Gene therapy ‘viable’ long-term treatment for haemophilia A


By Natasha Doyle

22 Nov 2021

An Australian and international study has shown gene therapy can help reduce bleeding episodes in haemophilia A patients for up to four years, despite previous studies suggesting otherwise.

The phase 1–2 trial, funded by vector manufacturer Roche Group-member Spark Therapeutics, assessed adeno-associated viral (AAV) vector SPK-8011’s ability to support safe and durable hepatocyte expression of factor VIII in 18 male haemophilia A patients over a median observation period of 36 months.

It found single, intravenous doses up to 2 x 1012 vector genomes per kilogram led to a 91.5% reduction in annualised bleeding events from median 8.5 per year pre-treatment to 0.3 post treatment.

Sixteen patients sustained factor VIII expression throughout the study, with the 12 patients followed for more than two years showing “no apparent decrease in factor VIII activity over time” (mean: 12.9% of normal at 26 to 52 weeks while patients weren’t receiving glucocorticoids versus 12% of normal > 52 weeks after vector administration), University of Sydney haematologist Professor John Rasko and colleagues wrote in the New England Journal of Medicine.

The annualised bleeding rate of 0 events in 60 to 100% of those 16 patients with sustained expression was “similar to the results with emicizumab prophylaxis in severe haemophilia A”.

Only two patients lost all factor VIII expression during the trial due to an anti-AAV capsid cellular immune response that wasn’t sensitive to suppression.

While the authors noted no major safety concerns, they did report 33 treatment-related adverse events in eight patients, including vector-related alanine and liver aminotransferase elevation, pyrexia, myalgia, back pain and vomiting and glucocorticoid-related adrenal insufficiency, gastroesophageal reflux, osteoporosis, generalised oedema and muscle spasms, among other symptoms.

“These data provide support for our hypothesis that hepatocyte expression of factor VIII after AAV gene transfer is a viable approach for long-term stable phenotypic amelioration of haemophilia A,” the authors wrote.

The findings contrast with earlier gene transfer studies in haemophilia A, where factor VIII expression halved in almost all patients infused with vector AAV5-hFVIII-SQ from Year 1 to Year 2 and continued to decline over the four years’ follow-up, despite being associated with 10 x greater factor VIII activity one-year post treatment and 30 to 120 x higher dosage than SPK-8011.

“One proposed explanation is that factor VIII expression induces an unfolded protein response that, unmitigated, can produce apoptosis and loss of expression; this has been observed in factor VIII mammalian cell culture and with supratherapeutic, but not low, levels of factor VIII expression after liver-directed gene transfer with AAV vectors in mice,” the authors suggested.

However, an AAV serotype 5 vector administered at similar doses to AAV5-hFVIII-SQ supported sustained factor IX expression in haemophilia B patients for more than two years post administration, suggesting dose alone may “not [be] responsible for differences in the durability of of factor VIII expression across trials of gene therapy for haemophilia A”.

Capsid manufacturing method (baculovirus transduction of Spodoptera frugiperda for AAV5-hfVIII-SQ versus human embryonic kidney cell transfection for SPK-8011) likely didn’t affect durability, but expression level and heterogeneous cell sources may have, the authors wrote, noting that, although both vectors used promoters targeting hepatocyte expression, cell specificity was not confirmed.

While they suggested the gene-transfer approach is viable in haemophilia A, loss of activity in two patients meant “the safe achievement of sustained, stable, and predictable factor VIII levels in all participants, even in the presence of immune responses, remains an unrealised goal of gene therapy for [the disease],” the authors wrote.

“Potential solutions are under investigation and may include the use of less immunogenic AAV capsids, gain-of-function factor VIII transgenes, improved immune modulation regimens, or all of these.”

Meanwhile, safety and efficacy monitoring in this study’s patients is ongoing.

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