Gene Therapy AMT-061 Shows Clinical Benefit in Hemophilia B Patients in Recent Trial


New data demonstrates clinical benefit in hemophilia B patients with pre-existing anti-AAV5 neutralizing antibodies.

New data presented by the gene therapy company uniQure at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting held in Chicago, Illinois, has shown that the company’s gene therapy product candidate, AMT-061, is clinically beneficial in hemophilia B patients with pre-existing anti-AAV5 neutralizing antibodies (NABs).

In fact, in a study looking at pre-treatment sera samples of 10 patients enrolled in a phase 1/2 clinical trial of AMT-060, investigators did not detect a relationship between the presence of pre-treatment anti-AAV5 NABs and clinical outcomes of AMT-060 in hemophilia B patients.

uniQure’s AMT-061 is comprised of an AAV5 viral vector carrying a gene cassette with the Padua variant of Factor IX (FIX-Padua), according to the company website. The hope for AMT-061 is to develop a gene therapy for hemophilia B that is not only safe and effective but one that can be broadly applied to patients.

The data presented at ASGCT, which showed successful liver transduction with the AAV5 vector in non-human primates as well as patients with pre-existing anti-AAV5 NABs, has proved favorable, according to uniQuire’s chief scientific officer Sander van Deventer, MD, PhD.

“The study suggests that, in contrast to experience with other AAV vectors, detectable pre-existing neutralizing antibodies do not prevent successful gene transfer using AAV5 at clinical doses,” Dr. van Deventer said in a recent statement. “In patients pre-exposed to AAV5 who tested positive for anti-AAV5 antibodies, therapeutic transgene expression was established with no cellular immune response observed after systemic administration of AAV5.”

Where patients with anti-AAV NABs have typically been excluded in most ongoing gene therapy clinical trials using AAV vectors, over concerns that the anti-AAV NABs may have a negative impact on vector delivery, in this study, investigators decided to find out if those concerns held water.

For the phase 1/2 clinical trial of AMT-060, investigators used a highly-sensitive, luciferase-based anti-AAV5 NAB assay to re-assess the pre-treatment sera of 10 patients. They found that 7 of the 10 patients “returned results below the limit of detection of the assay,” whereas 3 of the 10 patients had “positive anti-AAV5 NAB titers, of whom 2 were confirmed positive by additional assays,” according to a recent press release. However, it is important to note that a relationship was not found between the presence of anti-AAV5 NABs pre-treatment and the clinical outcomes of the trial.

“In particular, the patient with the highest anti-AAV5 NAB titer (340) presented the highest mean FIX activity in his dose cohort,” the press release reads. Neither of the 2 patients that had confirmed positive anti-AAV5 NABs showed to have elevated liver enzymes. Furthermore, none of the patients were found to have any clinically relevant T-cell immune responses to the capsid.

Data was also presented at ASGCT pertaining to another analysis of pre-treatment sera of 14 non-human primates administered AMT-060, for which investigators used the same NAB assay. Previous to receiving the gene therapy (AAV5-FIX), the animals were found to have a wide range of anti-AAV5 NAB titers, spanning from 56 to 1,030. Despite this, administration of AAV5-FIX in the primates proved to be successful overall, with comparable transduction found in all of the primates at each dose.

The investigators concluded that anti-AAV5 titers as high as 340 did not negatively impact the clinical outcomes of AAV5-FIX in the trial. They note that other studies support these phase 1/2 findings in that anti-AAV5 titers as high as 1,030 have not been found to impair the efficacy of AAV5-FIX in non-human primates.

Taking these findings into account, the investigators went on to screen for anti-AAV5 NAB in 100 additional healthy male donors. They deemed that about 97% of the donors to be eligible for AAV5-based therapy by using an anti-AAV5 NAB cut-off titer of 1,030. The investigators also looked at anti-AAV2 NAB and anti-AAV8 NAB titers in the donors and found that 37% of the group would be excluded from AAV8-based studies, while 49% of the donors would be excluded from AAV2-based studies; they based their analysis on patient exclusion criteria currently being used in ongoing trials of gene therapy.

“uniQure’s mission is to deliver on the promise of gene therapy to patients, and these findings suggest that AAV5-based gene therapies may be applicable to all, or nearly all, patients with hemophilia, Huntington’s disease, and other life-altering disorders,” uniQure’s chief executive officer Matthew Kapusta, commented in a recent statement.

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