Study shows Skyclarys helps heart function in FA mice
Therapy aids its ability to pump blood, lowers inflammation, heart failure markers
A new study reports that Skyclarys (omaveloxolone) improves the heart’s ability to contract and pump blood while reducing inflammation and heart failure markers in a mouse model of Friedreich’s ataxia (FA) with severe heart disease.
Skyclarys had no impact on the development of scar tissue, or fibrosis, in the heart muscle, however, and also didn’ extend survival. This suggests that “combinational therapy of [Skyclarys] with antifibrotic compounds should be tested next in this model of Friedreich’s ataxia to verify its potential therapeutic value to increase animal survival,” the researchers wrote. The study, “Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich’s Ataxia Mice With Severe Cardiomyopathy,” was published in the Journal of the American Heart Association.
In FA, mutations in the FXN gene lead to a deficiency in frataxin, a protein needed for the energy-producing components of the cell, called mitochondria, to function normally. Because nerve and muscle cells have high energy demands, they are particularly vulnerable to the lack of frataxin, which leads to the disease’s symptoms.
Hypertrophic cardiomyopathy is the most common heart-related manifestation of FA and is characterized by an abnormal thickening of the heart muscle walls. It can lead to irregular heartbeats (arrhythmias) and fibrosis buildup, making it a common cause of death.
Biogen’s Skyclarys is an oral treatment approved to slow or stop disease progression in people with FA, ages 16 and older. It works by activating Nrf2, a protein whose signaling is impaired in FA.
Its effects on cardiomyopathy haven’t been thoroughly researched, however. FA patients with heart issues were excluded from Skyclarys clinical trials and elevated levels of BNP, a classic heart failure marker, were reported in Skyclarys-treated patients, “raising concerns about Skyclarys’ safety in terms of cardiovascular health,” the researchers wrote.
Dimethyl fumarate (DMF), sold as Tecfidera, among others, is an oral medicine that also activates Nrf2. It’s widely approved to treat certain forms of multiple sclerosis and has moved to Phase 2 clinical testing in adolescents and adults with FA, based on positive preclinical studies.
Testing Skyclarys, DMF on cardiomyopathy
Researchers at the University of California, Davis set out to examine the effects of either medicine on a mouse model that mimics late‐stage severe cardiomyopathy in FA.
“Comparison of these [two] Nrf2 inducers is important to determine efficacy of one over another and elucidate any negative impacts of these Nrf2 inducers on severe cardiomyopathy in the context of FA,” wrote the researchers, who found that neither drug affected body weight nor extended the lifespan of FA mice. Skyclarys appeared to accelerate death in female FA mice, a finding the researchers said “demands further investigation.”
“This observation is highly important and suggests that women living with FA may experience negative side effects of Skyclarys and therefore, may require dose adjustment,” they wrote.
Skyclarys, but not DMF, significantly reduced the mass of the left ventricle, the heart’s lower chambers, in FA mice overall, and reduced the diameter and volume of the left ventricle during a heartbeat.
The FA therapy also partially restored various measures of heart function, including contractility, or the ability of the heart muscle to contract and thereby pump blood, and the amount of blood the heart pumps out with each contraction. DMF had no impact on these parameters.
Consistent with improved contractile function, Skyclarys decreased markers of heart failure and inflammation. Still, neither treatment protected against heart fibrosis.
“These data suggest that a combinational therapy of [Skyclarys] with the drugs that could target fibrotic tissue formation could potentially improve [heart] function and survival,” wrote the researchers, who are conducting a study to investigate this possibility.
Further experiments to understand the molecular mechanisms of these therapies showed that in the heart muscle, both Skyclarys and DMF suppressed oxidative stress, a type of cellular damage that’s a hallmark feature of mitochondrial dysfunction and FA. The results were verified in lab-grown cells derived from FA patients.
Both medications also restored the activity of genes involved in calcium signaling in the heart, which controls contraction and relaxation. However, neither drug significantly improved mitochondrial function in mice nor the integrated stress response, a cellular pathway activated by various forms of stress.
“These data suggest that [Skyclarys], but not DMF, could improve [heart] contractile performance and potentially enhance the quality of life in FA patients with a late‐stage cardiomyopathy,” the researchers wrote. “More studies are needed to determine the cause of premature death in Skyclarys‐treated [FA] females.”
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