	1.19 (0.39)	Month 6: 39.0 (18.7) Month 12: 41.5 (21.7) Month 18: 36.9 (21.4)
FIX Activity (chromogenic assay), mean (± SD), range	Not reported	Month 6: 38.95% ± 18.72, 8.2 to 97.1%) Month 12: 41.48% ± 21.71, 5.9 to 113.0%) Month 18: 36.90% ± 21.40, 4.5 to 122.9%)

 

ABR: annualized bleeding rate; CI: confidence interval; FIX: factor IX; SD: standard deviation.

a During the observational lead-in period individuals used their individualized approach to factor IX prophylaxis derived prior to enrollment in the study, rather than a standardized approach to factor IX prophylaxis. Not all individuals complied with their prescribed prophylaxis regimen during the lead-in period.

b Efficacy evaluation started from month 7 after Etranacogene dezaparvovec-drlb (Hemgenix) treatment, to allow factor IX expression to reach a steady state.

c An ABR of 20 was imputed for the period when three individuals were on continuous prophylaxis.

d Non-inferiority comparison and mean ABR estimates were based on a repeated measures generalized estimating equations negative binomial regression model.

e For spontaneous and joint bleed counts, no imputation was done for the three individuals receiving continuous prophylaxis during months 7 to 18.

 

The purpose of the study limitations tables (see Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of evidence supporting the position statement. The limited representations of African Americans, Asians, and Hispanics makes it challenging to reach conclusions about the efficacy of Etranacogene dezaparvovec-drlb (Hemgenix) in these racial groups. The FDA reviewer noted higher ABRs (during months 7 to 18 compared with the lead-in period) among 14 non-white study participants compared to white study participants.33, Because of the uncontrolled study design, limited sample size and relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of Etranacogene dezaparvovec-drlb (Hemgenix) compared with FIX prophylaxis. It is not yet clear that the initial increase in FIX levels will be maintained for decades. In addition, there are uncertainties about the long-term impact of the therapy on liver function and the risk for hepatocellular carcinoma. The small sample size creates uncertainty around the estimates of adverse events. Some serious harms are likely rare occurrences and as such may not be observed in small trials. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect and safety.

 

Table 7. Study Relevance Limitations

 

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow- upe
HOPE-B 32,33,	4. Enrolled populations do not reflect relevant diversity				1.  Not sufficient duration for benefit 2.  Not sufficient duration for harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.

b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.

c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.

d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.

e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

 

 

Table 8. Study Design and Conduct Limitations

 

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
HOPE-B 32,33,	1.  Participants not randomly allocated 2. Allocation not concealed 3. Allocation concealment unclear 4.  Inadequate control for selection bias	1.  Participants or study staff not blinded 2.  Outcome assessors not blinded 3.  Outcome assessed by treating physician 4.  Outcomes not assessed centrally			1.  Power calculations not reported 2.  Power not calculated for primary outcome 3.  Power not based on clinically important difference

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.

b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.

c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.

d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.

e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference;

4. Other.

f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

 

Section Summary: Etranacogene dezaparvovec-drlb (Hemgenix) for Congenital Hemophilia B

The evidence for use of Etranacogene dezaparvovec-drlb (Hemgenix) for congenital hemophilia B consists of a single study. In the pivotal, open-label, phase III single-arm HOPE-B study, 54 study participants received a single intravenous infusion of Etranacogene dezaparvovec-drlb (Hemgenix). Of the 54 participants, 53 were included in the efficacy analysis. The estimated mean ABR during months 7 to 18 after treatment with Etranacogene dezaparvovec-drlb (Hemgenix) was 1.9 bleeds/year (95% CI: 1.0 to 3.4) compared with an estimated mean ABR of 4.1

 

(95% CI:, 3.2 to 5.4) during the lead-in period. The ABR ratio (months 7 to 18 post-treatment/lead-in) was 0.46

(95% CI, 0.26 to 0.81) demonstrating non-inferiority of annualized bleeding rate during months 7 to 18 compared to the lead-in period. The ABR represents an appropriate clinical benefit endpoint for individuals with hemophilia B and the evidence of clinical benefit was demonstrated by reduction of bleeds in the efficacy evaluable period post treatment. Limitations include uncontrolled study design, limited sample size and relatively short follow-up. There is considerable uncertainty about the long-term net benefits of Etranacogene dezaparvovec-drlb (Hemgenix) compared with FIX prophylaxis. It is not yet clear that the initial increase in FIX levels will be maintained for decades. In addition, there are uncertainties about the long-term impact of the therapy on liver function and the risk for hepatocellular carcinoma as limited sample size is prone to uncertainty around the estimates for adverse events. Some serious harms are likely rare occurrences and as such may not be observed in small trials. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect and safety.

