Heart function OK with high dose of Skyclarys in study
Assessment matched blood levels when FA therapy is taken with food
A high dose of the Friedreich’s ataxia (FA) treatment Skyclarys (omaveloxolone), far above the approved dose to match blood levels when the therapy is taken with food, did not affect heart function in healthy individuals, a study confirms.
The study, “Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected QT Interval in Healthy Participants: A Randomized, Double-Blind, Placebo- and Active-Controlled, Three-Way Crossover Study,” was published in Clinical and Translational Science.
FA is a neurodegenerative disorder characterized by ataxia, a lack of coordination and muscle control during voluntary movements. Most people with FA experience symptoms including heart abnormalities, most commonly cardiomyopathy, in which the muscles lining the heart become thick and enlarged.
Biogen‘s Skyclarys is the first therapy approved for people with FA, ages 16 and older. It’s given as an oral dose of 150 mg once daily on an empty stomach, either one hour before eating or two hours after.
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 14 guideline states that most drugs need to be assessed for their effects on the QT interval, which is the time it takes the heart muscle to contract and recover.
QT intervals in healthy participants tested
At the approved 150 mg dose, analysis confirmed Skyclarys did not affect the QT intervals in healthy participants, either in a fasted or fed state, the report stated. A fed state is considered the worst-case clinical exposure because when taken with a high-fat meal, the levels of Skyclarys in the bloodstream can be 4.5 times higher than when taken on an empty stomach in a fasted state.
In this study (NCT05927649), scientists at Biogen further evaluated the effect of a supratherapeutic dose of Skyclarys, or one at levels higher than those typically used in treatment, on the QT interval in healthy individuals.
In total, 30 participants, ages 18 to 49, were randomly assigned to receive a single oral dose of Skyclarys at 450 mg, a placebo (negative control), or moxifloxacin at 400 mg (positive control, meaning it was used to show what a positive result looks like) over three separate periods. Doses were administered 30 minutes after participants received a high-fat meal approved by the U.S. Food and Drug Administration to ensure supratherapeutic exposure.
No clinically significant effect from exposure to high blood levels of Skyclarys
Blood samples were collected to measure the levels of the drugs in the bloodstream. The QT interval, corrected for heart rate, was measured using an electrocardiogram, which records the heart’s electrical activity. A change in the QT interval longer than 10 milliseconds (ms) is considered a clinically significant adverse effect.
Blood tests showed a 450 mg dose of Skyclarys in a fed state resulted in a mean maximum blood concentration of 319 nanograms per milliliter (ng/mL). This value was 4.5 times higher than the predicted maximum blood concentration in FA patients when given the approved 150 mg dose (71.5 ng/mL).
A supratherapeutic dose of [Skyclarys] … that covers the worst-case clinical exposure scenario did not have a clinically significant effect on [QT interval] and was generally safe and well tolerated.
Exposure to these high blood levels of Skyclarys and the major byproducts of its metabolism (M17 and M22) did not have a clinically significant effect on the QT interval. In particular, the mean QT intervals were within the normal range (less than 450 ms), and the mean changes were less than 10 ms for all post-dose timepoints.
The upper limit of the 90% confidence intervals for the placebo-corrected change in QT interval following Skyclarys administration, or the longest changes in QT values that are most likely to be true, were also less than 10 ms at all timepoints.
No deaths, serious adverse events, or discontinuations were reported. Six participants reported a treatment-emergent adverse event (TEAE) after Skyclarys administration and six after the placebo. The most common TEAEs associated with Skyclarys were nausea and feeling hot, all of which resolved before the end of the study. There were also no clinically significant findings in laboratory tests, vital signs, and other electrocardiogram measures.
The team noted a potential limitation of this study was enrolling healthy adults who may not share the same coexisting conditions or cardiomyopathy prevalent in FA patients.
“This study is the first report to provide conclusive data demonstrating that [Skyclarys] and its major [blood] metabolites (M17 and M22) did not prolong the QT interval,” the scientists concluded. “A supratherapeutic dose of [Skyclarys] (450 mg administered in the fed state) that covers the worst-case clinical exposure scenario did not have a clinically significant effect on [QT interval] and was generally safe and well tolerated.”
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