Elevation of liver health biomarkers before and after etranacogene dezaparvovec gene therapy in hemophilia B: Associations with long-term clinical outcomes

Abstract Introduction Gene therapy with etranacogene dezaparvovec has emerged as a transformative treatment for individuals with hemophilia B, offering sustained endogenous factor IX (FIX) expression and reduced bleeding rates. Due to etranacogene dezaparvovec being a liver-targeting adeno-associated virus-mediated gene therapy, pre-existing hepatic conditions or post-treatment liver-related events may influence therapeutic outcomes and are areas of clinical interest. This analysis presents 4-year follow-up data from participants treated with etranacogene dezaparvovec, stratified by liver-related clinical characteristics, particularly alanine aminotransferase (ALT) elevation, to explore the relationship between hepatic status and long-term efficacy, safety, and durability of FIX expression. Methods HOPE-B (NCT03569891) was a single-arm phase 3 study involving adult males with hemophilia B (FIX activity ≤2%). Liver-related exclusion criteria included serum liver chemistries >2 x upper limit of normal (ULN); active hepatitis B (HBV) or C (HCV) infection or HIV replication; and advanced liver fibrosis. Fifty-four participants received a single dose of 2 x 1013 genome copies/kg etranacogene dezaparvovec after a ≥6-month lead-in period on FIX concentrate prophylaxis. Participants were grouped by (1) pre-dose ALT/aspartate aminotransferase (AST) >1 to <2x ULN (pre-ALT+/-), (2) post-dose ALT elevations requiring corticosteroids (CS) (ALT/CS+/-), and (3) ALT elevations within 18 weeks post-dose regardless of CS use (post-ALT+/-), and for these, FIX activity and adjusted annualized bleeding rate (ABR) were studied. Additionally, late confirmed ALT elevations (ALT >ULN in 2 consecutive samples during months [M]7–48) and treatment-related ALT elevations (ALT >ULN) are reported. Results Eight participants (14.8%) had an ALT/AST >1 to ≤2x ULN prior to dosing. Mean±standard deviation (SD) FIX activity at Y4 in pre-ALT+ and pre-ALT- was 32.6±21.7% and 38.4±15.6%, respectively. Both groups showed ABR reductions: pre-ALT+ from 2.6 (95% CI 1.2–5.4) during lead-in to 1.32 (0.4–4.8) over the first year following stable expression (M7–18), maintained at 0.4 (0.1–1.5) during Y4; pre-ALT-: lead-in: 4.5 (3.4–5.9), M7–18: 1.5 (0.8–2.9), Y4: 0.4 (0.2–0.7). Nine participants (16.7%) experienced ALT elevations consistent with vector-associated liver inflammation beginning weeks 3–7 post-infusion, prompting oral CS therapy. Mean FIX activity, stably expressed over 48 months follow-up (M6: 18.7±11.1%; Y4: 19.4±12.6%) was lower in ALT/CS+ participants compared to the ALT/CS- (M6: 43.3±17.2%; Y4: 40.6±15.4%). Despite this, both groups had substantial ABR reductions: from 4.3 (3.2–5.8) during lead-in to 1.8 (0.9–3.8) in M7–18 and 0.33 (0.2–0.6) during Y4 in the ALT/CS- group; from 3.8 (2.3–6.0) during lead-in to 0.82 (0.3–2.4) in M7–18 and 0.56 (0.2–1.3) during Y4 in the ALT/CS+ group. Including two additional participants with ALT elevations (week 11 and 18) for whom no post-ALT CS were initiated did not alter this pattern. Confirmed ALT increase beyond M6 after treatment was observed in six (11.1%) participants at 1 to ≤2.5 x ULN; all but one had ALT 1 to ≤2 x ULN during lead-in, including two from the ALT/CS group. Although the one participant without baseline ALT elevation had a history of HIV, HBV, and HCV, the late ALT elevation was assessed by the investigator as alcohol related. Late increases in ALT did not affect FIX activity in these participants. Treatment-related transaminitis following M6 occurred in only one participant (ALT 1.2 ULN) at a single timepoint in Y4, which resolved without sequelae. Conclusion Following a single dose of etranacogene dezaparvovec, participants with pre-dose elevated ALT/AST or post-dose (CS-treated) ALT elevation maintained FIX expression (albeit lower in the ALT/CS group) and had similar bleed reduction up to 4 years post-dose, compared to those without ALT elevations. Long-term liver deterioration following liver-targeted gene therapy was not observed over four years, not even in those identified as potentially at risk due to subacute liver inflammation following vector delivery.These findings demonstrate that in cases of mild ALT/AST elevation prior to treatment, and/or with appropriate surveillance and management of ALT increase post-treatment, etranacogene dezaparvovec achieves hemostatic protection similar to that observed in individuals without ALT elevation, with comparable long-term safety.