FDA Puts 2nd Clinical Hold on IGNITE DMD Trial of Gene Therapy SGT-001 Due to Patient Reaction

Owing to a serious adverse event in a patient, the U.S. Food and Drug Administration (FDA) has put another clinical hold on a Phase 1/2 clinical trial of SGT-001, an investigational gene therapy for Duchenne muscular dystrophy (DMD).

Solid Biosciences, the company developing SGT-001, is working with the FDA to determine next steps for this trial, which was first put on hold in March 2018 after a serious reaction possibly related to treatment in the first child given this therapy, and due to manufacturing concerns. This hold was lifted about three months later.

The trial, called IGNITE DMD (NCT03368742), has been evaluating the safety and efficacy of SGT-001 in children and adolescents with this disease at University of Florida.

So far, six patients have been dosed, three at a dose of 5E13 vector genomes (vg)/kg and three at a higher dose (2E14 vg/kg), both given via intravenous infusion in a single administration.

The recent serious adverse event that led to the clinical hold was reported in an ambulatory 7-year-old boy, and considered related to treatment.

Ask questions and share your knowledge of Muscular Dystrophy News in our forums.

In the weeks after receiving the higher dose of SGT-001 in late October, his platelet count and red blood cell levels dropped, and he showed acute kidney injury and activation of the complement system — a set of over 20 blood proteins that form part of the body’s immune defenses. He also developed signs of cardiopulmonary decline, or problems with the heart and lungs.

The early decreases in platelets and red blood cells, as well as transient kidney problems and complement activation, had already been seen with the lower dose in a non-ambulatory male adolescent, which led to the first clinical hold. The FDA lifted this hold in June 2018, considering that Solid had addressed all questions and had changed the trial’s design to give glucocorticoids intravenously in the first weeks of treatment.

In a webcast, company officials said that the newly observed heart and lung problems, indicating progression, were a major reason to reach out to the FDA. Prior to receiving the regulatory decision in a phone call the next day, Solid had decided to pause dosing to thoroughly investigate these events, and informed the trial’s independent data monitoring board.

The boy is getting appropriate treatment and his condition is improving, the company said. He is being closely monitored, and is expected to be discharged from the hospital in the coming weeks.

All five other patients dosed in this trial, including the two also given the higher dose, are doing well and will continue to be examined, Solid added.

“We had, of course, hoped for a different clinical trial experience for this boy and are extremely grateful for his ongoing recovery,” the company said in a letter to the Duchenne community. “We are hopeful the child will soon leave the hospital – and that he will have experienced meaningful clinical benefit from this therapy.”

Solid intends to release efficacy data on treated patients by year’s end. At the same time, the company will provide an update on the status of the boy who experienced the serious adverse event.

“In the coming weeks, we anticipate that we will have a better understanding of the biological activity and potential benefit of SGT-001. We look forward to sharing this additional data and working with the FDA to resolve the clinical hold and determining next steps for the program,” Ilan Ganot, Solid’s CEO, president and co-founder, said in a press release.

“We remain committed to bringing meaningful new therapies to the Duchenne community and continue to believe in the differentiated construct of SGT-001 and the potential benefits it may offer to patients,” he added.

People with DMD make no or very little dystrophin due to mutations in the DMD gene, resulting in muscle degeneration. SGT-001 uses an adeno-associated viral vector, specifically AAV9, to deliver a gene coding for a small synthetic dystrophin (called a microdystrophin) to muscle cells. Microdystrophin has the key components of the normal protein.

Preliminary results from three patients given the lower dose showed microdystrophin production in muscles, but at low levels.

SGT-001 was designated an orphan drug by both the FDA and the European Commission in October 2016. The FDA has also granted rare pediatric disease designation to SGT-001 and placed the therapy on “fast track” to speed up its development.