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

IGNITE DMD had been on a partial clinical hold since November pending submission to the FDA of “additional CMC [chemistry, manufacturing, and control] information that demonstrates that manufacturing capacity and product attributes can support the high-dose group,” Solid disclosed in a January 25 update to its preliminary prospectus for its S-1 initial public offering (IPO) filing.

Last month, IGNITE DMD dosed its first patient—described by Solid as a male “non-ambulatory adolescent who received 5E13 vg [viral genomes]/kg of SGT-001 on February 14.”

Several days later, he 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.”

“The patient showed no signs or symptoms of coagulopathy (bleeding disorder) and no relevant changes from baseline in liver function tests. The patient responded well to medical treatment and is currently asymptomatic,” Solid said yesterday in a statement. “All laboratory parameters have either improved or returned to normal, and he is continuing outpatient assessments per protocol.”

Dosing Concerns

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.

Solid said it reported the unforeseen incident to the FDA, which classified it as a Suspected Unexpected Serious Adverse Reaction (SUSAR)—and upgraded the clinical hold from partial to full.

The company has halted enrollment in IGNITE DMD and awaits a formal Clinical Hold letter from the FDA, which is expected to include what the company must do to resume the clinical trial: “Solid will work closely with the Agency to resolve the Clinical Hold.”

Stock Price Falls 60%

Investors responded to Solid’s announcement of the full clinical hold—made after the close of trading yesterday—with a selloff that sent the company’s share price down 60% from yesterday’s close of $26.31, to $10.50 in premarket trading as of 9:24 a.m. EDT.

Shares had peaked at $33.17 on March 2, more than double the IPO price of $16—lower than the earlier projected range of $18 to $19 because the company had not disclosed the partial clinical hold until a day before the company traded its first shares on the NASDAQ Global Select Market.

Among companies expected to benefit from Solid’s clinical setbacks is rival DMD gene therapy developer Sarepta Therapeutics, which on Monday announced it intended to complete a rolling New Drug Application (NDA) submission by year’s end for golodirsen (SRP-4053), a phosphordiamidate morpholino oligimer engineered to treat DMD patients with genetic mutations subject to skipping exon 53 of the DMD gene.

Sarepta won the FDA’s first-ever approval for a DMD treatment in September 2016, when the agency authorized Exondys 51®, indicated for DMD amenable to exon 51 skipping.

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)—envisioned three dosing levels, with the Investigational New Drug (IND) application for SGT-001 permitting Solid to proceed with administering the low dose.

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. The 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.

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