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uniQure says new data demonstrates favorable immunogenicity profile of AAV5.

uniQure presented data showing successful liver transduction with the AAV5 vector in both non-human primates and humans with pre-existing anti-AAV5 neutralizing antibodies. In a study re-analyzing pre-treatment sera samples of the ten patients in the Phase I/II clinical trial of AMT-060, no relationship was detected between the presence of pre-treatment anti-AAV5 NABs and clinical outcomes of AMT-060 in patients with hemophilia B. In ongoing gene therapy clinical trials using adeno-associated virus vectors, patients who present levels of anti-AAV NABs are excluded from treatment due to concern that the efficacy of AAV vector delivery may be negatively influenced by their presence. In this study, uniQure researchers explored the impact of anti-AAV5 NAB levels on the efficacy of gene therapy delivery by an AAV5-based vector. Using a highly-sensitive, luciferase-based anti-AAV5 NAB assay, uniQure researchers re-analyzed the pre-treatment sera of the ten patients who entered the Phase I/II gene therapy clinical trial of AMT-060. Seven of the ten patients returned results below the limit of detection of the assay, and three of the ten had positive anti-AAV5 NAB titers, of whom two were confirmed positive by additional assays. Yet no relationship was determined between the presence of pre-treatment anti-AAV5 NABs and clinical outcomes in the trial. In particular, the patient with the highest anti-AAV5 NAB titer presented the highest mean FIX activity in his dose cohort. Neither of the two patients with confirmed positive anti-AAV5 NABs experienced elevated liver enzymes. Additionally, no clinically relevant T-cell immune responses to the capsid were detected in any of the ten patients. uniQure also analyzed with the same NAB assay the pre-treatment sera of 14 non- human primates administered AMT-060. Prior to the administration of AMT-060, animals had anti-AAV5 NAB titers ranging from 56 to as high as 1,030. Despite the presence of these anti-AAV5 antibodies, researchers were able to administer AAV5-based gene therapy resulting in successful and comparable transduction in all of the non-human primates at each dose. In summary, anti-AAV5 NAB titers as high as 340 did not impair the clinical outcomes of AAV5-FIX therapy in the Phase I/II trial. These findings are further supported by the results of studies demonstrating that anti-AAV5 NAB titers as high as 1,030 did not impair the efficacy of AAV5-FIX liver transduction in non-human primates. Based on these data, uniQure researchers performed an anti-AAV5 NAB screening of an additional 100 healthy male donors. Using an anti-AAV5 NAB cut-off titer of 1,030, at least 97% of this group would be eligible for AAV5-based gene therapy. Anti-AAV2 NAB and anti-AAV8 NAB titers were also analyzed in the donor group, and based on patient exclusion criteria currently applied in ongoing gene therapy trials, 37% of this group would be excluded from AAV8-based studies and 49% would be excluded from AAV2-based studies.

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Publication:The Fly
Date:May 21, 2018
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