Improved Joint Health in the Phase 3 HOPE-B Trial of Etranacogene Dezaparvovec Gene Therapy for Hemophilia B over 36 Months of Follow up

Background: Chronic arthropathy characterized by pain, reduced mobility and decreased Health Related Quality of Life, is the most common debilitating outcome of severe hemophilia. By providing sustained Factor IX (FIX) levels in the normal or mild hemophilia B (HB) range, etranacogene dezaparvovec gene therapy has the potential to abrogate or markedly reduce the severity of HB phenotype. The present analysis explores the impact of sustained FIX Padua expression on the joint health of participants of the HOPE-B trial during the initial 36 months following etranacogene dezaparvovec administration.

Methods: HOPE-B is a phase 3 open-label, single-dose, multicenter study in males aged ≥18 years with severe or moderately severe HB (FIX activity ≤2% of normal). After a ≥6-month lead-in period with continuous FIX concentrate prophylaxis, participants received a single IV dose of etranacogene dezaparvovec (2×10¹³ gc/kg bw). Following an initial 18-month safety and efficacy evaluation period, participants entered an ongoing, long-term follow-up period of up to 5 years. The present study analyzes data from the 36-month follow-up. Primary and secondary endpoints were the annualized rates (ABRs) for all bleeds, (treated) joint bleeds, FIX activity, the presence and development/resolution of target joints (TJ) and arthralgia, and the Hemophilia Joint Health Scores (HJHS).

Results: The analysis included 54 male participants with a median age (range) of 41.5 (19–75) years. At screening, medical history of pre-existing hemarthropathy and/or orthopedic surgery related to hemophilia B was reported in 43/54 participants (79.6%). Most participants (81.5%) had bleeding episodes in the year prior to screening, and 55.6% had bleeding into joints during that period. All participants were on continuous FIX prophylaxis prior to screening. Following etranacogene dezaparvovec dosing, durable FIX expression was demonstrated by the mean (± SD) FIX activity (one-stage) of 38.6 ± 17.8 % at month 36. The ABR for all bleeds 7−36 months post-gene therapy (1.52, 95% CI: 0.81, 2.85) was significantly lower (p<0.001) than during the lead-in phase (4.17; 95% CI: 3.20, 5.44). Similarly, the incidence of joint bleeds was significantly lower (p<0.0001) than during the lead-in phase (ABR 0.47, 95% CI: 0.24, 0.95, vs 2.34, 95% CI: 1.74, 3.16), a reduction of 80%, and the ABR for joint bleeding episodes requiring exogenous FIX (0.41, 95% CI: 0.19, 0.88) was 81% reduced compared to that during the lead-in phase (2.13, 95% CI: 1.58, 2.87); p<0.0001. There was a significant relationship between steady state FIX level and joint bleeding rate during the 7 to 36 months post-treatment period (p=0.0006). Although ten participants reported 22 active TJs at screening (≥3 spontaneous bleeds in a consecutive 6-month period), only two participants had TJ bleeding during the lead-in, with one TJ each at time of dosing; these two participants had zero joint bleeding after gene therapy. Of the 52 participants who expressed transgenic FIX and discontinued prophylaxis, 51 were free of TJ bleeding between month 7 and 36 months; one participant with mean FIX expression of 12.1% and screening history of bilateral ankle TJ developed recurrent bleeding in the right ankle during year 3 after gene therapy. The proportion of participants with zero joint bleeding was 44.4% in the year prior to screening and increased to 75.9%, 81.5% and 88.5% in years 1, 2, and 3 post gene therapy.

Adverse events of arthralgia or associated terms were experienced by 24 participants (44.4%) during the 36-month period post-gene therapy, most commonly in the first 6 months (median [range] onset day 171 [1−1129]). The majority were judged unrelated to etranacogene dezaparvovec by investigators. Total HJHS significantly improved over 36 months post-gene therapy (18.2) compared to the lead-in period (21.7), with a least square mean difference of -3.5 (p=0.0014).

Conclusions: A single infusion of etranacogene dezaparvovec resulted in a discontinuation of continuous FIX concentrate prophylaxis, a reduction of (treated) joint ABR, which was significantly related to the steady state FIX level, and improved HJHS, with a positive effect on TJ resolution and prevention. The etranacogene dezaparvovec trial population, despite highly prevalent baseline hemophilic joint damage, demonstrated stable or improved joint health over 36 months of sustained endogenous FIX Padua expression.