Mixed results

Companies face both trial roadblocks and progress as they tackle DMD

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CAMBRIDGE, Mass. & LOS ANGELES—Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene, is progressive and irreversible, according to Ilan Ganot, co-founder, CEO and president of Solid Biosciences. Characterized by progressive muscle degeneration and weakness, the disease still lacks treatment options despite increased knowledge regarding its nature.
In February, Solid Biosciences, a life-sciences company focused solely on finding meaningful therapies for Duchenne muscular dystrophy, announced preliminary findings from IGNITE DMD, its Phase 1/2 dose-ascending clinical trial to evaluate the safety and efficacy of SGT-001 microdystrophin gene transfer for DMD treatment. The company reported that initial three-month biopsy data showed low levels of microdystrophin protein expression, and said that it was engaging with “the appropriate parties to dose escalate as planned and as soon as possible.”
As Ganot explained, “We believe that SGT-001 will be a meaningful treatment for patients with DMD and are confident we have the right approach in place to evaluate its potential at higher doses. We have already begun working to expedite the planned dose escalation strategy outlined in our clinical trial protocol. This strategy is further supported by our scalable manufacturing process, from which we have sufficient drug product available to dose escalate without delay. We have the financial resources to execute on our plan and look forward to communicating additional data later this year.”
SGT-001, an adeno-associated viral (AAV) vector-mediated gene transfer, is being investigated for its ability to address the underlying genetic cause of DMD. SGT-001 is a systemically administered candidate that delivers a synthetic dystrophin transgene, called microdystrophin, to the body. This microdystrophin encodes for a functional protein surrogate expressed in muscles and stabilizes essential associated proteins, including neuronal nitric oxide synthase (nNOS). SGT-001 has been granted Rare Pediatric Disease Designation, or RPDD, and Fast Track Designation in the United States and Orphan Drug Designations in both the United States and European Union.
Six patients were included in IGNITE DMD. Three were in the active treatment group, and three were in the delayed treatment control group. The safety profile of SGT-001 was unchanged, and all patients are being followed according to the study protocol.
The FDA stopped the IGNITE DMD study last year after a patient who received SGT-001 was hospitalized with low red blood cell and platelet counts and evidence of complement activation. The ban was removed in June 2018.
Solid Biosciences reported that preliminary analyses reflected three-month biopsy data from the first three patients dosed with 5E13 vg/kg of SGT-001, the lowest dose outlined in the study protocol. According to the company, “In one patient, microdystrophin was detected via western blot below the 5 percent level of quantification of the assay, and in approximately 10 percent of fibers via immunofluorescence. There were also signs of co-localization of neuronal nitric oxide synthase (nNOS) and beta-sarcoglycan associated with microdystrophin expression. In the second and third patients, microdystrophin was detected via immunofluorescence at very low levels, but it was undetectable via western blot.”
As Dr. Barry Byrne, professor of pediatrics and principal investigator for IGNITE DMD, explained, “The patients who have received SGT-001 as part of the IGNITE DMD clinical trial are all doing well, and we are encouraged to explore higher doses moving forward. It is extremely important to advance innovative research with the ultimate goal to bring therapies to patients with Duchenne muscular dystrophy.”
Meanwhile, Capricor Therapeutics, a clinical-stage biotechnology company focused on rare disorders, announced that it has resumed per-protocol dosing of patients already enrolled in its HOPE-2 clinical trial of CAP-1002, the company’s novel cell therapy candidate to treat DMD. About 20 young men and boys in advanced stages of DMD have been enrolled in the randomized, double-blind, placebo-controlled trial to date.
Capricor had put a voluntary hold on dosing in December after a patient in the HOPE-2 trial had a serious adverse event in the form of anaphylaxis. According to Capricor, the patient may have been allergic to something contained in the investigational product, including an excipient (inactive ingredient) in the formulation. To reduce the risk of future events, Capricor launched a pre-medication strategy to prevent and treat allergic reactions. The FDA and the Data and Safety Monitoring Board have granted permission to resume enrollment in the HOPE-2 study.
The trial in question is studying the safety and effectiveness of CAP-1002 in older Duchenne patients not currently eligible for gene therapy clinical trials. CAP-1002 consists of allogeneic cardiosphere-derived cells, or CDCs, a type of progenitor cell that exerts potent immuno-modulatory activity. It is being investigated for its potential to modify the immune system’s activity to encourage cellular regeneration.

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