The bubble bursts for Proteostasis

Clinical updates from Proteostasis are known for prompting more questions than providing answers, and today’s keenly anticipated readout from the company’s cystic fibrosis programme was no exception. Classic red flags like excluded patients and a highly selective approach to releasing actual numbers immediately set off alarm bells, and a swift selloff in the company’s stock confirmed that this was bad news. 

The biggest disappointment was weak data on the company’s triple therapy, topped off with a decision to abandon work looking at adding Proteostasis’s proprietary CFTR modulators to Vertex’s suite of cystic fibrosis medicines. Proteostatis shares plunged 58% at the open, leaving the company’s value below its cash balance.

Those shareholders that bought into the company’s placement at $6.75 last October have been left nursing heavy losses – shares were trading at $1.72 this morning – and few are likely to be comforted by the company’s pledge to push on with development work. 

Triple trouble

Proteostatis has run several combination studies of its CFTR modulators, and hints of promise in doublet data last October raised hopes for even greater efficacy from a triple therapy. 31 patients were recruited to test two different dosage combinations of PTI-801, PTI-808 and PTI-428, six of whom were assigned to placebo, though the company presented only certain snapshots of that study today. 

Only the cohort given a high dose of PTI-801 generated data worth detailing, and Proteostasis focused on a mean absolute increase in lung function, as measured by ppFEV1, of five percentage points versus baseline over 14 days. It said this was statistically significant, stressing that lung function improvements had not plateaued by day 14. 

However this number was generated by a per protocol population; the company excluded four patients deemed to have violated protocol, and when pressed for the intent to treat number on a conference call, admitted this dropped to a four percentage point improvement. This is way below the 10 point or more improvement that was considered the bar for Proteostasis to beat.

The result also looks much weaker than data seen with Vertex’s two triplets, which have reported 10-point improvements in a similar F508del homozygous population. However, the results are not directly comparable, partly because the Vertex data are longer term.

Despite all this, Proteostasis intends to push on with longer, 28-day studies of the high-dose cohort: 600mg PTI-801 and 300mg PTI-808 have been identified as the sweet spot, with or without PTI-428. Somewhat ominously, data from an ongoing doublet trial of 600mg PTI-801 and 300mg PTI-808 were not released today, and these remain a crucial measure of this strategy. 

Fizzling out

Another dent to confidence came with Proteostasis’s admission that PTI-801 or PTI-428 had failed to add anything to Vertex's Symdeko in terms of lung function. Its “add on” programmes have therefore been scrapped, cutting off another way forward for these projects. 

This decision will at least save cash, which must now be a priority for Proteostasis. The company ended last year with $118m, and today’s share price plunge rules out another cash call anytime soon. 

On a conference call executives stressed the need for more options for cystic fibrosis patients, suggesting that “healthy competition” in the market could help improve access to medicines. These are certainly valid points, although any new medicines must also offer real therapeutic benefit, something that Proteostasis has yet to definitively show. 

Perhaps longer-term data will change the story once again. But for many investors who had previously managed to detect glimmers of light in the fog of Proteostasis’s updates, today those sparks fizzled out.