The FDA has lifted its clinical hold on Solid Biosciences’ Phase I/II trial for its lead candidate, the Duchenne muscular dystrophy (DMD) gene therapy SGT-001, the company said today.

Solid said it has begun activities to resume the clinical trial and plans to reinitiate enrollment “as quickly as possible,” after the FDA acknowledged in a letter that the company answered to its satisfaction all questions related to the clinical hold.

“We are pleased to have been able to provide the FDA with a comprehensive response resulting in the removal of the clinical hold so we can continue development of this important potential treatment,” Solid’s founder and CEO Ilan Ganot said in a statement. “We believe SGT-001 has the potential to offer significant benefit to patients with DMD, regardless of their age or stage of disease.”

The FDA last month imposed a full clinical hold on the IGNITE DMD trial in March after the first patient dosed with SGT-001 was hospitalized “due to laboratory findings that included a decrease in platelet count followed by a reduction in red blood cell count and evidence of complement activation,” Solid acknowledged at the time.

In today’s statement, Solid stated: “There were no signs of bleeding or clotting abnormalities and no laboratory evidence of liver dysfunction. The patient received standard medical care, a modified steroid regimen, and a limited course of eculizumab for the observed complement activation. He remained clinically stable and generally asymptomatic throughout the event, which fully resolved.”

The trial’s principal investigator, Barry Byrne, M.D., Ph.D., director, University of Florida Powell Gene Therapy Center and a professor at the University of Florida College of Medicine, declared in the statement: “After a thorough analysis of the clinical and laboratory data for the patient, I am confident the event was easily monitored and medically manageable. Our patient quickly returned to his normal activities and planned study assessments.”

That first patient has been described by Solid in its Form 10-K annual report for 2017, filed March 29, as a male “non-ambulatory adolescent who received 5E13 vg [viral genomes]/kg of SGT-001 on February 14.”

Following his hospitalization, Solid reported the incident to the agency, which classified it as a Suspected Unexpected Serious Adverse Reaction (SUSAR). Solid halted enrollment and dosing in IGNITE DMD, and the FDA placed the trial on full clinical hold.

The FDA had also imposed a partial clinical hold barring Solid from dosing patients in the higher of two dosage groups in IGNITE DMD “until we decrease the number of vials and utilize no more than a single production lot per patient, as well as demonstrate that we have the appropriate manufacturing processes in place to support the higher-dose group,” Solid stated in the Form 10-K.

Changes to Trial Protocol

Launched in November 2017, IGNITE DMD is a randomized, controlled, open-label, single-ascending dose Phase I/II study designed to enroll approximately 16 to 32 patients with DMD who are to be randomly assigned to either an active treatment group or a delayed treatment group. The trial—titled Microdystrophin Gene Transfer Study in Adolescents and Children With DMD (NCT03368742)—envisions three dosing levels, with the Investigational New Drug (IND) application for SGT-001 permitting Solid to proceed with administering the low dose.

However, in connection with the lifting of the clinical hold, Solid acknowledged changing the IGNITE DMD protocol to include the addition of IV glucocorticoids in the initial weeks after administration of SGT-001, as well as enhanced monitoring measures that include a panel for complement activation. The amended protocol also specifies that eculizumab will be available as a treatment option if complement activation is observed, according to Solid.

SGT-001 is designed to address the underlying genetic cause of DMD—mutations in the dystrophin gene that result in the absence or near-absence of dystrophin protein—by delivering a synthetic dystrophin gene, called microdystrophin, to the body. Microdystrophin encodes for a functional protein surrogate expressed in muscles and stabilizes essential associated proteins, including neuronal nitric oxide synthase. Solid has cited preclinical data showing that SGT-001 has potential to slow or stop the progression of DMD, regardless of genetic mutation or disease stage.

SGT-001 was developed based on research by Jeffrey Chamberlain, Ph.D., of the University of Washington, and Dongsheng Duan, Ph.D., of the University of Missouri. SGT-001 has been granted Rare Pediatric Disease Designation in the U.S., as well as orphan drug designations in the U.S. and European Union.

Concerns over the dosing of patients in IGNITE DMD led to gene therapy pioneer James M. Wilson, M.D., Ph.D., resigning from Solid’s Scientific Advisory Board. According to an amended IPO filing, Dr. Wilson’s resignation followed “emerging concerns about the possible risks of high systemic dosing of AAV [adeno-associated virus].”

Days after the resignation disclosure, on January 30, Dr. Wilson and colleagues raised concerns about high-dose gene therapy by publishing a study that detailed instances of severe, life-threatening toxicity in monkeys and piglets given high doses of gene therapy delivered using an adeno-associated virus serotype 9 (AAV9) vector capable of accessing spinal cord neurons.

The study, “Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an AAV Vector Expressing Human SMN,” was published in Human Gene Therapy, a journal of GEN publisher Mary Ann Liebert Inc.

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