It looks like Biogen Inc.’s Nrf2 activator, Skyclarys (omaveloxolone), will maintain its status as the sole therapy approved for treating patients with Friedreich’s ataxia (FA), at least for now. The U.S. FDA asked for another “adequate and well-controlled study” in the complete response letter (CRL) issued to PTC Therapeutics Inc. for 15-lipoxygenase inhibitor vatiquinone. The agency said “substantial evidence of efficacy was not demonstrated.”

The CRL had been somewhat anticipated, with RBC Capital Markets analyst Brian Abrahams predicting in an Aug. 7 research note following PTC’s second-quarter earnings call what “will probably be a regulatory delay or rejection for vatiquinone in FA later this month.” He cited statements by management regarding a late-cycle meeting with the agency in July and interpreted as a negative omen the fact that labeling discussions had not yet begun despite being only a couple of weeks away from the Aug. 19 PDUFA date.

"We are of course disappointed … ,” said PTC’s CEO Matthew Klein. "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.” The company plans to meet with the agency to discuss next steps.

Approval was not exactly a sure bet, in part to the recent upheaval at the FDA, which PTC executives acknowledged during the Aug. 7 earnings call, along with the disclosure that, while a late-cycle review meeting with the agency had taken place, labeling discussions had not yet begun despite being only a couple of weeks out from the Aug. 19 PDUFA date.

There was also the fact that vatiquinone missed the primary endpoint in the phase III Move-FA study, failing to hit statistical significance on the modified FA Rating Scale (mFARS) score at 72 weeks. Top-line data reported in 2023 from the primary analysis population showed mean placebo-corrected change in the mFARS score of 1.6 (p=0.14). Move-FA enrolled a total of 146 pediatric, adolescent and adult FA patients, most of them under age 18.

Secondary endpoints data, however, proved compelling. PTC pointed to significant benefit recorded in the bulbar and upright stability subscales (with nominal p values of 0.044 and 0.021, respectively), assessments linked to disease morbidity and predictive of loss of time to loss of ambulation in FA. Initial results also showed a statistically significant difference on the Modified Fatigue Scale, designed to capture one of the more impactful sources of disease morbidity (p=0.025).

The company also bolstered its NDA filing with data from two FA long-term extension studies, both of which yielded highly statistically significant evidence of durable treatment benefit on disease progression. Analysis from the long-term extension part of the Move-FA study, which evaluated vatiquinone treatment over 144 weeks, showed a 3.7-point benefit (p<0.0001, n=70) on mFARS relative to a matched natural history cohort from the Friedreich Ataxia Clinical Outcome Measures disease registry. And long-term open-label extension data from an earlier study of vatiquinone in adults with FA showed that, following 24 months of treatment, subjects had a 4.8-point benefit on mFARS relative to a matched natural history population (p-value less than 0.0001, N=41).

Vatiquinone also proved well-tolerated across all studies.

Warren, N.J-based PTC submitted the NDA in late December 2024. The FDA accepted the application for priority review in February.

A rare, inherited disease, FA is a neuromuscular condition affecting both the central nervous system and the heart. It usually stems from a single genetic defect in the frataxin gene, which leads to reduced production of the mitochondrial protein vital for cellular metabolism and energy production. Vatiquinone is designed to work by targeting 15-lipoxygenase, an enzyme described as a key regulator of the energetic and oxidative stress pathways that are disrupted in patients with FA.

Other approaches are making their way through the clinic, perhaps most notable is Larimar Therapeutics Inc.’s nomlabofusp, a recombinant fusion protein designed to deliver human frataxin into the mitochondria, essentially acting as a protein replacement therapy. Nomlabofusp is in phase II trials, though Larimar already has been meeting with the FDA on the details for a BLA filing seeking accelerated approval for use in adults and children, with an anticipated submission in the second quarter. Bala Cynwyd, Pa.-based Larimar, which recently padded its coffers with a $69 million public offering, expects to report additional data, including open-label extension results, in September 2025.

Lexeo Therapeutics LLC has moved into phase II testing with LX-2006, an AAV-based gene therapy targeting FA cardiomyopathy, while Design Therapeutics Inc. is in phase I with DT-216P2, a small molecule based on the firm’s GeneTAC platform, designed to increase expression of the frataxin gene, specifically by  binding to the expanded GAA sequence frataxin gene. Another gene therapy program, in preclinical development, is in development through a collaboration between Neurocrine Biosciences Inc. and Voyager Therapeutics Inc.

The FDA accepted for review in October 2024 PTC’s resubmitted NDA seeking clearance for Translarna (ataluren) for treating nonsense mutation Duchenne muscular disorder. Since the FDA is not obligated to follow PDUFA review timelines for resubmissions, there is no action date for the Translarna decision.

PTC posted a cash position of nearly $2 billion as of June 30, helped in part by a December 2024 Huntington’s deal with Novartis AG that came with $1 billion up front. The company’s shares  (NASDAQ:PTCT) were trading down by 5.3% to $47.15 premarket Aug. 19.