OC 52.1 - Assessing the safety profile of AMT-060 and etranacogene dezaparvovec gene therapies across clinical trials in people with severe/moderately severe hemophilia B

Background: AMT-060 and etranacogene dezaparvovec are adeno-associated virus vector-based gene therapies. AMT-060 encodes wild-type factor IX (FIX); etranacogene dezaparvovec encodes the highly active FIX-Padua variant. Etranacogene dezaparvovec is the first gene therapy to obtain FDA approval for hemophilia B.

Aims: Report safety across AMT-060 and etranacogene dezaparvovec trials.

Methods: Three ongoing trials in hemophilia B have data over 5 (Phase 1/2 AMT-060; N=10; NCT02396342), 3 (Phase 2b etranacogene dezaparvovec; N=3; NCT03489291), and 2 years (Phase 3 HOPE-B etranacogene dezaparvovec; N=54; NCT03569891). Investigator-reported adverse events (AEs) of alanine transaminase (ALT) elevations were defined per protocol as ≥2-fold baseline and/or >laboratory upper limit of normal (Phase 3; Phase 2b) or >1.5–2-fold baseline (Phase 1/2).

Results: Across studies, all participants experienced ≥1 AE; most mild (Table), with no FIX inhibitor development or T-cell responses.

In HOPE-B, 38 participants (70.4%) experienced 93 treatment-related AEs (TRAEs) and no treatment-related serious AEs (SAEs); a SAE of hepatocellular carcinoma was assessed as unrelated to treatment. There was one death, also assessed as unrelated to treatment. Eleven participants (20.4%) had ALT elevations; nine (16.7%) received corticosteroids (mean: 79.8 days; standard deviation: 26.6; range: 51–130), FIX activity was maintained. Seven participants experienced infusion-related reactions; three required temporary dose interruptions, four received supportive care (including antihistamines, corticosteroids, narcotics, epinephrine) and one discontinued treatment after partial dosing (~10%).

In Phase 2b, there were two TRAEs in one participant (headache; elevated C-reactive protein), that resolved without intervention, and one SAE unrelated to treatment (worsening of pre-existing avascular necrosis). Two participants experienced transaminase elevations that resolved without steroids and no impact on FIX activity.

In Phase 1/2, seven participants experienced 15 TRAEs; five experienced six SAEs (three treatment related). Three participants received corticosteroids for ALT elevations.

Conclusion(s): Across AMT-060 and etranacogene dezaparvovec studies, favorable safety profiles are observed. Most AEs were mild with few treatment-related SAEs.