PTC Therapeutics reported a phase 2 win for its Novartis-partnered Huntington's disease candidate. But the readout failed to convince investors, who wiped almost 20% off PTC’s share price amid doubts about the path to accelerated approval of the asset.
The study compared two doses of PTC518, a small-molecule splicing modifier, to placebo in people with stage 2 or stage 3 Huntington's. After 12 weeks, PTC saw significant reductions in blood Huntingtin (HTT) protein levels, achieving its primary endpoint. The reductions persisted through the 12-month analysis, when levels were down between 23% and 39% from baseline across the doses and patient populations.
William Blair analysts said in a note to clients that there was “large amount of skepticism” from investors about whether the data would definitely show a correlation between HTT reductions and clinical outcomes. The analysts also noted skepticism about the ability of PTC518 to significantly slow the rate of clinical decline.
The reaction of PTC’s stock, which fell almost 19% to $40.65, suggests “investors are still grappling with these two points and if the data are sufficient to support an accelerated approval pathway based on reductions in mHTT,” the analysts said.
PTC said there were “dose-dependent trends of benefit on clinical scales” for stage 2 patients. The effect of PTC518 on stage 3 patients is less clear, with PTC seeing trends favoring the low dose but not the high dose. Blood HTT levels fell by similar amounts in stage 2 and stage 3 patients. The fact that comparable changes in HTT had different outcomes could weaken PTC’s case, but the analysts see a path forward.
“We believe the biomarker and clinical outcomes data at 12 and 24 months in the stage 2 patients are likely sufficient for productive conversations with the FDA regarding a registrational path in patients with less advanced disease,” the analysts said.
Stage 2 patients account for around 85% of the total population, PTC CEO Matthew Klein, M.D., said on a call with investors to discuss the data. There is more work to do to show whether PTC518 has a future in the 10% to 15% of patients with stage 3 Huntington's.
“We know we're getting HTT lowering and the drug is working as it's supposed to work. Our exposure data show the drug is going where it's supposed to go in these patients,” Klein said. “Question is, how amenable are they to disease modification at this late stage? And if they are modifiable, how much time is it going to take to really see a clear and consistent signal?”
Klein also discussed the extent to which the data show associations between HTT reductions and other measures of the disease. The CEO said the dose-dependent effects are “a great association because what that's telling you is that if you tend to lower Huntingtin protein more, you're tending to see better clinical effect.” PTC believes it has multiple such associations that it can present to the FDA.
The biotech plans to discuss the data with Novartis, which paid $1 billion upfront for PTC518 last year, before outlining the next steps for the asset. Speaking to analysts before the PTC518 readout, Novartis CEO Vas Narasimhan said improvements in clinical endpoints would be needed to file for approval using the phase 2 data. Alternatively, the Swiss drugmaker could run a phase 3 trial before seeking approval.