Congenital Hemophilia A

 

Clinical Context and Therapy Purpose

 

The purpose of gene therapy in adults who have congenital severe hemophilia A is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this therapy may include the following:

A novel mechanism of action or approach that may allow successful treatment of many individuals for whom other available treatments are not available or have failed or have yielded sub-optimal response

 Reduced treatment complexity such as avoidance of repeated intravenous infusion or subcutaneous injections.

The following PICO was used to select literature to inform this review.

Populations

 

The relevant population of interest is individuals who are adults with congenital severe hemophilia A.

Interventions

 

The therapy being considered is valoctocogene roxaparvovec-rvox, an AAV5 mediated gene therapy designed to deliver a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation factor VIII (hFVIII-SQ). Transcription of this transgene occurs within the liver, using a liver-specific promoter, which results in the expression of hFVIII-SQ. The expressed hFVIII-SQ replaces the missing coagulation factor VIII needed for effective hemostasis.

Comparators

 

Life-long prophylaxis with exogenous factor replacement therapy is currently being used to manage individuals with congenital severe hemophilia A.

Outcomes

 

The general outcomes of interest are disease-specific survival, change in disease status, health status measures, quality of life, resource utilization, treatment-related mortality and treatment-related morbidity. Relevant outcome measures in alphabetical order are summarized in Table 1.

Study Selection Criteria

 

Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

 Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

 Studies with duplicative or overlapping populations were excluded.

Valoctocogene roxaparvovec-rvox (Roctavian) Review of Evidence

The clinical development program is summarized in Table 15 and consists of 2 interventional studies (301 and 201). Both are single-arm, open-label trials. Of these, study 201 is a phase I/II study and is not reviewed in detail. The key trial for Valoctocogene roxaparvovec-rvox (Roctavian)is the phase III trial (study 301) that includes 134 participants and is reviewed in detail.

Table 15. Clinical Development Program for Valoctocogene Roxaparvovec-rvox

 

Study	NCT No	Phase	Study Population	Status	Study Dates	Design	Sample Size	Follow- Up
BMN 270- 301	NCT03370913	3	Adult males with hemophilia A and residual FVIII levels ≤1 IU/dL	Ongoing (results published at 1 year follow-up37, and 2 year follow-up38,)	2017- Ongoing	Open- Label, Single- Arm Study	134	52 weeks (efficacy analysis)
BMN 270- 201	NCT02576795	2	Adult males with hemophilia A and residual FVIII levels ≤1 IU/dL	Ongoing (results published at 1 year follow-up39, and 3 year follow-up40,)	2015- ongoing	Open- Label, Single- Arm Study	15	52 weeks (efficacy analysis)

FVIII: Factor VIII; IU: international units; NCT: national clinical trial

 

Nonrandomized Studies

 

Study characteristic and baseline patient characteristics and results are summarized in Tables 16 and 17, respectively. The prospective, open-label, single-dose, single arm, multi-national study enrolled adult males 18 years and older with severe hemophilia A (endogenous factor VIII [FVIII] level ≤1 IU/dL) as evidenced by their medical history. Study design involved a prospective lead-in period of at least 6 months with the intent to receive standard of care routine factor prophylaxis along with bleeding events. Of the 134 participants who received valoctocogene roxaparvovec-rvox, 112 had baseline ABR data prospectively collected during a period of at least 6 months on FVIII prophylaxis prior to receiving gene therapy (rollover population). The remaining

22 participants had baseline ABR collected retrospectively (directly enrolled population). All patients are intended to be followed for 5 years. The study is on-going. For the efficacy evaluation for the U.S. FDA approval, all patients were followed for at least 3 years.

The primary efficacy outcome was a non-inferiority test of difference in ABR in the efficacy evaluation period. All bleeding episodes were counted. Participants were allowed to continue prophylaxis if needed. Results are summarized in Table 18. The mean ABR after treatment and pre-treatment while patients were on FVIII prophylaxis in the rollover population (N=112) was 2.6 bleeds/year versus 5.4 bleeds/year. The mean difference in ABR was -2.8 (95% CI, -4.3 to -1.2) bleeds/year. The non-inferiority analysis met the pre-specified margin of 3.5. According to the label, a total of 5 participants (4%) did not respond and 17 (15%) lost response to treatment over a median time of 2.3 years (range: 1.0 to 3.3). In the directly enrolled population with a longer follow-up, a total of 1 participant (5%) did not respond and 6 (27%) lost response to treatment over a median time of 3.6 years (range: 1.2 to 4.3).

