Vatiquinone not likely to raise cardiac risk with FA, study finds
Healthy adults show scant changes in heart rate or activity at extra high doses
A study of heart health with vatiquinone, an investigational oral Friedreich’s ataxia (FA) therapy, found no increased risk of cardiac problems in healthy adults, including when doses about 3.5 times above the therapeutic dose were evaluated, scientists reported.
Blood levels of vatiquinone did not correlate with changes in the heart’s electric activity or a patient’s heart rate. The treatment’s safety profile also was favorable, consistent with that seen in clinical trials of the treatment, with no new safety issues reported.
“These findings suggest that there is a minimal cardiac risk for vatiquinone concentrations up to a supratherapeutic [above therapeutic] dose level,” the scientists wrote.
The study, “Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses,” was published in Clinical Pharmacology in Drug Development.
Vatiquinone aims to ease neuroinflammation, nerve cell damage
FA is caused by mutations in the FTX gene that result in the loss of frataxin, a protein important for the function of mitochondria, the energy producing components of cells.
Nerves and muscles are particularly sensitive to a loss of cellular energy, and disease symptoms range from gait and balance problems and muscle weakness, to neurological and heart issues.
Vatiquinone (PTC-743), a vitamin D derivative being developed by PTC Therapeutics, is a small molecule designed to block the activity of 15-lipoxygenase, an enzyme that regulates molecular processes involved in brain inflammation and nerve cell damage.
The therapy was evaluated against a placebo in the Phase 2/3 MOVE-FA study (NCT04577352) that found some meaningful benefits, and its long-term safety and efficacy in reducing neuroinflammation and nerve cell damage is being assessed in a Phase 3 (NCT05515536) trial due to end in 2027. In both studies, vatiquinone has been given as an oral solution or capsules, taken three times daily, at doses of 200 mg or 400 mg depending on a patient’s age and weight.
Scientists led by those at PTC now conducted a two-part study in 33 healthy men and women, ages 18 to 65, to assess vatiquinone and its impact on parameters of heart health, as determined via an electrocardiogram — an exam that records the heart’s electrical activity. In the trial’s first part, five adults were given 1,400 mg of vatiquinone and two others took a placebo.
This dose, which was about 3.5 times higher than the 400 mg therapeutic dose, was found to be well tolerated, with all reported side effects being mild, and no serious adverse events starting or worsening with treatment. No differences between the 400 mg and 1,400 mg doses also were seen in the frequency of reported side effects.
Findings support likelihood of a ‘minimal cardiac risk’ with therapy’s use
In its second part, 28 patients were randomly assigned to vatiquinone at a 400 mg or 1,400 mg dose, a placebo, or to moxifloxacin — an antibiotic used as a positive control — in a crossover design, meaning that each person took part in each of the four groups. This design was meant “to reduce the variability between treatments because each participant serves as their own control,” the researchers wrote. A minimum of eight days separated each assigned therapy or the placebo.
Continuous electrocardiogram monitoring was used to assess QT interval, the time it takes for the heart muscle to contract and then recover or recharge.
At baseline (the study’s start), participants had a mean heart rate between 60.7 and 62.7 beats per minute (bpm), and a mean corrected QT interval between 404.2 and 407.2 milliseconds (ms).
The placebo-corrected QT interval varied from a mean of minus 4.1 ms at 14 hours after the therapeutic 400 mg vatiquinone dose, to a mean change of 1.5 ms at two hours after the 1,400 mg dose. With moxifloxacin, the corrected QT interval rose to a peak value of 21.1 ms after four hours.
Vatiquinone also “did not have a clinically relevant effect” on heart rate, the scientists reported, with the mean placebo-corrected interval ranging from minus 0.1 bpm after a 1,400 mg dose to 3.8 bpm with the 400 mg dose.
Further analysis did not show a significant relationship between blood levels of vatiquinone and the placebo-adjusted QT interval. In fact, changes in QT interval did not exceed 10 ms up to a vatiquinone level in blood plasma of about 11,500 nanograms/mL, well above the study’s initially targeted supratherapeutic dose.
“A safe and well-tolerated supratherapeutic dose of 1400 mg was identified,” the scientists wrote. Study “findings suggest that there is a minimal cardiac risk for vatiquinone concentrations up to a supratherapeutic dose level.”
