FA treatments that target mitochondria may best help patients
Clearer goals and longer durations needed in trials of slow progressing disease
Therapies that aid mitochondria, cellular organelles responsible for producing most of the energy needed by cells, may help with physical function and heart health in people with Friedreich’s ataxia (FA), according to a review of published studies.
Findings appear to support the benefits of Skyclarys (omaveloxolone), the only approved FA therapy in the U.S., and possibly experimental treatments also working to boost mitochondrial function. But clearer trial goals are needed, and studies should run for longer than the current norm, its researches wrote.
The study, “Therapeutic Biomarkers in Friedreich’s Ataxia: a Systematic Review and Meta-analysis,” was recently published in The Cerebellum.
Lack of frataxin in Friedreich’s ataxia patients affects mitochondria
Friedreich’s ataxia is caused by mutations that disrupt the production of the protein frataxin, which is vital for mitochondria — the so-called powerhouses of a cell — to work as intended.
Various ways of treating FA have been explored over the years. Some experimental treatments, along with Skyclarys, have aimed to boost mitochondrial function, while others looked to increase frataxin levels or to address particular disease symptoms.
When developing a potential treatment for a rare and multisystem disease like FA, a major consideration is figuring out exactly what a clinical trial should measure to determine whether and how well a treatment is working. As FA usually progresses slowly and varies from person to person, it can be hard to define trial endpoints, or goals, that provide meaningful results in a feasible length of time, the study noted.
Scientists in Greece conducted a review of the scientific literature to assess what’s currently known about FA treatment approaches and trial endpoints. Their review included data on 1,409 patients followed across 43 studies, including 19 randomized and controlled and 25 open-label (no placebo group) clinical trials.
“An ideal valuable biomarker should be able to detect both subtle changes in the natural course of a slowly progressive disorder such as Friedreich ataxia and concurrently be responsive to any treatment effect,” they wrote.
Researchers also conducted meta-analyses, pooling data from multiple studies to analyze them collectively, which can allow for a more precise estimate of a given therapy’s effects.
A total of 21 drugs or drug combinations were tested in the reviewed studies. Nine aimed to improve mitochondrial function, four were designed to increase frataxin levels, and eight were meant to ease specific symptoms.
Treatment outcomes in FA should be measured in trials running for 2 years
Results indicated that treatments targeting mitochondria had statistically significant effects on patients’ motor function, as measured by the Friedreich Ataxia Rating Scale (FARS) or the modified FARS (mFARS).
This finding was mainly driven by the results of clinical trials into Skyclarys, a mitochondria-boosting first FA therapy, approved by U.S. regulators in February based on data showing its use slowed a worsening in mFARS scores. As such, it “should be interpreted with caution,” the scientists wrote.
Available data also suggested a positive effect of mitochondria-boosting drugs on left ventricular mass index (LVMI), a marker of heart health, but most of these studies were observational and evidence of “low quality.” All other assessed outcomes, including imaging findings, biomarkers, and other functional tests, showed no significant effects with any of the treatment approaches.
Researchers also noted that most of the analyzed studies were relatively small and ran for less than a year, which likely isn’t enough time to capture meaningful changes in FA.
“The median follow-up period for these outcomes was extremely limited considering the slow natural disease progression,” the scientists wrote, adding that a study’s “duration should be least 24 months … to demonstrate any clinical benefit.”
Based on their findings, the researchers proposed that combining FARS/mFARS with LVMI data might be a useful way to test a potential treatment’s benefits in future FA clinical trials, which ideally would run for at least two years.
Biogen markets Skyclarys through its subsidiary Reata Pharmaceuticals, and neither company was not involved in this study.