FDA Lifts Clinical Hold on Solid’s DMD Clinical Trial

Rare Daily Staff

The U.S. Food and Drug Administration lifted a clinical hold on Solid Biosciences’ phase 1/2 study of an experimental gene therapy for the rare neuromuscular condition Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration and weakness that primarily affects boys with symptoms beginning as early as three years of age. It is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas of the body. The condition is universally fatal, and death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

Solid’s SGT-001 is a novel adeno-associated viral vector-mediated gene transfer therapy designed to address the underlying genetic cause of Duchenne. Duchenne is caused by mutations in the dystrophin gene that result in the absence or near absence of dystrophin protein. SGT-001 is a systemically administered candidate that delivers a synthetic dystrophin gene, called microdystrophin, to the body. This microdystrophin encodes for a functional protein surrogate that is expressed in muscles and stabilizes essential associated proteins, including neuronal nitric oxide synthase nNOS. Data from Solid’s preclinical program suggests that SGT-001 has the potential to slow or stop the progression of Duchenne, regardless of genetic mutation or disease stage.

In November 2019, the FDA place a clinical hold on the study after a seven-year-old boy dosed in the study experienced a serious adverse event deemed related to the study drug that was characterized by complement activation, thrombocytopenia, a decrease in red blood cell count, acute kidney injury, and cardio-pulmonary insufficiency. Neither cytokine- nor coagulopathy-related abnormalities were observed.

In July 2020, the FDA requested further manufacturing information, updated safety and efficacy data for all patients dosed, and direction on total viral load to be administered per patient. The FDA requested additional information regarding the comparability between SGT-001 made using Solid’s prior manufacturing process and its current, improved process.

Solid implemented and shared with the FDA manufacturing process changes that remove the majority of empty viral capsids, allowing target dosing to be achieved with fewer viral particles. This reduction in the total amount of virus delivered to each patient is intended to support safe dosing of SGT-001 for the duration of the IGNITE DMD trial.

The company said it is reducing the maximum weight of the next two patients dosed to 18 kg per patient, with safety outcomes from these two patients driving potential weight increase of patients dosed subsequently. This reduction, in conjunction with the delivery of fewer viral particles as a result of the company’s manufacturing process improvements, will reduce patients’ total viral load while continuing dosing at the 2E14 vg/kg dose.

Solid provided the FDA with updated safety and functional efficacy data (including 6-Minute Walk Test and North Star Ambulatory Assessment data) for all patients dosed to date in IGNITE DMD. There have been no additional drug-related adverse events up to 30 months post dosing. Additionally, to mitigate the risk of serious drug-related adverse events, Solid is amending the IGNITE DMD clinical protocol to include the prophylactic use of both anti-complement inhibitor eculizumab and C1 esterase inhibitor, and increasing the prednisone dose in the first month post dosing.

Based on the company’s response to these requests, Solid said the FDA acknowledged that the company satisfactorily addressed all clinical hold questions.

“We are pleased that our team was able to address the FDA’s clinical hold questions, allowing us to restart the trial,” said Carl Morris, chief scientific officer at Solid Biosciences. “We are working diligently to complete all activities necessary to resume dosing, which we expect to occur in the first quarter of 2021.”

Photo: Carl Morris, chief scientific officer at Solid Biosciences