Solid Biosciences restated its commitment to developing its lead candidate, the Duchenne muscular dystrophy (DMD) gene therapy SGT-001, despite the FDA’s full and partial clinical holds on a Phase I/II trial for the treatment.

The FDA last month imposed a full clinical hold on the IGNITE DMD trial 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 on March 14, and restated yesterday.

Solid has described the patient as a male “nonambulatory 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, though the company said it still awaits a formal letter to that effect from the FDA.

“We believe that SGT-001 has the potential to significantly benefit patients with DMD,” Solid’s founder and CEO Ilan Ganot said yesterday in a statement. “We look forward to working with the FDA to understand the requirements for resuming the clinical trial and will provide an update as soon as appropriate.”

In a regulatory filing also made public yesterday, Solid restated that the hospitalized patient “showed no signs or symptoms of coagulopathy (bleeding disorder), had no relevant changes from baseline in liver function tests, and responded well to medical treatment.”

However, in that same filing, Solid acknowledged that a lifting of the full clinical hold may not alone bring development of SGT-001 back on track.

“Assuming successful resolution of the full clinical hold and data from the clinical trial, we will determine next steps for SGT-001 clinical development, including additional clinical trials that may include other patient populations, as well as the need for larger confirmatory clinical trials,” Solid stated in its Form 10-K annual report for 2017, filed yesterday.

Addressing Partial Hold

The full clinical hold is in addition to a partial clinical hold imposed by the FDA in November 2017. The partial hold bars Solid from dosing patients in the higher-dose group of 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.

“We have submitted our response to the FDA and are awaiting their feedback,” Solid added, without disclosing details.

Solid earlier said that it needed to submit to the FDA “additional CMC [chemistry, manufacturing, and control] information” in order to show it had that manufacturing capacity and product attributes capable of supporting patients randomized to the higher dose of SGT-001.

Following imposition of the full clinical hold, the price of Solid shares plunged by nearly two-thirds, falling 65% from $26.31 on March 14 before the announcement, to $9.32 the following day. Shares have plummeted further since then, to a low of $7.19 a share on Wednesday, before inching up to $7.50 at yesterday’s close.

The 73% cratering of Solid shares has led to several lawsuits being filed in recent days by shareholders who alleged that the company violated federal securities law by failing to disclose material information between the time the company carried out its initial public offering (IPO) on January 25, and March 14 when the full clinical hold was disclosed. Solid told the Boston Business Journal on Wednesday it will not comment on the suits.

Shares of Solid peaked at $33.17 on March 2, more than double the IPO price of $16, which was 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. Solid raised $124.8 million in the IPO by selling 7.8 million shares, up from the company’s original proposal to sell 5.9 million shares.

Advisor Resigns, Citing Dosing

Tucked within an amended IPO filing was a disclosure by Solid that 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 the 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 Adeno-Associated Virus Vector Expressing Human SMN,” was published in Human Gene Therapy, a journal of GEN publisher Mary Ann Liebert Inc.

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 (IGNITE 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.

Previous articleUsing AI to Predict Biological Age
Next articleImmunotherapy Calls Up Natural Killer Cells in the Fight against Cancer