The most common adverse reactions (incidence ≥5%) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. Most common laboratory abnormalities (incidence ≥10%) were ALT, AST, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), FVIII activity levels, gamma-glutamyl transferase (GGT) and bilirubin above ULN. Transaminitis is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of AAV-vector based gene therapy. Most ALT elevations occurred within the first year following administration of gene therapy, especially within the first 26 weeks, were low-grade and resolved. The median time (range) to the first ALT elevation (defined as ALT ≥1.5 x baseline or above ULN) was 7 weeks (0.4 to 159 weeks) and the median duration (range) was 4 weeks (0.1 to 135 weeks). Some ALT elevations were associated with a decline in factor VIII activity. As per the prescribing label, integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. As per the label, for individuals with preexisting risk factors (e.g., cirrhosis, advanced hepatic fibrosis, hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, and advanced age), regular (e.g., annual) liver ultrasound and alpha-fetoprotein testing should be performed following treatment.

Table 16. Summary of Key Nonrandomized Trial

 

Study	Study Type	Country	Dates	Participants	Treatment	Follow- Up
Study 301	Open- label, single- arm	Global	2017- 2024	Inclusion Males ≥18 years of age with severe hemophilia A and residual FVIII levels ≤1 IU/dL. On prophylactic FVIII replacement therapy for at least 12 months prior to study entry. No previous documented history of a detectable FVIII inhibitor. Exclusion Detectable pre-existing antibodies to the AAV5 capsid. Any evidence of active infection or any immunosuppressive disorder, including HIV infection. Active infection, chronic or active hepatitis B or C, immunosuppressive disorder including HIV. Stage 3 or 4 liver fibrosis, cirrhosis, liver function test abnormalities, history of thrombosis or thrombophilia, serum creatinine ≥1.4 mg/dL, and active malignancy. Primary endpoint Non-inferiority test of the difference in ABR in the efficacy evaluation perioda compared with baseline period in the rollover population. Non-inferiority margin was 3.5 bleeds per year.	Single intravenous dose of 6 X 1013 vg/kg body weight of valoctocogene roxaparvovec- rvox Of the 134 participants, 112 patients had ABR data prospectively collected for at least 6 months (rollover population); for remaining 22 participants baseline ABR data was collected retrospectively (directly enrolled population).	5 years

AAV5; adeno-associated virus serotype 5; ABR; annualized bleeding rate; FVIII: factor VIII; IU: international units.

a All bleeding episodes, regardless of treatment, were counted towards ABR. The efficacy evaluation period started from study day 33 (week 5) or the end of FVIII prophylaxis including a washout period after treatment with gene therapy, whichever was later, and ended when a participant completed the study, had the last visit, or withdrew or was lost to follow-up from the study, whichever was the earliest.

 

 

Table 17. Summary of Baseline Demographics and Disease Characteristics

 

Patient Characteristics in Study 301	N=134
Age, median (min to max), years	30 (18 to 70)
Race, n (%)
White	72%
Asian	14%
Black	11%
Positive HIV status, n (%)	1%
Prior hepatitis B infection, n (%)	15%
Prior hepatitis C infection, n (%)	31%

 

HIV: human immunodeficiency virus

 

 

Table 18. Summary of Results

 

Outcomes (Study 301)	Pre-Study Period (n=112)	Post-Study Period (n=112)
Median (range) follow-up duration in years	0.6 (0.5 to 1.3)	3.0 (1.7 to 3.7)
Follow-up duration in person-years	78.3	342.8
Bleeding Related Outcomes (Primary)
Mean (SD) ABR in bleeds/year	5.4 (6.9)	2.6 (6.2)a
Median (min to max) ABR in bleeds/year	3.3 (0 to 34.6)	0.3 (0 to 35.0)a
Observed spontaneous bleed count (proportion of total bleeds)	176 (42%)	179 (41%)
Observed joint bleed count (proportion of total bleeds)	240 (57%)	195 (45%)
Secondary Outcomes (Factor VIII Activity Thresholds)
Chromogenic assay	Year 1 (n=111), n (%)	Year 2 (n=99), n (%)	Year 3 (n=97), n (%)
>150 IU/dL	6 (5%)	2 (2%)	2 (2%)
40 to ≤150 IU/dL	37 (33%)	14 (14%)	9 (9%)
15 to <40 IU/dL	37 (33%)	27 (28%)	23 (24%)
5 to <15 IU/dL	18 (16%)	33 (34%)	35 (36%)
3 to <5 IU/dL	3 (3%)	10 (10%)	8 (8%)
<3 IU/dL	10 (9%)	12 (12%)	19 (20%)
One-stage clotting assay, n (%)
>150 IU/dL	12 (11%)	5 (5%)	4 (4%)
40 to ≤150 IU/dL	44 (40%)	25 (25%)	17 (18%)
15 to <40 IU/dL	37 (33%)	36 (36%)	36 (37%)
5 to <15 IU/dL	10 (9%)	20 (20%)	26 (27%)
1 to <5 IU/dL	6 (5%)	11 (11%)	12 (12%)
<1 IU/dL	2 (2%)	2 (2%)	2 (2%)

ABR: annualized bleeding rate; IU: international units; Min: Minimum; Max: Maximum; SD: standard deviation.

a A total of 13 participants (12%) had used FVIII replacement products or emicizumab during the efficacy evaluation period for prophylaxis, with a

 

median start time at 2.3 (range: 0.1 to 3.3) years. An ABR of 35 was imputed for the periods when these patients were on prophylaxis.

