Gene Therapy for Hemophilia B: Results From the Phase1/2 101HEMB 1/2 Studies

• Participants with hemophilia B in the 101HEMB01/101HEMB02 studies failed to achieve plasma Factor IX levels of 20 IU/dL with DTX101

• No treatment-related serious adverse events occurred during either study, and all related treatment-emergent adverse events resolved

Hemophilia B (HemB) is a rare, X-linked bleeding disorder predominantly affecting males caused by Factor IX (FIX) gene variants leading to spontaneous bleeding and impaired ability to clot following injury or surgeries. Standard-of-care is prophylaxis to increase FIX levels. DTX101 is a non‑replicating, AAV serotype rh10 gene transfer vector containing a codon-optimized wild-type human FIX coding sequence. The Phase 1/2 open-label, single-arm, multicenter, dose-finding 101HEMB01 study (NCT02618915) examined the safety/efficacy of DTX101 in adult males with HemB; the 101HEMB02 follow-up study (NCT02971969) assessed long-term outcomes. Participants received DTX101 as 1.6x1012 genome copies/kg (Cohort 1; N=3) or 5.0x1012 genome copies/kg (Cohort 2; N=3) at baseline and were monitored through Week 44 (Cohort 2)/52 (Cohort 1) (101HEMB01), then 4 additional years (101HEMB02). The primary endpoint of 101HEMB01, peak plasma FIX level at Week 6, showed median (range) levels of 7.0 (5.0,8.0) and 10.0 (6.0,16.0) IU/dL in Cohorts 1 and 2, respectively. Levels failed to reach the 20 IU/dL target criteria; all participants required adjunct FIX replacement therapy based on low FIX activity at intermediate time points. In 101HEMB01, 4/6 participants experienced treatment-related adverse events of elevated transaminase levels (3) and fatigue (1), and 1 experienced fatigue in 101HEMB02; none experienced related serious adverse events. Elevated transaminase levels were asymptomatic and resolved with steroids in all subjects. The DTX101 program was halted for insufficient treatment response; however, from its completion, lessons can be learned regarding the design and execution of gene therapy clinical trials including additional optimization of transgene sequence and immunosuppression protocols.