As we look forward to reporting more news to patients, family members, and caregivers dealing with MD in 2019, here are the Top 10 most-read articles of 2018, with a brief description of their relevance to the MD community.
An investigational treatment for facioscapulohumeral muscular dystrophy (FSHD) called ACE-083 was granted fast track designation by the U.S. Food and Drug Administration. ACE-083 is a locally-acting compound that inhibits proteins in the TGF-beta family, such as myostatin. This action is intended to increase muscle strength in FSHD patients, who have skeletal muscle weakness and loss. The designation aims to accelerate the development of promising therapies for conditions with serious unmet needs. It was based on the positive results of the first part of a Phase 2 clinical trial (NCT02927080; see No. 3 on this list).
No. 9 — “Family’s Quest for ‘Overlooked’ Duchenne Treatments Leads to Breast Cancer Medicine Tamoxifen”
In August, we published a story on the use of the breast cancer therapy — tamoxifen — to treat Duchenne MD (DMD). Tamoxifen is a selective estrogen receptor modulator hormonal therapy that, when used with Evista (raloxifene), improved cardiac, respiratory and skeletal muscle functions, and increased bone density in a mouse model of the disease. Our article focused on Gavin Ward, an 8-year-old boy who was one of the first DMD patients in the U.S. to receive tamoxifen. He started this treatment six weeks after diagnosis. His father, Bruce, said Gavin’s hand grip strength and exercise capacity markedly improved with the therapy, and he also grew 2 inches and gained 9 pounds. His pediatrician, Vikki A. Stefans, MD, said that, unlike steroids, the chances for significant side effects with tamoxifen in males are not high. Two studies are being conducted to evaluate tamoxifen in DMD, one of which is a Phase 3 trial (NCT03354039) that is still recruiting participants in Germany and Switzerland.
Givinostat is an investigational therapy intended to boost muscle regeneration in DMD patients. A multicenter, international Phase 3 trial (NCT02851797) on this treatment by Italfarmaco is enrolling boys older than 6 years. Givinostat’s ability to slow disease progression will be evaluated, measured by a change in the time taken to climb four stairs after 18 months of treatment. Other functional tests will be conducted, and muscle tissue will be analyzed by imaging. Givinostat is an inhibitor of enzymes called histone deacetylases (HDACs), which changes the 3D folding of DNA. Patients with DMD have higher-than-normal HDAC levels, which may prevent muscle regeneration and proper muscle contraction. An earlier Phase 2 trial (NCT01761292) showed that one-year treatment in boys ages 7-11 slowed their disease progression, among other benefits.
A gene editing strategy based on the CRISPR-Cas9 technology restored dystrophin production and contraction force in heart muscle cells of DMD patients. The new approach, called myoediting, targets the top 12 “hot spots” of mutations along the DMDgene so that a wide region of these hot spots is skipped from the final dystrophin protein. The team from the U.S. and Germany found that editing only 30-50% of heart muscle cells was sufficient to restore their cardiac function to near-normal levels.Exonics Therapeutics has licensed the new method, aiming to develop it for DMD and other neuromuscular disorders.
No. 6 — “UT Researcher, with Cure Duchenne Support, Launches Company to Treat DMD Using CRISPR/Cas9 Technology”
In April, we reported the launch of Exonics, which resulted from a collaboration between Eric Olson — a scientist with a long career in muscle biology and the director of UT Southwestern’s Hamon Center for Regenerative Science and Medicine in Dallas — and the nonprofit group CureDuchenne. The new company is using the SingleCut CRISPR-Cas9 technology aiming to correct up to 80 percent of the 3,000 mutations that cause DMD. “We are really encouraged about the data suggesting this can be a life-changing therapy for patients who need it,” Olson said. Olson’s work had been supported by Parent Project Muscular Dystrophy (PPMD), a nonprofit group. The scientists will assess the method’s safety, whether it generates an immune response, and also if the benefits are stable. “We believe it will be, particularly in the heart,” Olson said.
Four boys with DMD treated with a single dose of Sarepta Therapeutics‘ intravenous gene therapy in an ongoing Phase 1/2 trial (NCT03375164; see No. 4 and No. 1) showed improvements in all four functional parameters tested — such as time to rise and the four-stair climb test — as well as a pronounced increase in dystrophin production in their muscles. The potential treatment, called AAVrh74.MHCK7.micro-dystrophin, delivers a version of the DMD gene that is shorter but still able to restore dystrophin’s function. It specifically targets muscle tissue, in particular the heart muscle. The four boys also showed a marked decrease (more than 78%) of blood levels of creatine kinase, a marker of muscle inflammation. No serious adverse events were reported. The company plans to start a confirmation trial, which, if successful, may make the new therapy available for DMD patients.
Our No. 4 article of 2018 covered preliminary findings of the Phase 1/2 trial of Sarepta’s DMD gene therapy, developed by scientists at Nationwide Children’s Hospital (see No. 5 and No. 1). The study’s design included two groups — one with have infants and toddlers ages 3 months to 3 years, and the second with children 4 to 7 years old. Muscle biopsy at three months revealed that the first three boys treated (ages 4-7) had robust (76.2%) microdystrophin gene expression in muscle tissue. As found later in the trial (see No. 5), all three patients showed a significant decrease in blood levels of creatine kinase, suggesting effective muscle protection.
No. 3 — “Acceleron Therapy Increases Facioscapulohumeral Dystrophy Patients’ Muscle Mass, Trial Shows”
Besides its fast track designation described in No. 10 of this list, the Phase 2 results of Acceleron’s ACE-043 also received significant interest from our readers in 2018. The main goals of the dose-escalation study (NCT02927080) were to see if the FSHD treatment candidate was safe and if it increased the patients’ muscle mass. Preliminary results from 23 patients revealed that injecting ACE-083 once every three weeks into the lower leg’s tibialis anterior and the upper arm’s biceps brachii increased muscle mass by 12.6% and 13.2%, respectively. An associated decrease in muscle fat was also observed. No serious adverse effects were reported.
The start of Pfizer’s ascending dose Phase 1b trial (NCT03362502) of an investigational mini-dystrophin gene therapy was the second most-read article of 2018. PF-0693992 is a shortened version of the DMD gene, which uses a carrier — the adeno-associated virus serotype 9 capsid — known for its ability to specifically target the muscles. Twelve boys ages 5-12 years were included. The first patient received the intravenous therapy on March 22. The scientists will assess the therapy’s safety and tolerability, dystrophin’s expression and distribution, and muscle function and strength. Results are expected in the first half of 2019, when all patients will have completed one year of treatment.
No. 1 — “Young Boy Becomes First DMD Patient to Receive Investigational Systemic Microdystrophin Gene Therapy”
Our most-read article of 2018 reported the start of the Phase 1/2 trial (NCT03375164) testing Sarepta’s microdystrophin gene therapy for DMD patients (see No. 4 and No. 5). Besides muscle biopsies at baseline (the beginning of the trial) and three months of treatment, the study design included safety assessments up to three months after therapy delivery. PPMD partially funded the trial through a $2.2 million grant. Other funding and support was provided by Sarepta.