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Solid Discloses Duchenne Problems in IPO & Raises Rival’s Hackles

Xconomy Boston — 

[Updated, 1/26/18, see below] Solid Biosciences was expected to ride gene therapy’s wave of recent momentum to an IPO this week. But new revelations have clouded the offering, as the company revealed just before going public that its most advanced drug candidate has been under FDA scrutiny since mid-November.

The gene therapy, SGT-001, is being developed to treat Duchenne muscular dystrophy, an inherited disease that affects boys, often robbing them of the ability to walk in their teens and killing them at a young age. Now that the FDA has approved its first-ever gene therapy, Duchenne is widely seen as one of the next targets for the field; SGT-001 is one of four either in human clinical testing or slated to start this year.

[Updated with pricing details] The news was delivered Thursday through a regulatory filing, hours before Solid raised roughly $125 million by selling 7.8 million shares at $16 apiece (It will make its Nasdaq debut on Friday morning). Solid revealed that testing of SGT-001 has been partially suspended since November. The FDA’s “partial clinical hold,” as it is known, has stopped Solid from administering a high dose of its gene therapy to patients in its early-stage clinical study. The company said it is allowed to continue testing a lower dose.

According to Solid, the FDA wants Solid to ensure that it has the “appropriate manufacturing processes in place to support the higher-dose group.” Solid said it “doesn’t expect overall timing for clinical development to be affected.”

A spokesperson declined to comment further, citing an SEC-mandated “quiet period” that limits what a company can say to the public near an IPO.

The disclosure is the second in the span of nine days to cast a shadow over Solid’s program. On Jan. 16, also through a regulatory filing, Solid revealed that James Wilson, a gene therapy pioneer at the University of Pennsylvania, had resigned as the chair of the company’s scientific advisory board on Jan. 11. Wilson cited “emerging concerns about the possible risks” involved with the procedure, according to the filing. The filing also disclosed possible safety concerns in animal testing—one monkey in a preclinical test on a high dose of SGT-001 was euthanized. Solid “believe[s] the event was attributed to procedural errors,” though it couldn’t rule out the possibility that the virus used to deliver the gene therapy was a contributing factor.

Taken together, the disclosures raise questions about the push to use gene therapy for Duchenne. Side effects stemming from immune reactions to the engineered virus that delivers the restorative gene would resurface a problem that has haunted the field in the past.

Wilson has played a key role in that history. He co-led the study at UPenn that led to the death of teenager Jesse Gelsinger in 1999, a development that chilled investment in gene therapy work for many years. Continuing his lab work, however, Wilson helped advance the gene therapy delivery tool known as an adeno-associated virus, or AAV, which has become a critical part of gene therapy’s renaissance. Wilson’s AAV work led to a company called RegenXBio (NASDAQ: RGNX), which has deals in place with a number of gene therapy developers.

Wilson did not return a request for comment, and a UPenn spokeswoman deferred questions back to Solid.

Others working on Duchenne gene therapy responded quickly to the Solid revelations.

One high-profile doctor involved in a study of a different Duchenne gene therapy says he hasn’t seen safety problems, either in animals during preclinical testing or in the one patient who has received the treatment. “We have followed FDA guidelines. We’ve done similar toxicology studies in similar animals and haven’t seen any toxic effects,” said Jerry Mendell, the director of the gene therapy center at Nationwide Children’s Hospital in Columbus, Ohio.

Mendell has treated Duchenne patients for more than four decades. One patient in a study—one of two that Sarepta Therapeutics (NASDAQ: SRPT) is backing at Nationwide—hasn’t had any side effects related to the gene therapy. “As far as I can see, we have a very safe product,” Mendell said. The study is expected to produce data in mid-2018.

“Whatever is going on with Solid that has required the chairman of their scientific advisory board to resign in protest and has required the FDA to place them on clinical hold is, to the best of our knowledge, something unique to whatever is going on at Solid,” said Sarepta CEO Doug Ingram. “It probably would benefit all of us, and the patient community, if Solid would provide more information about exactly what is going on with their program that is causing problems.”

A Pfizer spokesperson said that the company hasn’t identified preclinical data that would preclude it from bringing its Duchenne gene therapy into human testing.

Pat Furlong, the founding president and CEO of the nonprofit patient advocacy group Parent Project Muscular Dystrophy, which has helped fund the Nationwide trial and collaborated with Solid, added: “We have the utmost respect for Dr. Wilson and value his opinion, but we also believe in the work of Solid, as well as Pfizer and have confidence in the scientific progress leading up to these studies.”

These therapies are being closely watched because gene therapy offers the potential for a one-time, long lasting treatment. Two Duchenne treatments are on the market—eteplirsen (Exondys 51), from Sarepta, and deflazacort (Emflaza), now owned by PTC Therapeutics (NASDAQ: PTCT). Neither are cures. Sarepta’s drug is supposed to slow the progression of the disease in a subset of patients, roughly 13 percent with a specific genetic malfunction. Deflazacort is a muscle-boosting steroid already widely available in other countries, also meant to help slow Duchenne.

Companies and academic institutions have been increasingly investing in gene therapy, however, for a longer lasting solution that can reach a wider swath of patients. Methods being advanced by Solid, Sarepta, and Pfizer would supply genetic instructions for a patient’s body to produce an engineered form of the muscle-protecting protein dystrophin, which Duchenne patients lack.

Solid, Sarepta, and Pfizer are doing this by engineering a smaller version of the dystrophin gene that is easier to deliver into patients’ cells. The hope is this will slow or halt the disease’s progress. Mendell says the major question with this approach is whether the so-called microdystrophin “will compromise function.”

“We hope that it doesn’t, but we won’t know until we start seeing,” he said.

In Solid’s Jan. 16 regulatory filing, Jim Wilson’s concern that prompted his resignation is “high systemic dosing of AAV.”

AAV-related side effects have not been a problem with gene therapies such as Spark Therapeutics’s (NASDAQ: ONCE) voretigene neparvovec (Luxturna)—the first approved in the U.S.—that are delivered to a specific tissue—the eye, for Luxturna, for instance. For Duchenne, however, the gene therapy is infused into the bloodstream and travels in less controlled fashion to various parts of the body, like skeletal and cardiac muscle.

Mendell respects why Wilson might be “risk-averse” about Duchenne gene therapy, but he’s encouraged by what he’s seen so far given his own experience.

In addition to Duchenne gene therapy, Mendell was also the lead investigator in an early stage study of the experimental AVXS-101 from AveXis (NASDAQ: AVXS), for spinal muscular atrophy, another rare genetic disease that affects motor function. Patients in that study were given high doses of AAV. The most significant issue was a spike in liver enzymes in four patients that was suppressed with steroids and didn’t lead to any notable side effects, Mendell says. Meanwhile, children who typically die before the age of two didn’t, and two were walking who wouldn’t have been otherwise expected to.

Mendell said experienced scientists had warned that the doses in the trial would probably be unsafe. But if he and his team hadn’t tested high doses, “we wouldn’t have saved lives and wouldn’t have had patients walking.”

The study results were published in the New England Journal of Medicine in 2017.