Givinostat halted muscle shrinkage and fat infiltration in men with Becker muscular dystrophy (BMD) despite failing to ease muscle scarring, compared to a placebo, according to top-line, one-year results of an ongoing Phase 2 clinical trial.
“We are very encouraged by the significant difference in muscle fat infiltration between the two groups after 12 months, indicating a beneficial effect of Givinostat in delaying muscle deterioration,” Paolo Bettica, MD, PhD, chief medical officer of Italfarmaco, the therapy’s maker, said in a press release. “These, as well as other measures, support the further development of Givinostat in BMD and we will evaluate the best path forward in discussion with the regulatory bodies.”
The investigational medication seeks to promote muscle repair, while reducing inflammation, muscle fibrosis or scarring, and fat infiltration. It is designed to accomplish this by blocking the action of histone deacetylases (HDACs), which limit genes’ accessibility. Overactive HDACs are thought to contribute to muscle degeneration in BMD and other dystrophies, such as Duchenne muscular dystrophy.
Besides being evaluated as a therapy for BMD, givinostat is being tested as a treatment for DMD. Participants in that ongoing Phase 2/3 trial (NCT03373968) — some of whom were on givinostat alongside corticosteroids for over seven years — showed delayed loss of ambulation, or the ability to walk, and a slower decline in respiratory function. These results and the similarities between the two types of muscular dystrophy encouraged Italfarmaco to explore the therapy in both conditions.
The trial in BMD (NCT03238235) mainly sought to show changes in fibrosis compared to placebo in 51 men with Becker MD. Secondary goals included changes in fat infiltration, muscle atrophy, or shrinkage — measured as contractile cross-sectional area (CSA) — functional tests, and safety. The trial failed to achieve its main goal, but this could be attributed to differences between the givinostat and placebo groups at study start, Bettica said.
“We actually had a significant imbalance between the groups in histology [tissue analysis], so the randomization on histology did not work as well as we wanted,” Bettica said in a presentation at Parent Project Muscular Dystrophy 2021 Virtual Conference.
Despite the setback, the company “will continue to analyze the data to understand better the lack of meeting the primary endpoint” or goal, Bettica said.
Fat infiltration into muscle and contractile CSA in the study were both measured by MRI. This showed that while both features progressed among placebo-treated participants, no progression occurred among those taking givinostat.
“There was actually a deterioration in the placebo group,” Bettica said about contractile CSA, “which was not observed in the givinostat group, and this was highly significant in the whole thigh and was nearly significant for the quadriceps [in the thigh].”
“We believe that the results that we obtained in MRI will eventually translate also into a functional benefit,” he added.
Functional tests used in the study included the six-minute walk test, four-stair climb, 10-meter walking test, and time-to-rise, as well as several strength tests. Overall, the investigators observed no significant differences between the two patient groups in these tests.
However, standing and transfer in the Motor Function Measure, a 32-question scale related to mobility, showed differences that rose close to the statistical cutoff for significance. “In this case,” said Bettica, “we did see a decline throughout the time of this parameter, and if we look at the result at month 12, the decline in [the givinostat] group was actually slower than in the placebo group.”
No serious side effects occurred throughout the trial. The most frequent treatment-emergent side effects included diarrhea, decreased platelet count, and increased triglycerides, in keeping with past results. Finally, the dose given to participants was lowered to 50 mg twice daily, down from 70 mg twice daily, to reduce the incidence of adverse events. Italfarmaco now plans to discuss givinostat’s path forward with regulators in the U.S. and Europe, while continuing to evaluate trial data. “We have many more analyses to conduct,” Bettica said.
The U.S. Food and Drug Administration has granted givinostat rare pediatric disease designation, as well as orphan disease and fast track status. Collectively, these designations help to bring promising medicines to market more quickly.