Solid Biosciences CEO, president, and co-founder Ilan Ganot

The FDA has placed a second clinical hold in as many years on Solid Biosciences’ Phase I/II trial for its lead candidate, the Duchenne muscular dystrophy (DMD) gene therapy SGT-001, the company acknowledged today, sending the company’s shares plunging about 70%.

The latest clinical hold came after Solid told the FDA and the Data Safety Monitoring Board (DSMB) of the IGNITE DMD trial (NCT03368742) that one of three patients dosed at the high-dose cohort of 2E14 vg [viral genomes]/kg suffered a serious adverse event that was considered to be related to the study drug.

That patient, identified only as a man, experienced complement activation, thrombocytopenia, a decrease in red blood cell count, acute kidney injury, and cardio-pulmonary insufficiency, Solid said, adding that neither cytokine- nor coagulopathy-related abnormalities were observed.

The patient is now being “closely followed” by his care team, the company added.

“We are encouraged that this patient is recovering,” Solid CEO, president, and co-founder said in a statement. “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.”

To date, Solid said today, six patients have been dosed with SGT-001. All three patients in the first cohort of 5E13 vg/kg dose “continue to do well and are being followed per the study protocol,” according to the company, as are the other two of the three patients dosed at the higher dose of 2E14 vg/kg.

Solid said it will work with the FDA to resolve the latest clinical hold and determine next steps for IGNITE DMD. The company added that it continues to plan to report additional biomarker data from the study before year end.

“I would like to thank both the patient and his family for their participation in our study, as well as the team at the University of Florida for the excellent care they provide,” Ganot added. “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.”

71% stock plunge

Investors responded to the latest clinical hold with a stock selloff that sent Solid’s shares plummeting as much as 71% from yesterday’s closing price of $11.03, to $3.18 at the start of trading 9:33 a.m., before rebounding somewhat to $3.50 a share as of 10:42 a.m., a 68% one-day decline.

Launched in 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—envisioned three dosing levels.

Soon after the trial started in November 2017, the FDA imposed a partial clinical hold 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.

In February 2018, IGNITE DMD dosed its first patient—described by Solid as a male “non-ambulatory adolescent who received 5E13 vg/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 FDA responded by imposing a full clinical hold on IGNITE DMD in March 2018. The agency lifted the clinical hold three months later after Solid changed the trial’s 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 specified that eculizumab will be available as a treatment option if complement activation is observed, Solid said at the time.

Scientific advisor resigns

Concerns over the dosing of patients in the trial led to gene therapy pioneer James M. Wilson, MD, PhD, resigning from Solid’s Scientific Advisory Board. According to an amended IPO filing, 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, 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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