Givinostat (Duvyzat) had favorable outcomes in both functional tests and histological findings in patients with Duchenne muscular dystrophy (DMD) but not in those with the less severe form of the disease, Becker muscular dystrophy (BMD), according to a systematic review of drug trials presented in November at the Child Neurology Society annual meeting.
The drug, which the US Food and Drug Administration approved in February, is used to treat patients 6 years and older.
Three clinical trials—two of which tested the efficacy of givinostat in DMD and the other in BMD—included 250 total participants in the review, which was led by Roba Al Shouli of Al Qassimi Women and Children Hospital in United Arab Emirates. In the pivotal phase 3 EPIDYS trial involving DMD, which led to the drug's approval, patients treated with givinostat showed significantly less decline on the primary endpoint, the standard timed four-stair climb test, compared with the placebo group after 18 months of treatment. The mean change from baseline to month 18 in time to climb four stairs was 1.25 seconds for patients receiving givinostat compared with 3.03 seconds for patients receiving placebo. The givinostat cohort also experienced less worsening on the secondary efficacy endpoint, the change from baseline to month 18 in physical function as assessed by the North Star Ambulatory Assessment, but that difference did not reach statistical significance.
“Without the dystrophin protein, the muscle cell membranes are vulnerable to injury, and over time, the inflammatory process within injured muscle tissue results in replacement by fat and fibrosis. As a consequence of this, boys with DMD experience relentlessly progressive muscle weakness. Since the 1970s, we have been treating boys with DMD with prednisone in an attempt to decrease this inflammation and slow the progression of muscle weakness," said Jessica Nance, MD, assistant professor of neurology and director of the pediatric neuromuscular clinical trials group at Johns Hopkins University in Baltimore, who was not involved in the study. “
Because prednisone has a lot of undesirable systemic side effects, research has focused on finding other drugs that decrease muscle degeneration and slow the progression of weakness in a more targeted way. Givinostat is a histone deacetylase inhibitor that appears to target the pathways that promote replacement of muscle with fat and fibrosis in Duchenne muscular dystrophy."
That theory is supported by additional findings from EPIDYS, which also included MR spectroscopy studies in a subset of patients and found reduced fat fraction of the vastus lateralis muscle in patients treated with givinostat. It also correlated with findings from another 2016 study included in the review, which primarily investigated givinostat's histological effect in DMD and found that it increased the fraction of muscle tissue by 29.1 percent and cross-sectional area by 77 percent while reducing the amount of necrosis by 43.5 percent and fatty replacement by 37.5 percent.
“This is striking data in support of the medicine helping to decrease muscle degeneration," Dr. Nance said. “Anything we can do to slow the progression of weakness is beneficial. In doing so, we may allow boys to walk longer, and it may give families more time to prepare emotionally and practically for the transition to a power wheelchair."
The systematic review noted that an additional 2023 trial of givinostat in BMD found no effect on mean total fibrosis, which did not change in either the treatment or placebo group. The two groups did not differ at month 12 (least squares mean difference 1.04 percent; p=0.8282). But this partly may be because of the relatively slow progression of BMD as well as its much more variable presentation.
“It's a milder form of the disease and a much broader phenotype," Dr. Nance said. “Because progression of weakness may be slower in Becker, you may not be able to demonstrate efficacy over the same period of time that you can with Duchenne. Given the combination of the functional and imaging results showing the drug's efficacy, and the fact that the overall underlying pathophysiologic process is the same in BMD as in DMD, I think it's reasonable to assume we can extrapolate efficacy. The difficulty is often related to medication side effects; for drugs with a more problematic side effect profile—like the significant weight gain, osteopenia, and behavioral issues associated with long-term prednisone treatment —those side effects might outweigh any potential benefit."
But givinostat has a much more limited side effect profile, with the most commonly reported adverse events being gastrointestinal in nature, typically loose stools and diarrhea. “That is something more inconvenient than dangerous, and it can usually be ameliorated by dose adjustments," Dr. Nance said. High levels of triglycerides and the potential for low platelet counts are the other side effects of most concern with givinostat and require close monitoring. “Overall, this might be a good drug for Becker, but we need to think about how we can better demonstrate its efficacy," she added.
However, givinostat's average annual cost of $700,000 is a major shift from the extremely inexpensive prednisone. “Getting this medication approved by insurance is labor intensive, requiring prior authorization and often multiple appeals, but it's worth it if we can help these boys stay even a little bit stronger for longer," Dr. Nance said. “Though we are not yet able to provide a cure for Duchenne muscular dystrophy, it's been satisfying to be on this frontier. Because of these new therapies, my conversations with patients and their parents are much more hopeful than they were five or 10 years ago."
Child Neurology Society Abstract 295: Al Shouli R, Sohal A. The efficacy of givinostat in patients with muscular dystrophy: A systematic review.
https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersCNSAnnualMeeting/pages/post.aspx?PostID=66
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