 

The purpose of the study limitations tables (Tables 19 and 20) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of evidence supporting the position statement. The limited representation of African American, Asian, and Hispanic individuals makes it challenging to reach conclusions about the efficacy of Valoctocogene roxaparvovec-rvox (Roctavian)in these racial groups. The FDA reviewer noted a trend of lower FVIII activity levels in Black participants within the study population. Given the small sample size, the limited number of sites enrolling Black participants relative to the total population, the existence of potential confounding factors, and multiple post hoc analyses, this trend was insufficient to allow meaningful conclusions about the differences in response rates based on race or other factors influencing FVIII expression following Valoctocogene roxaparvovec-rvox (Roctavian)infusion. Despite differences in FVIII activity levels, ABR, and annualized FVIII usage was similar across races. Because of the uncontrolled study design, limited sample size and relatively short follow- up, there is still considerable uncertainty about the long-term net benefits of Valoctocogene roxaparvovec-rvox (Roctavian)compared with factor prophylaxis. It is not yet clear that the initial increase in factor levels will be maintained for decades. In addition, there are uncertainties about the long-term impact of the therapy on liver function and the risk for hepatocellular carcinoma. The small sample size creates uncertainty around the estimates of adverse events. Some serious harms are likely rare occurrences and as such may not be observed in small trials. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect and safety.

Table 19. Study Relevance Limitations

 

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Study 301	4. Enrolled populations do not reflect relevant diversity				1. Not sufficient duration for benefit 2. Not sufficient duration for harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.

b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.

c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.

d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.

e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

 

 

Table 20. Study Design and Conduct Limitations

 

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Study 301	1. Participants not randomly allocated 2. Allocation not concealed 3. Allocation concealment unclear 4. Inadequate control for selection bias	1.  Participants or study staff not blinded 2.  Outcome assessors not blinded 3.  Outcome assessed by treating physician 4.  Outcomes not assessed centrally			1.  Power calculations not reported 2.  Power not calculated for primary outcome 3.  Power not based on clinically important difference

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for

 

selection bias; 5. Other.

b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.

c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.

d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.

e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference;

4. Other.

f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

 

Section Summary: Valoctocogene roxaparvovec-rvox

The evidence for use of Valoctocogene roxaparvovec-rvox (Roctavian)for congenital hemophilia A consists of a single study. In the pivotal, open-label, phase III single-arm study, 134 study participants received a single intravenous infusion of valoctocogene roxaparvovec-rvox. Of the 134 participants, 112 were included in the efficacy analysis. The mean ABR after treatment with Valoctocogene roxaparvovec-rvox (Roctavian)was 2.6 bleeds/year compared with a mean ABR of 5.4 during the lead-in period yielding a mean difference of -2.8 (95% CI, -4.3 to

-1.2) bleeds/year. This was within pre-specified non-inferiority margin of 3.5. The ABR represents an appropriate clinical benefit endpoint for individuals with hemophilia A, and the evidence of clinical benefit was demonstrated by reduction of bleeds during the post-treatment period. However, factor levels declined over time, and therefore benefits of Valoctocogene roxaparvovec-rvox (Roctavian)could be relatively short-lived. According to the label, a total of 5 participants (4%) did not respond and 17 (15%) lost response to treatment over a median time of 2.3 years (range: 1.0 to 3.3). In the directly enrolled population with a longer follow-up, a total of 1 participant (5%) did not respond and 6 (27%) lost response to treatment over a median time of 3.6 years (range: 1.2 to 4.3). Limitations include uncontrolled study design, limited sample size, and relatively short follow-up. There is considerable uncertainty about the long-term net benefits of valoctocogene roxaparvovec- rvox compared with FVIII prophylaxis. It is not yet clear that the initial increase in FVIII levels will be maintained for decades. In addition, there are uncertainties about the long-term impact of the therapy on liver function and the risk for hepatocellular carcinoma as limited sample size is prone to uncertainty around the estimates for adverse events. Some serious harms are likely rare occurrences and as such may not be observed in small trials. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect and safety.

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