, et al
Gene therapy with etranacogene dezaparvovec for hemophilia B
N Engl J Med

Hemophilia B is an X-linked recessive hereditary bleeding disorder caused by alterations in the factor 9 gene, resulting in partial or complete deficiency of coagulation factor IX. Hemophilia B severity is classified by factor IX activity: severe <1%, moderate 1-5%, and mild >5%-40%. In the absence of prophylaxis, patients with severe hemophilia B can develop life-threatening bleeds and other disease-related complications – most prominently, arthropathy which impacts quality of life. Treatment of hemophilia has evolved rapidly in the past few decades, transitioning from plasma and plasma-derived clotting factor concentrate (CFC) to recombinant CFC, some of which are molecularly modified to extend their in vivo half-lives. Traditionally, patients were taught to self-administer CFCs for prevention and management of bleeding with a goal of reducing their annualized bleeding rates (ABRs), long-term complications, hospitalizations, and absences from school and work. Recently introduced non–factor-based therapies for hemophilia A and agents in clinical trials for both hemophilia A and B, including gene therapy, have heralded a paradigm shift in the delivery of care for patients with hemophilia B. Preliminary data suggest stable and durable expression of factor IX after infusion of a gene therapy product and a reduction in ABR. For the first time, the possibility of a cure for hemophilia is being discussed.

This open-label, multicenter phase III study enrolled 54 males (>18 years) with severe or moderate hemophilia B. Participants were on stable factor IX prophylaxis prior to enrollment for a lead-in period of six months, during which ABRs were documented. They then received a single infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies/kg) regardless of preexisting AAV5 neutralizing antibodies. Participants were followed for 18 months for efficacy and safety and for five years for extended follow-up.

The primary endpoint was ABR, evaluated in a noninferiority analysis comparing the rate during months seven through 18 after administration of etranacogene dezaparvovec to the rate during the lead-in period. Key secondary endpoints were chosen to assess the efficacy of etranacogene dezaparvovec compared to the standard of care, including endogenous factor IX activity at six, 12, and 18 months after treatment and 12 months after stable factor IX expression. These endpoints included: the number of infusions and annualized consumption of factor IX replacement therapy; the percentage of participants with trough factor IX activity lower than 12%; the superiority of etranacogene dezaparvovec (based on the ABR for all bleeding episodes); the ABR for episodes of spontaneous bleeding and joint bleeding; the percentage of participants who discontinued routine prophylaxis; and the correlation between pretreatment AAV5 neutralizing antibody titers and post-treatment ABR and factor IX activity.

Principal safety outcomes included adverse events that occurred or worsened during or after treatment, liver function abnormalities, vector shedding, and an immune response directed at the AAV5 vector or the transgene product (factor IX)

The authors reported a reduction in ABR from 4.19 (95% confidence interval [CI], 3.22-5.45) during the lead-in period to 1.51 (95% CI, 0.8-2.82) during months seven through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20-0.64; p < 0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec versus factor IX prophylaxis (Figure). They also reported an increase in factor IX activity from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4-41.0) at six months and 34.3 percentage points (95% CI, 29.5-39.1) at 18 months after treatment. This increase was first noted as early as three weeks in some patients and was sustained at 18 months. Nearly all participants (96%) discontinued factor IX prophylaxis during the period between week three and month 18. Lastly, the usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (p < 0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No difference was noted in the analysis of quality-of-life endpoints at 12 months.


Trial Schema, Primary Efficacy, and Safety Outcomes

Pipe SW, et al. N Engl J Med. 2023;388(8):706-718


Trial Schema, Primary Efficacy, and Safety Outcomes

Pipe SW, et al. N Engl J Med. 2023;388(8):706-718

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Immunogenicity leading to infusion reactions and hepatotoxicity were the most frequently noted therapy-related side effects. Steroids were used successfully to manage these complications.

The authors concluded that etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to ABR, and it had a favorable safety profile.

This study provides high-grade evidence on the use of gene therapy in hemophilia B care which has led to the Food and Drug Administration’s (FDA) approval of etranacogene dezaparvovec. We are at the dawn of a new era of advanced therapy in hemophilia care; this was the first FDA approval, and several others are already in the queue.

Current therapeutic options are safe and effective and have a long-term track record. As we look toward adoption of gene therapy in the real world, several issues need to be addressed. It is difficult to anticipate what proportion of patients with hemophilia may benefit from gene therapy, as multiple factors have been described that could limit its application. The trial had strict exclusion criteria, for example. Patients with inhibitors, thrombocytopenia, active infection with HIV, hepatitis B, hepatitis C, and liver disease were excluded; these are frequent comorbidities in persons with hemophilia. Authors observed only limited response rates in patients with high-titer AAV5 neutralizing antibodies. If this is a curative option, more data on long-term adverse effects would be vital to know.

Operationally, there would be a learning curve for patients and care team members while this therapy is adopted as standard of care. New clinical guidelines and protocols addressing initial administration and management of side effects — plus integration of the traditional therapies — would need to be created at societal and institutional levels.

The high cost of gene therapy needs to be balanced against the cost of ongoing factor replacement. Further economic studies are required to address this question. Other issues to be addressed include the willingness for health care insurance payers to pay for advanced therapeutics, such as gene/cellular therapy in the future in the case of a suboptimal outcome. Regulatory agencies, payers, and patients will play key roles in the evolution of adoption practices in years to come. Lastly, the existing issue of disparities in global health equity in hemophilia care will be further highlighted by the availability of gene therapy.

Dr. Shah indicated no relevant conflicts of interest. Dr. Pruthi has received consulting honoraria (for attending advisory boards) for CSL Behring, Genentech Inc., Bayer Healthcare AG, HEMA Biologics, and Instrumentation Laboratory Co.