Imlifidase enables gene therapy in Duchenne patients with AAV antibodies

Between 14% and 32% of patients with Duchenne muscular dystrophy (DMD) are unable to receive the gene therapy delandistrogene moxeparvovec-rokl, marketed by Sarepta Therapeutics and Roche as ELEVIDYS, because antibodies targeting the therapy’s AAVrh74 vector neutralise it before therapeutic effect can be achieved. According to Hansa Biopharma, treatment with imlifidase – a recombinant bacterial IgG-degrading enzyme – offers a potential solution. The enzyme works by cleaving immunoglobulin G (IgG) molecules into two non-functional fragments, thereby reducing the prevalence of AAV-targeting antibodies.

Data from three DMD patients demonstrate that a single dose of imlifidase led to a rapid reduction in total IgG antibodies, achieving at least a 95% decrease from baseline levels. Furthermore, anti-AAV antibodies were lowered to titres below 1:400, allowing administration of delandistrogene moxeparvovec-rokl.

Twelve weeks following gene therapy, all three patients exhibited AAV-mediated transduction and expression of micro-dystrophin, the therapeutic protein designed to functionally compensate for the lack of dystrophin caused by mutations in the DMD gene. However, expression levels were lower than those observed in previous trials involving delandistrogene moxeparvovec-rokl. Based on these findings, Hansa and Sarepta intend to determine appropriate next steps for the programme.

Commenting on the results, Renée Aguiar-Lucander, CEO of Hansa Biopharma, stated:“These are the first clinical data evaluating imlifidase’s potential to enable access to an approved gene therapy for patients with high levels of anti-AAV antibodies. We are encouraged that imlifidase was able to markedly reduce both IgG and anti-AAV antibodies, facilitating administration of gene therapy.”

Duchenne muscular dystrophy is a rare and fatal inherited disorder caused by mutations in the DMD gene, which encodes the protein dystrophin. The disease is progressive and irreversible, leading to muscle degeneration. Most patients require wheelchair support by the age of 12.