Conference Coverage

Gene therapy effective in hemophilia B patients with neutralizing antibodies



The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.

Steven W. Pipe, MD, of the University of Michigan in Ann Arbor

Dr. Steven W. Pipe

All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.

These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.

Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.

Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.

AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).

The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.

All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.


Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.

At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.

All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.


Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.

There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.

Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.

Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.

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