DMD Trial to Test Imlifidase as Pre-treatment for SRP-9001

The proposed combo targets certain Duchenne MD patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Sarepta Therapeutics plans to begin a clinical trial to test the antibody-cleaving therapy imlifidase as a pre-treatment for SRP-9001 (delandistrogene moxeparvovec) — its experimental gene therapy for Duchenne muscular dystrophy (DMD) — in patients with pre-existing antibodies against the gene therapy’s viral carrier.

Preclinical work conducted by Sarepta and its partner Hans Biopharma, imlifidase’s developer, showed that the antibody-cleaving therapy may improve the effectiveness of SRP- 9001 in this specific subset of DMD patients.

“We are very excited about the results we have seen in the preclinical phase of our collaboration with Sarepta,” Søren Tulstrup, president and CEO of Hansa, said in a press release.

“These results strengthen our hope that the unique features of imlifidase may potentially enable gene therapy treatment in patients who today are not eligible for these breakthrough therapies due to pre-existing antibodies,” Tulstrup added.

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DMD is caused by mutations in the gene that provides instructions for making dystrophin, a protein that helps protect muscles from wear-and-tear over time.

SRP-9001, being co-developed by Sarepta and Roche, is designed to deliver to muscle cells a gene that provides instructions for making a shortened, but working, version of this protein called micro-dystrophin. It does so by using a modified and harmless version of the adeno-associated virus (AAV), called rAAVrh74, to deliver the gene.

By promoting the production of a working dystrophin protein, the therapy is expected to improve motor function in DMD patients.

Last month, Sarepta submitted an application to the U.S. Food and Drug Administration seeking SRP-9001’s approval for the treatment for DMD patients who are able to walk. The application is supported by clinical trial data suggesting that the therapy can improve walking ability and motor function in these patients.

Of note, DMD patients with higher-than-normal levels of pre-existing antibodies against rAAVrh74 were not eligible for SRP-9001 trials

While AAV doesn’t typically cause illness in people, it’s common in the environment and many people have been exposed to it. And, as with any virus, this exposure triggers the immune system to go on the defensive against the potential threat.

Immune cells produce antibodies that can bind and neutralize the virus, and these antibodies may stick around in the body long after the initial virus exposure.

Pre-existing antibodies

This means that some DMD patients have pre-existing antibodies that can bind to SRP-9001’s viral carrier, rAAVrh74. These antibodies could stop the therapy from delivering its genetic payload to cells, reducing its efficacy.

Imlifidase is an enzyme that works to cleave or cut antibodies, rendering them ineffective within hours of administration, according to Hansa. The enzyme was isolated originally from Streptococcus pyogenes, the bacteria that cause strep throat.

“Pre-existing antibodies against AAV [carriers] used in a broad range of gene therapies can be a barrier to treatment and we see significant potential for our antibody-cleaving enzyme technology to help overcome this barrier,” Tulstrup said.

If the upcoming trial shows that imlifidase can safely and effectively boost SRP-9001’s efficacy, this may mean that nearly all DMD patients who can walk may be eligible for the therapy.

In 2020, Hansa granted an exclusive, worldwide license to Sarepta to develop and promote imlifidase as a pre-treatment for its potential gene therapies for DMD and limb-girdle muscular dystrophy.