Promising Interim Results Reported for uniQure’s Gene Therapy AMT-061 in Phase 2b Hemophilia B Trial

A single injection of uniQure‘s gene therapy AMT-061 (etranacogene dezaparvovec) is well-tolerated, effectively increases the levels of clotting factor IX (FIX), and completely prevents bleedings without the need for additional FIX injections in people with hemophilia B, even in the presence of neutralizing antibodies against the treatment, Phase 2b clinical trial data show.

The study, “Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B,” was published recently in Blood Advances.

Hemophilia B is caused by a lack of functional FIX, a clotting factor. The current standard of care involves administering FIX via injections. However, gene therapy may render that approach obsolete by allowing the body to make its own working FIX.

AMT-061 is one such gene therapy. It uses a viral vector (adeno-associated virus 5, or AAV5) to deliver a healthy version of a gene that provides instructions for creating FIX in people with hemophilia B. Specifically, it delivers a variant of the gene called the Padua variant, which occurs naturally in some human populations.

The protein created by this variant is up to 10 times more active than the most common variant. The idea is that, by delivering a more active version of FIX, not as much of the protein needs to be made in order to have the same therapeutic effect.

The investigational gene therapy has received the designation of breakthrough therapy from the U.S. Food and Drug Administration, and priority medicines (PRIME) designation from the European Medicines Agency.

The ongoing Phase 2b trial (NCT03489291) is testing if a single infusion of AMT-061 is safe and effective in three adults with hemophilia B. Its primary goal is to determine FIX activity six weeks after an intravenous injection of AMT-061, at a dose of 2×10¹³ genome copies (gc)/kg.

Secondary measures include patients’ annual bleeding rate (number of spontaneous bleeding episodes per year), use of FIX replacement therapy over a period of 52 weeks, and the incidence and severity of adverse side effects over five years.

Results showed that a single infusion of the experimental gene therapy was able to increase the activity of FIX up to 31% (ranging from 23.9% to 37.8%) after six weeks of dosing. After six months, the average FIX activity increased to 47% (33.2%–57%).

While patients had a median of three bleeding episodes per year before entering the trial, requiring FIX treatment, none of the three participants have had bleeding events or required additional injections of FIX up to 26 weeks into the trial, researchers reported.

Importantly, these were seen even though all three participants had low levels of antibodies against AAV5. In theory, these antibodies could have neutralized the viral vector, preventing it from delivering its payload. But in these cases, and at the therapeutic dose used, this doesn’t appear to have caused a problem.

There were two treatment-related adverse events reported: a mild headache on the day of injection, and a slight elevation in levels of the inflammatory C-reactive protein above the normal range two weeks after injection, both of which occurred in the same participant.

No serious adverse side effects were reported and there were no clinically significant changes in levels of liver enzymes or inflammatory markers, and none of the participants required corticosteroid treatment. All of that is suggestive of a good safety profile, although the small sample size makes it inadvisable to draw sweeping conclusions based on this data alone.

The participants will continue to be monitored for up to five years following the injection.

“In individuals with severe and moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically-relevant increases in FIX activity, cessation of bleeds and abrogated the need for FIX replacement, despite the presence of pre-existing anti-AAV5 neutralizing antibodies detected by the highly sensitive luciferase assay,” Steven Pipe, MD, a professor at the University of Michigan and co-author of the study, said in a press release.

“While these observations are limited to three participants, the consistency of results among participants supports the ongoing pivotal Phase III HOPE B trial which will further assess the safety and efficacy of etranacogene dezaparvovec, Pipe said. If these results are confirmed by the Phase III trial, physicians will be provided with increased confidence that reliable clinical outcomes can be achieved following gene transfer.”

The Phase 3 HOPE-B trial (NCT03569891) is similarly assessing AMT-061 in people with hemophilia B, but with a larger sample size (56 people). It has already completed recruitment and is currently underway.

Robert Gut, MD, PhD, the chief medical officer of uniQure and also a study co-author, said: “This publication supports the potential of etranacogene dezaparvovec to substantially improve the quality of life for hemophilia B patients through a one-time administration that results in sustained Factor IX activity and may result in a cessation of bleeding episodes. We are pleased to have these interim safety and efficacy data of etranacogene dezaparvovec [AMT-061] published in a peer-reviewed journal and look forward to sharing top-line data from the pivotal Phase III HOPE-B study in 2020.”