Hemophilia B Gene Therapy AMT-061 Safe, Effective, Trial Data Show

AMT-061 (etranacogene dezaparvovec), uniQure‘s investigational gene therapy for hemophilia B, is safe and effective — even in patients with pre-existing antibodies against the treatment’s viral carrier, according to new trial data.

Data from the Phase 3 HOPE-B trial suggest that nearly all hemophilia B patients, regardless of pre-existing viral inhibitors, may benefit from AMT-061.

“Patients in the trial who may not have been eligible for other gene therapies because of pre-existing neutralizing antibodies have achieved similar results with [AMT-061] compared to those who did not have pre-existing NAbs [neutralizing antibodies],” Ricardo Dolmetsch, PhD, uniQure’s president of research and development, said in a press release.

“We believe this distinguishes [AMT-061] as the only hemophilia gene therapy shown in a clinical trial to have the potential to treat nearly all patients, regardless of NAb levels in the generally prevalent range,” Dolmetsch said.

Only one patient, who had exceptionally high levels of the antibodies, did not respond to the gene therapy, according to investigators.

The findings were shared by Michael Recht, MD, PhD, a trial investigator and a professor of pediatrics at the division of hematology and oncology at the Oregon Health & Science University School of Medicine, in an oral presentation at the 24th American Society of Gene and Cell Therapy Annual Meeting, held virtually May 11–14.

The presentation was titled “Clinical Outcomes in Patients with and Without Pre-existing Neutralizing Antibodies to the Vector: 6 Month Data from the Phase 3 HOPE-B Gene Therapy Trial of Etranacogene Dezaparvovec.”

Administered directly into the bloodstream, AMT-061 uses a modified and harmless version of the adeno-associated virus variant 5 (AAV5) to deliver FIX-Padua, a highly functional copy of the F9 gene, to patients’ cells. The F9 gene is mutated in hemophilia B patients, impairing the production of a clotting protein called factor IX and known as FIX.

AAVs are widely used in gene therapy to deliver a gene of interest to cells. Due to the body’s natural immune reaction against the carrier virus, this type of viral-based therapy can normally only be given once.

Thus, most gene therapy clinical trials exclude participants with pre-existing antibodies against the carrier virus, since such antibodies are indicative of previous exposure to that type of virus. The patients are excluded due to the carrier’s potential to trigger an immune response that prevents gene delivery and limits treatment effectiveness.

However, previous data from uniQure’s early clinical and preclinical studies suggested no association between generally prevalent levels of anti-AAV5 antibodies and the AAV5-based gene therapy’s safety and effectiveness.

As such, while pre-existing anti-AAV5 neutralizing antibodies were assessed in patients participating in uniQure’s Phase 3 HOPE-B study (NCT03569891), their presence was not used as an exclusion criterion. That provided investigators more data about the therapy’s efficacy.

HOPE-B is evaluating the five-year safety and effectiveness of a single dose of AMT-061 in 54 men, mean age 41.5, with moderate to severe hemophilia B. These patients required prophylaxis, or preventive treatment, prior to enrollment.

A total of 23 participants (42.6%) had pre-existing neutralizing antibodies against AAV5, with a median titer of 56.9, and a distribution representative of the general population. A titer is a measure of how much a sample can be diluted before antibodies can no longer be detected, with higher titers indicating that more dilutions are needed until no antibodies can be detected.

The trial met its main goal of significantly increasing FIX activity levels at six months post-dosing, with a 36% rise relative to the start of the trial. The results were sustained over 1.5 years.

Now, researchers compared AMT-061’s efficacy and safety between patients with and without antibodies against AAV5. One participant with a neutralizing antibody titer of 198 received a partial dose of AMT-061 and was therefore not included in the efficacy analysis.

The results showed that mean FIX activity levels at six months were similar in men with neutralizing antibodies (32.7% of normal) and in those without (41.3% of normal).

No clinically significant association of pre-existing anti-AAV5 antibodies with FIX activity was observed up to a titer of 678 — a range expected to include more than 95% of the general population, according to uniQure.

All but one participant discontinued routine preventive treatment and remained prophylaxis-free at six months post-dosing. The exception was a man with a remarkably high neutralizing antibody titer of 3,212, who did not respond to AMT-061.

Still, “there were insufficient data” to properly assess the relationship between higher antibody titer and FIX activity, the researchers wrote. Less than 1% of the general population are expected to have a pre-existing antibody titer of more than 3,000, uniQure stated.

In addition, there was no association between anti-AAV5 antibodies and the rates of adverse events. Some of the most common AMT-061-related adverse events — infusion-related reactions and common flu-like illness — were more frequent among men with neutralizing antibodies. Others, including high levels of liver enzymes and headaches, were more common among those without.

“This study demonstrates for the first time, successful treatment of patients with pre-existing NAbs at generally prevalent levels with an AAV5 construct, supporting broad eligibility for AAV5-based therapies,” the researchers wrote.

CSL Behring recently acquired AMT-061’s global commercialization and licensing rights from uniQure, which will remain responsible for completing the ongoing Phase 3 HOPE-B trial. HOPE-B is expected to conclude in March 2025.