James M. Wilson, M.D., Ph.D.
James M. Wilson, M.D., Ph.D.

[This report has been updated from an earlier version that misidentified the scientific founder and CSO of AveXis].

James M. Wilson, M.D., Ph.D., has joined the Gene Therapy Consortium of the Rett Syndrome Research Trust (RSRT), the Trust said today.

The announcement came 10 days after the separate disclosure that he resigned from the Scientific Advisory Board of Solid Biosciences, which is set to begin an initial public offering (IPO) today.

RSRT said it will fund the research of Dr. Wilson, director of the University of Pennsylvania Gene Therapy Program and the Rose H. Weiss Orphan Disease Center. His lab will receive an award of $1.6 million over two years for research specific to Rett Syndrome.

RSRT has invested a total $4.7 million in the Gene Therapy Consortium, which was launched in 2014. The Consortium brought together the efforts of two labs focusing on gene therapy—Brian Kaspar, Ph.D. (then at Nationwide Children’s Hospital, now at gene therapy developer AveXis) and Steven Gray, Ph.D. (then at University of North Carolina Chapel Hill, now at University of Texas Southwestern)—as well as well two labs studying therapies targeting the MECP2 gene, those of Gail Mandel, Ph.D. (Oregon Health and Sciences University) and Stuart Cobb, Ph.D. (then at University of Glasgow, now at University of Edinburgh).

RSRT’s Consortium was the outgrowth of the Trust funding a collaboration between Drs. Mandel and Gray. In June 2017, AveXis said it will advance into clinical trials the Consortium-developed gene therapy candidate for Rett Syndrome targeting MECP2.

Beyond traditional gene therapy, RSRT said, it is also pursuing RNA approaches and biological approaches to reactivate the silent MECP2 gene on the inactive X chromosome. The reagents for these approaches will require delivery into cells via vectors, drawing upon research made by the Consiortium’s investigators, according to the Trust.

“Recent advances by RSRT Consortia researchers are providing insights for novel genetic therapeutics that will very likely benefit from enhanced delivery and regulation. I believe this exciting collaboration will leverage our collective expertise and increase our ability to develop novel and improved gene therapies,” Dr. Wilson said in a statement.

RSRT is funding Rett syndrome research through its three-year, $33 million Roadmap to a Cure strategic research plan, launched last year.

“The enthusiastic support of Rett families in the U.S. and around the world has made it possible for RSRT to recruit scientists, like Dr. Wilson, who are tops in their field to aggressively pursue curative approaches,” added Monica Coenraads, RSRT’s executive director. “As a mother of an adult daughter who suffers daily from the effects of Rett I know that time is of the essence.”

Dosing Concerns Cited in Resignation

RSRT’s announcement comes 10 days after Solid Biosciences first disclosed in an amended IPO filing that Dr. Wilson resigned from the company’s Scientific Advisory Board, “citing emerging concerns about the possible risks of high systemic dosing of AAV [adeno-associated virus].”

Dr. Wilson’s lab has pioneered vector technology for nearly three decades, including the discovery and development of novel serotypes of AAV, and has contributed to the development of a variety of nonviral and viral platforms. He led the research team in the 1999 clinical trial in which a patient who suffered from a liver enzyme deficiency, 18-year-old Jesse Gelsinger, died four days after treatment with gene therapy. Gelsinger received the highest dose in the trial, 38 trillion virus particles.

In November, Solid launched IGNITE DMD, a randomized, controlled, open-label, single-ascending dose Phase I/II clinical study of its lead gene therapy candidate SGT-001. The study is planned to enroll approximately 16 to 32 patients with Duchenne muscular dystrophy (DMD), who are to be randomly assigned to either an active treatment group or a delayed treatment group. The trial (NCT03368742) envisions three dosing levels.

“The relatively high dosing requirements for SGT-001 may amplify the risk of adverse side effects relating to the AAV vector,” Solid acknowledged in amendments to its registration filing submitted January 16, and again Wednesday and yesterday.

The potential for adverse side effects for AAV gene therapies as viral vectors are neutralized by immune response has led some researchers to investigate synthetic viral vectors. For example, Charles Venditti, M.D., Ph.D., senior investigator with the NIH’s National Human Genome Research Institute, has published results of a study assessing a synthetic AAV capsid, Anc80L65, developed by scientists at the Massachusetts Eye and Ear Infirmary, made from an ancestor of present-day AAV serotypes.

“If in the future we are unable to demonstrate that any such adverse events were not caused by the administration process or related procedures, the FDA, the European Commission, the EMA, or other regulatory authorities could order us to cease further development of, or deny approval of, SGT-001 or our other product candidate for any or all targeted indications,” Solid stated in its amended IPO filing. “Even if we are able to demonstrate that any serious adverse events are not product related, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the clinical trial.”

Partial Clinical Hold Affects Higher-Dose Patients

However, in a separate additional filing yesterday, Solid acknowledged that dosing concerns were behind the FDA’s placing a Phase I/II clinical trial of SGT-001 on partial clinical hold in November. Solid said it will have to resolve that hold before it can treat its higher-dose patients with SGT-001; lower-dose patients can be treated as planned.

“In order to do so we will need to decrease the number of vials and utilize no more than a single production lot per patient and demonstrate that we have the appropriate manufacturing processes in place to support the higher-dose group,” Solid stated. “We expect that we will be able to address the specific deficiencies identified by the FDA by submitting additional information demonstrating manufacturing capacity and product attributes that will support the high-dose group. The Company intends to submit a response to the FDA addressing the specific deficiencies in the near future.”

Manufacturing capacity for virus lags behind growing demand as gene therapies advance through clinical trials and into the market—a challenge that has vexed gene therapy developers, which have responded by stepping up their own manufacturing or by partnering with contract research and manufacturing organizations.

In its IPO, Solid said it plans to sell 7,812,500 shares of common stock at $16 per share—the low end of its projected range of $16 to $18—on the Nasdaq Global Select Market under the symbol “SLDB.” The IPO will generate total gross proceeds of approximately $125 million.

The company has estimated net proceeds of approximately $89.3 million, or approximately $103.3 million if the underwriters exercise in full their option to purchase up to 1,171,875 additional shares of Solid common stock. Actual net proceeds will be lower since the projections were based on a price of $17.

Based on its earlier estimates, Solid has said it will spend approximately $130 million to fund R&D, including advancing SGT-001 through preliminary Phase I/II results, and the rest for general and administrative expenses and other general corporate purposes.

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