PTC, chasing BioMarin, posts phase 3 rare disease win but fails to silence skeptics

PTC Therapeutics’ phase 3 clinical trial in the rare inherited disorder phenylketonuria (PKU) has met its primary endpoint. And yet, the design of the study means analysts remain unsure about the strength of PTC’s hand and whether it can rival BioMarin’s Kuvan and live up to its $400 million peak sales forecast.

The study compared sepiapterin to placebo in 98 patients. Sepiapterin, like Kuvan, is designed to treat PKU by lowering elevated blood phenylalanine (Phe), an amino acid that builds up in people with the disease and can cause intellectual disability. The phase 3 trial confirmed sepiapterin can significantly cut Phe levels. What that means for the prospects of the drug candidate is less certain.

While the primary endpoint was met with a 63% mean blood Phe reduction in the main population, "we still have outstanding questions, and it remains unclear if estimates for this program are achievable,” analysts at SVB Securities wrote in a note to investors.

The trial showed “minimal” improvements in the placebo arm, causing the study to hit its primary endpoint with a p-value of 0.0001. The analysis was limited to patients who had at least a 30% reduction in Phe in the first part of the clinical trial.

The reduction in Phe far exceeds the 29% decline seen in BioMarin’s Kuvan trial, but there are doubts about whether the cross-trial assessment is comparing like with like. Participants in the Kuvan trial had a higher baseline Phe, 843µmol/L in the treatment group, than their counterparts in the sepiapterin study, 646µmol/L. It is possible BioMarin’s smaller decline in Phe reflects its enrollment of sicker patients.

PTC separated out the data on patients with classical PKU, a severe form of the disease. The reduction in Phe in the subgroup was 69%, a deep reduction that has question marks hanging over it because of the limitations of the data set. As the SVB Securities analysts note, the randomized portion of the trial included six classical patients, and their baseline Phe, 761µmol/L, was only a little above that of the overall study population and well below the 1,200µmol/L threshold used to diagnose the severe form of PKU.

“We wonder if the six randomized classical PKU patients in the sepiapterin arm will be sufficient to include this patient group on the label. Moreover, we believe the way Classical patients were defined in the study is rather loose, especially considering their baseline blood Phe levels were not much higher than the overall study population,” the analysts wrote. 

The doubts have led the analysts to review their estimates. Previously, the SVB Securities team forecast peak sales of $400 million, reflecting their assumption that sepiapterin will penetrate 25% of Kuvan-responsive patients and 25% of non-responders to the BioMarin drug.