“The clinical study results confirm that the CYP3A4 enzyme plays an important role in vatiquinone metabolism and the effect on vatiquinone PK when coadministered with a potent CYP3A4 inhibitor or inducer. Additional work was performed to understand the impact of moderate CYP3A4 inhibitors and inducers on vatiquinone exposures via physiologically based pharmacokinetic modeling and will be presented elsewhere,” coauthor Lee Golden, MD, chief medical officer at PTC Therapeutics, and colleagues wrote.1
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Top Clinical Takeaways
- Coadministration with CYP3A4 modulators like itraconazole and rifampin significantly altered vatiquinone’s pharmacokinetics, increasing or decreasing its systemic exposure.
- Despite changes in pharmacokinetics, the terminal half-life of vatiquinone remained unaffected by CYP3A4 inhibitors or inducers.
- The safety profile of vatiquinone in the presence of CYP3A4 modulators was generally favorable, with only mild treatment-emergent adverse events reported.
Although 3 patients (13.04%) reported 4 treatment-emergent adverse events (TEAEs), investigators observed no treatment-emergent serious adverse events (TESAEs) during the study. Only 2 participants experienced temporary clinically significant elevations in hepatic enzymes. As for the reported TEAEs, they were in the Gastrointestinal System Organ Class (SOC) and, for 1 patient, also in the Nervous System SOC.
Authors noted that all TEAEs were mild and resolved by the completion of the study or shortly thereafter. The reported TEAES were considered unrelated to vatiquinone although the elevated alanine transaminase and aspartate transaminase enzymes might have possibly been related to itraconazole, according to the principal investigator of the study.1
“The results of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant,” Golden et al noted.1 According to a recent company update, PTC Therapeutics has plans to submit a new drug application (NDA) for vatiquinone for the treatment of FA in late 2024.2
Presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 3-6, in Orlando, Florida, data from the placebo-controlled phase of the global phase 3 MOVE-FA trial (NCT04577352) assessing vatiquinone in patients with FA showed the treatment demonstrated clinically relevant benefits across multiple end points at 72 weeks.3 In the analysis, investigators observed a –1.61 (P=.144) change in modified FA Rating Scale (mFARS)compared with the placebo at 72 weeks in the modified intent-to-treat (mITT) population, which consisted of 123 participants with FA. The researchers reported a sustained vatiquinone treatment benefit observed across all end points including the primary, secondary, and exploratory end points.
"The recently completed MOVE-FA placebo-controlled study results demonstrate a statistically significant and meaningful effect on the upright stability subscale of the disease rating scale – the most relevant and sensitive component of the disease rating scale for pediatric and young adult ambulatory patients," Klein said. "The results in the study support that vatiquinone could have an important effect in delaying loss of ambulation as well as other important and burdensome aspects of the disease."
Conducted by lead author David Lynch, MD, PhD, a neurologist and director of the Friedreich's Ataxia Program at Children's Hospital of Philadelphia, and colleagues, the trial included patients 143 aged at least 7 years, with an mFARS score of between 20 and 70 and the ability to ambulate at least 10 feet in 1 minute with or without assistance. The primary end point of the current analysis was placebo-corrected change from baseline in mFARS at 72 weeks. The intent-to-treat (ITT) population had a mean age of 18.7 years and the primary analysis population—the mITT population—included participants between 7 years and 21 years of age (mean, 14.6).
Investigators observed a nominally significant benefit recorded in the Upright Stability subscale (USS), a relevant metric of disease progression in younger ambulatory patients with FA, of mFARS, with a change of –1.26 (P = .021). In addition, researchers observed nominally significant benefit in the Modified Fatigue Impact Scale, with a change of –5.05 (P = .025). Overall, the authors noted that the treatment was safe and well tolerated among the participants, with no differences in treatment-related adverse events observed between treatment and placebo groups.
"The effects observed in this trial along with the established safety profile will form the basis of the planned vatiquinone NDA submission later this year," Klein added.
REFERENCES
1. Lee L, Thoolen M, Ma J, Kaushik D, Golden L, Kong R. Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone. Clin Pharmacol Drug Dev. Published online August 12, 2024. doi:10.1002/cpdd.1461
2. PTC Therapeutics Provides Corporate Update and Reports Second Quarter 2024 Financial Results. News Release. PTC Therapeutics. August 8, 2024. Accessed August 22, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-provides-corporate-update-and-reports-second-2
3. Lynch D, Duquette A, França MC, et al. Safety and Efficacy of Vatiquinone Treatment in Friedreich Ataxia Patients from MOVE-FA: a Phase 3, Double-blind, Placebo-controlled Trial. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster S79.