FDA Denies Approval for Friedreich Ataxia Agent Vatiquinone, Citing More Efficacy Needed

Matthew B. Klein, MD

The FDA has handed PTC Therapeutics a complete response letter (CRL) for its investigational therapy vatiquinone, a first-in-class selective inhibitor of 15-lipoxygenase (15-LO), as a new treatment for both pediatric and adult patients with Friedriech ataxia (FA), a rare neuromuscular condition. In the CRL, the agency noted that the evidence of efficacy was not substantial enough for vatiquinone, and that another well-controlled study would be needed to support new drug application (NDA) resubmission.

"We are of course disappointed by the FDA's decision to not approve vatiquinone," Matthew B. Klein, MD, chief executive officer at PTC, said in a statement. "We believe the data collected to date demonstrate that vatiquinone could provide a safe and effective therapy for both children and adults living with Friedreich's ataxia. We plan to meet with the FDA to discuss potential steps to address the issues raised in the CRL."

Vatiquinone was aiming to become the second marketed treatment for FA, second to Biogen’s omaveloxolone, an FcRn inhibitor, which gained greenlight in early 2023 for those aged 16 and up with FA. The two therapies have a slightly different function: vatiquinone primarily works by reducing oxidative damage and ferroptosis, aiming to preserve mitochondrial integrity and neuronal survival in FA, whereas omaveloxolone enhances the body’s endogenous antioxidant and anti-inflammatory defenses, improving mitochondrial energy production and reducing oxidative stress.

Vatiquinone’s NDA, accepted by the FDA earlier this year, was primarily based on findings from the phase 3 MOVE-FA trial (NCT04577352), a large-scale study of 146 pediatric, adolescent, and adult patients with FA who were randomized to either active or placebo treatment for a 72-week period. The study did not meet its primary end point of change in overall modified Friedreich Ataxia Rating Scale (mFARS; P = .14); however, the therapy showed a statistically significant effect (P = .021) on mFARS Upright Stability Subscale (USS), a pre-specified end point. In addition, patients on the agent showed significant benefits in the bulbar (P = .044) and upright stability subscales (P = .021).²

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In addition to MOVE-FA, the NDA included 2 long-term trials of pediatric and adult patients with FA, both of which met their primary end points, demonstrating statistically significant impacts on disease progression. When compared with natural history cohorts from the Friedreich Ataxia Clinical Outcome Measures disease registry, treatment with vatiquinone resulted in a 3.7-point benefit in mFARS (P <.001; n = 70) at 144 weeks, representing a clinically meaningful 50% slowing of disease progression.

Vatiquinone was considered more effective in the open-label study of adults with FA. After 24 weeks of treatment with the therapy, participants reported a 4.8-point benefit on mFARS relative to natural history populations (P <.0001; n = 41). Above all, the therapy continued to show a safety profile that was well-tolerated, with no serious treatment-related adverse events reported.³

At the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, an analysis of MOVE-FA further showcased vatiquinone’s effect on USS progression. Of the 4 mFARS subscales, only the USS showed progression from baseline to week 72 in the placebo group–a finding consistent with natural history data indicating that disease progression in ambulatory pediatric and adolescent patients is primarily driven by declines in functions measured by the USS.⁴

A previously published phase 1, 2-part, open-label study showed that the pharmacokinetics (PK) of vatiquinone may be adjusted by coadministration of cytochrome P450 isoform 3A4 (CYP3A4) inhibitor itraconazole or CYP3A4 inducer rifampin. Overall, coadministration of of vatiquinone 400 mg with itraconazole 200 mg increased maximum observed concentration (C_max) of vatiquinone and systemic exposure (AUC_0-inf) by approximately 3.5- and 2.9-fold, respectively. Coadministration of vatiquinone 400 mg with rifampin 600 mg decreased vatiquinone C_max and AUC_0-inf by approximately 0.64- and 0.54-fold, respectively, while its terminal half-life remained unaffected by either itraconazole or rifampin.⁵

"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,” coauthor Lee Golden, MD, chief medical officer at PTC, and colleagues, wrote. “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."

REFERENCES
1. PTC Therapeutics Receives Complete Response Letter for Vatiquinone NDA. News release. PTC Therapeutics. August 19, 2025. Accessed August 19, 2025. https://www.prnewswire.com/news-releases/ptc-therapeutics-receives-complete-response-letter-for-vatiquinone-nda-302533332.html
2. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. News release. May 23, 2023. Accessed August 19, 2025. https://www.prnewswire.com/news-releases/ptc-therapeutics-announces-topline-results-from-vatiquinone-move-fa-registration-directed-trial-301832658.html
3. PTC Therapeutics Announces Positive Results from Long-Term Treatment Studies and Updates on Regulatory Progress for Vatiquinone Friedreich Ataxia Program. News release. PTC Therapeutics. Accessed August 19, 2025. https://www.prnewswire.com/news-releases/ptc-therapeutics-announces-positive-results-from-long-term-treatment-studies-and-updates-on-regulatory-progress-for-vatiquinone-friedreich-ataxia-program-302269891.html
4. Lynch D, Duquette A, França MC, et al. Improvement in Upright Stability subscale of mFARS with Vatiquinone Treatment in MOVE-FA: a Phase 3, Double-blind, Placebo-controlled Trial. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster S80.
5. 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