https://orcid.org/0000-0002-2258-3687
In this issue of Blood Advances, von Drygalski et al1 report the long-term, 5-year safety and efficacy data of the phase 2b trial of etranacogene dezaparvovec gene therapy for 3 patients with hemophilia B. This recombinant adeno-associated virus seroype 5 (AAV5) vector contains a codon-optimized human factor IX (FIX) Padua variant transgene and a liver-specific promoter. It is administered 1 time only as a peripheral vein infusion without the need for any preinfusion preparative treatment regimen. This vector is the first US Food and Drug Administration–approved gene therapy for hemophilia, and it has been prescribable since the end of 2022.
The treatment produced stable and durable FIX levels at near-normal ranges in all 3 trial participants. All participants discontinued regular infusions of factor concentrate for bleed prophylaxis; 2 participants had no bleeding for 5 years, and the third had no bleeding after the second year from vector infusion. All reported improved quality of life. These results reflect the much-decreased burden for the patients after having had this new form of treatment. In addition, over the 5-year period, no vector-related toxicity was observed during follow-up. These patients’ hopes for relief from the life-long burden of this disease and their courage in signing up for this research trial have been rewarded.
Although the reported results are based on data of only 3 participants, the subsequent phase 3 trial enrolled 54 patients, and their outcomes at 2 years after vector infusion align.2 In total, 52 participants stopped factor prophylaxis, and their FIX levels have remained stable mainly within the range of a mild hemophilia phenotype or above 40% for about a third of patients. The participants’ annual bleeding rate decreased from 4.19 to 1.51. Of the 2 participants who did not stop factor prophylaxis, 1 had received only a partial vector dose because of an allergic reaction during infusion. The other participant had a very high, preexisting anti-AAV5 neutralizing antibody (NAb) titer (3212) and no FIX expression.
Although outcomes after only 2 or 5 years are described, the future durability and safety could be similar to the preliminary results of the longest AAV8–mediated gene therapy trial for severe hemophilia B, which showed stable and durable FIX levels in 10 patients and no long-term vector-related toxicity over >10 years.3 It is critical that the participants of this study are followed on an extension study as noted and that all patients, worldwide, eventually are followed in long-term registry studies, such as the Gene Therapy Outcomes Arm of the American Thrombosis & Hemostasis Network Transcends study (ClinicalTrials.gov identifier: NCT04398628) in the United States or the global World Federation of Hemophilia Gene Therapy Registry (ClinicalTrials.gov identifier: NCT04883710).
Preexisting immunity to AAV has been identified as a drawback, making patients ineligible for AAV gene therapy if recognized during screening assays. Unrecognized adaptive immunity may be a setup for vector-induced immune transaminitis. This event requires immunosuppressive treatment for weeks with frequent monitoring to preserve factor expression, thereby posing a significant burden on the patient and creating uncertainty about the outcome.4 However, AAV5 immunity in the global population has been reported at relatively low rates when compared with other AAV subtypes.5,6
The case noted above is the only one reported with lack of FIX expression after etranacogene dezaparvovec therapy and is assumed to be due to immune-mediated interruption of sufficient transduction and factor expression. In contrast, low positive anti-AAV5 NAb titers in all 3 participants in this trial did not lead to vector-induced transaminitis. Similarly, low positive NAb titers of <678 in 20 participants in the phase 3 trial allowed similar long-term FIX levels as in those with negative-pretreatment NAb titers.2
It is worth noting that if corticosteroid therapy is needed for immunosuppression, it can be a significant burden to the patient. Although it is a transient therapy, it may be needed for several months, which can lead to interruptions in the patient’s daily life and include medical adverse effects that require clinical management.7 Nine phase 3 trial participants were treated with corticosteroids for 7 to 18 weeks for elevated liver enzyme levels, and this group achieved similar long-term FIX levels as participants with negative NAb titers.2 Together, 16% (9/57) of patients across both trial cohorts who were treated with etranacogene dezaparvovec had to take a course of steroids for about 2 to 4 months starting early after treatment. This is a low proportion when compared with experiences with other vectors for hemophilia B or hemophilia A. However, any reduction in the immunogenicity of future vector products would be of benefit to patients.
Altogether, the relatively low seroprevalence of AAV5 globally, limited AAV5 vector immunogenicity, and excellent treatment outcomes for patients with negative and low positive anti-AAV5 NAb titers could make a large proportion of the global hemophilia population eligible for etranacogene dezaparvovec. The global burden of hemophilia is carried mainly by patients in lower-resource countries, that is about 80% of the patient population worldwide.8 These underprivileged patients have limited access to factor concentrate and, therefore, would benefit the most from gene therapy. However, the high price of etranacogene dezaparvovec listed in high-income countries is unaffordable for them. Innovative approaches to manufacturing, regulatory requirements, budgeting using a societal perspective, and payment structures need to be developed to overcome the challenges to equitable access.9-11
Conflict-of-interest disclosure: The author declares no competing financial interests.
