FDA Lifts Clinical Hold on IGNITE DMD Gene Therapy Trial

The U.S. Food and Drug Administration (FDA) has lifted its clinical hold on the Phase 1/2 trial testing SGT-001, Solid Biosciences’ investigational gene therapy for people with Duchenne muscular dystrophy (DMD), the company announced.

Updated safety and effectiveness data for all patients dosed to date, modifications to the trial’s protocol, and improvements in the therapy’s manufacturing process allowed the restart of the trial, which was put on hold for a second time after a 7-year-old boy experienced serious adverse events related to SGT-001.

“We are pleased that our team was able to address the FDA’s clinical hold questions, allowing us to restart the trial,” Carl Morris, PhD, Solid’s chief scientific officer, said in a press release.

“We are working diligently to complete all activities necessary to resume dosing, which we expect to occur in the first quarter of 2021,” he added.

SGT-001 uses a modified and harmless adeno-associated virus (AAV) to deliver a gene producing microdystrophin to muscle cells. Microdystrophin is a shorter but functional version of dystrophin, the muscle protein lacking in Duchenne patients due to mutations in the DMD gene.

Preclinical data showed that SGT-001 has the potential to slow or halt DMD progression, regardless of underlying mutation or disease stage, according to Solid. The therapy received rare pediatric disease status in the U.S. and orphan drug designations in both the U.S. and the European Union for the treatment of DMD.

The open-label, Phase 1/2 trial, called IGNITE DMD (NCT03368742), intends to evaluate the safety, tolerability, and effectiveness of SGT-001 in 16 boys, ages 4 to 17, with DMD. Participants, recruited at the University of Florida and the University of Massachusetts Medical School-Worcester, will include children who are able to walk and teenagers who are not.

The trial’s main goals include changes in the levels of microdystrophin protein, assessed through muscle biopsies, and safety measures.

To date, six patients have been given a one-time, into-the-vein injection of SGT-001 — three at a dose of 5e13 vector genomes (vg)/kg and three at a higher dose, 2e14 vg/kg.

An analysis of muscle biopsies collected three months after treatment from two boys given the higher dose showed an increase in the number of muscle fibers producing microdystrophin — by 10%–20% in one patient and by 50%–70% in the other.

Using a different technique, researchers found that microdystrophin levels were up to 17.5% of the normal amount of dystrophin in people without DMD. Also, the boys showed a drop in the levels of a muscle damage marker.

After the first clinical hold in March 2018 (lifted about three months later) due to a serious reaction in the first treated patient, the FDA placed IGNITE DMD on a second hold in November 2019, as the sixth boy dosed experienced similar serious side effects.

The patient, who received the higher SGT-001 dose, showed low platelet and red blood cell levels, kidney damage, and activation of the complement system. All these complications were fully resolved. Notably, the complement system is a set of more than 30 blood proteins that are part of the body’s natural immune defenses.

Solid responded to the November hold in April, noting safety changes to the trial’s protocol and providing data on improvements in SGT-001’s manufacturing process. However, the regulatory agency decided to maintain the clinical hold in May, requesting further data.

After receiving the required information from Solid in June, the FDA sustained the hold and asked for additional manufacturing information and updated safety and effectiveness data for all patients dosed. It also provided direction on total viral load to be administered per patient.

Based on the company’s response to these requests, the FDA considered all questions were satisfactorily addressed, allowing the trial’s restart.

As part of its commitment to improve the manufacturing process, Solid implemented changes that remove most of SGT-001’s empty AAVs, a common byproduct of gene therapy. Empty AAVs do not contain the gene of interest, making them unable to provide a therapeutic benefit, but still add to the viral load.

By lowering the number of empty AAVs, target dosing can be achieved with fewer viral particles, which in turn can support the treatment’s safety. The company also submitted data from a new microdystrophin quantification method showing comparability between SGT-001 manufactured by the two processes.

Solid is also reducing the limit for the maximum weight of the next two boys dosed to 18 kg (about 39.7 pounds) per patient, with safety outcomes from these participants driving a potential increase in weight limits of following participants.

This reduction, in conjunction with the delivery of fewer viral particles, addressed the FDA’s guidance on total viral load while allowing continued dosing at the 2e14 vg/kg dose, Solid said.

Also, to lower the risk of serious treatment-related adverse events, the company changed the trial’s protocol to include preventive use of two complement system inhibitors — Soliris (eculizumab) and a C1 esterase inhibitor (sold as Cinryze, Berinert, and Haegarda) — and a higher dose of prednisone in the first month after dosing.

Notably, no additional SGT-001-related side effects have been reported up to 30 months (two and a half years) following dosing, the company added.