Gene Therapy Trial Data Suggests Efficacy in the Presence of Antibodies

The recent American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting featured updates from the phase III HOPE-B clinical trial of etranacogene dezaparvovec, an investigational gene therapy developed by uniQure for patients with severe and moderately severe hemophilia B. The data were summarized on May 12th via an oral presentation by Michael Recht, MD, PhD, MBA, professor of pediatrics, division of hematology and oncology at the Oregon Health & Science University School of Medicine.

Etranacogene dezaparvovec is developed to target the liver using adeno-associated virus serotype 5 (AAV5). AAV5 is a variant of the type of the adeno-associated virus (AAVs) vectors that are being evaluated in multiple gene therapy trials. Thus far AAVs have been demonstrated to be safe and well-tolerated modes of gene therapy delivery. In this case, the AAV carries the co-called “Padua variant” of factor IX (FIX), which generates significantly higher FIX activity then standard versions of the gene.

The data presented at the ASGCT meeting is notable as it suggests that etranacogene dezaparvovec performs well even in patients with pre-existing neutralizing antibodies (NAbs) – most gene therapy trials exclude patients with NAbs.

Participants in the phase III trial were initially enrolled into an observational lead-in period of at least six months during which bleeding events and FIX replacement therapy usage were monitored. All patients required prophylactic routine FIX replacement prior to entering the clinical trial, and patients were not excluded from the trial based on pre-existing NAbs to AAV5.

According to a new uniQure press release, 54 participants received the therapy and completed 26 weeks of follow-up, 31 of whom (57.4%) had no pre-existing NAbs to AAV5. Of the 23 participants (42.6%) with pre-existing NAbs, the median titer was 56.9, with “a distribution representative of the general population” – an antibody titer is a blood test that determines the presence and level of antibodies in an individual’s blood.

No clinically significant correlation of pre-existing NAbs with FIX activity was observed up to a titer of 678, a far-encompassing range expected to include more than 95% of the general population. Mean FIX activity at 26 weeks was 32.7% in participants with NAbs versus 41.3% in those without.

“The ASGCT presentation highlights these initial HOPE-B data that demonstrate the successful treatment with an AAV5 gene therapy of patients with pre-existing NAbs,” stated Ricardo Dolmetsch, PhD, president of Research and Development at uniQure. “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 etranacogene dezaparvovec compared to those who did not have pre-existing NAbs. We believe this distinguishes etranacogene dezaparvovec 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.”

Additional note: On May 5th uniQure and CSL Behring entered into a commercialization and license agreement providing CSL Behring exclusive global commercialization rights to etranacogene dezaparvovec.

Source: uniQure press release dated May 13, 2021

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