PTC pulls back from gene therapy, lays off staff after phase 3 fail but still hopes for rare disease approval

PTC Therapeutics’ phase 3 Friedreich ataxia (FA) clinical trial has missed its primary endpoint. But, while the biotech is cutting other programs and reducing its head count, it thinks the FA data reveal an active drug and justify opening talks with the FDA about a path to approval in the neurodegenerative disease. 

For PTC’s primary analysis, investigators randomized 123 patients to receive oral doses of vatiquinone, an inhibitor of 15-lipoxygenase, or placebo three times a day for 72 weeks. The study drug failed to beat placebo in terms of change from baseline in the modified Friedreich Ataxia Rating Scale (mFARS) score at Week 72, causing the study to miss its primary endpoint. But, as PTC sees it, the fail isn’t the whole story.

“We acknowledge that we failed the primary endpoint study,” CEO Matthew Klein, M.D., said on a conference call with investors. “We also acknowledge that there's many pieces of evidence on things that really matter in the disease, including the bulbar scale and upright stability subscales, both of which are regarded as really the key functional aspects in terms of clinical meaning in the overall mFARS.”

The nominal p-values for the bulbar and upright stability subscales were 0.044 and 0.021, respectively, in the overall population. The mFARS fail stemmed from the lack of effect on lower and upper limbs. The biotech also made vatiquinone look better on mFARS, bringing the p-value down to 0.054, by removing people who didn’t complete the study from the analysis. 

“Given the understood natural history of disease in pediatric patients, the 2.31 placebo-corrected point difference in Week 72 signifies about one year of slowing of disease progression after one and one half years of treatment, which is clearly clinically meaningful. We also see that the placebo and vatiquinone curves appear to be spreading further apart from 60 to 72 weeks,” Klein said.

Analyzing data on all participants, rather than conducting per-protocol assessments, is best practice, but PTC sees extenuating circumstances that support excluding subjects in this trial. Klein made the case to investors, explaining that PTC pre-specified a completer analysis because the “study was enrolled and conducted in the midst of the COVID-19 pandemic” and lasted 72 weeks. COVID-19 meant some people did not complete the study protocol on their assigned treatment without dose disruption.

Given the signs of efficacy, unmet need, safety data and extenuating circumstances, Klein thinks the data are strong enough to discuss paths to approval with regulators. However, while PTC is pushing forward in FA despite the primary endpoint fail, it's pulling back from other areas, discontinuing its preclinical and early research gene therapy programs to reduce its operating expenses by 15%.

PTC is also reducing its head count by 8% in conjunction with the pipeline prioritization. Klein cited PTC’s heavy investment in gene therapy R&D in recent years—the biotech spent $547 million from 2020 to 2022—as a factor in the decision.

“[It’s] a lot of spending,” Klein said. “When we take a step back and we look at what we now understand to be the likely timelines, the potential approval, the likely investment that's going to require to get these programs there, and the uncertain commercial landscape that will occur many years later at those times, it became a decision that for us was one of deprioritize these programs.” 

PTC also revealed that Chief Financial Officer Emily Hill “has been relieved of her responsibilities and will be leaving the organization.” Klein, who took over as CEO in March, said the “decision regarding Emily is done to ensure that we have the executive team in the best position to build PTC forward for its future.”