DTX101 Gene Therapy Ends Development, Offers Key Lessons for Future Hemophilia B Treatment Strategies
Hemophilia B remains a persistent treatment challenge despite advances in gene therapy. Standard care relies on prophylaxis to maintain adequate FIX levels, but new therapeutic approaches continue to be explored. One such effort, the DTX101 gene therapy program, recently concluded with important insights despite its discontinuation for insufficient efficacy.
DTX101 is a nonreplicating adeno-associated viral serotype rh10 vector designed to deliver a codon-optimized wild-type human FIX sequence. The program included 2 trials: the 101HEMB01 phase 1/2 study and the 101HEMB02 long-term follow-up. Together, these studies evaluated safety, efficacy, and durability of response in adult males with hemophilia B.
In 101HEMB01, participants received a single infusion of DTX101 at either 1.6 × 10¹² genome copies/kg (cohort 1; n = 3) or 5.0 × 10¹² genome copies/kg (cohort 2; n = 3). Follow-up extended through week 52 in cohort 1 and week 44 in cohort 2, with an additional 4 years of monitoring in 101HEMB02. The primary endpoint was peak plasma FIX activity at week 6. Median levels reached 7.0 IU/dL (range, 5.0–8.0) in cohort 1 and 10.0 IU/dL (range, 6.0–16.0) in cohort 2. While these results demonstrated modest FIX expression, they fell short of the 20 IU/dL target. All participants required ongoing FIX replacement therapy due to persistently low activity at later time points.
Treatment-related safety events were observed but did not lead to discontinuation. In 101HEMB01, 4 of 6 patients experienced adverse events: elevated transaminase levels (n = 3) and fatigue (n = 1). Elevated liver enzymes were asymptomatic and managed successfully with steroids. During the long-term follow-up, one participant reported fatigue. Importantly, no treatment-related serious adverse events were recorded across either study.
While safety outcomes were reassuring, the program was ultimately discontinued due to lack of sustained efficacy. Investigators acknowledged that design and execution challenges influenced outcomes. This underscores the manageable nature of immune-related effects but highlights the complexity of balancing safety with durable gene expression.
For payers and managed care stakeholders, these findings illustrate both the promise and pitfalls of gene therapy in hemophilia. The inability of DTX101 to achieve or maintain clinically meaningful FIX activity limited its therapeutic and economic viability, as ongoing prophylaxis remained necessary. From a coverage standpoint, the results reinforce the importance of demanding robust, durable efficacy data before adopting gene therapy into reimbursement frameworks.
At the same time, the program offered critical lessons to inform future development. Investigators emphasized the need for further optimization of transgene design and immunosuppression protocols. These insights are particularly relevant as multiple next-generation gene therapy candidates advance through clinical pipelines. For coverage decision-making, such incremental learning helps refine expectations for long-term safety, durability, and overall cost-effectiveness.
Reference
Pipe S, Poma A, Rajasekhar A, et al. Gene therapy for hemophilia B: results from the phase 1/2 101HEMB01/02 studies. Blood Adv. 2025 Jun 24;9(12):2980-2987. doi:10.1182/bloodadvances.2024015184
