Protagonist will need more than perseverance to play in bowel disease

A change in fortunes has given Protagonist Therapeutics a much-needed boost: the company yesterday revealed that PTG-100 did not in fact flunk a phase II study earlier this year, raising hopes that this asset might yet have a future in inflammatory bowel diseases.

The group laid the blame for the blow-up of the Propel trial at the feet of an unnamed contract research organisation, which apparently made mistakes that prompted a conclusion that the study would fail. The slip-up has lost Protagonist valuable time and money, but executives are confident that regulators will now allow the company to push straight into a registrational study. Investors must hope that the signals seen in the newly analysed data are real, because the tiny biotech has some big competitors on the horizon (see table below).

Still, BVF Partners, a private San Francisco-based investor, is apparently a believer. The firm led a $22m equity investment, also announced yesterday, to fund further development of PTG-100.

Protagonist says its three pipeline assets are now fully funded well into 2020; however, it seems that not all investors are ready to jump back into this story. Shares in the California biotech surged 59% yesterday to $11.12, but the stock remains well below $20, the level at which it was trading before the CRO debacle.

Proof of concept?

Protagonist claims that the re-analysed Propel data provide clinical proof of concept for PTG-100. The company describes the project as an oral, α4β7-specific, GI-restricted therapy for inflammatory bowel diseases (IBD). It was essentially designed as an oral version of Takeda’s Entyvio, an antibody that also targets α4β7 integrin, and which generated sales of almost $2bn last year.

This is very much the idea around Protagonist’s platform technology – generating first-in-class oral, peptide-based drugs that target validated biological pathways. The hope is that by minimising systemic exposure the company’s projects will prove safer, more tolerable and more convenient than antibodies.

This whole premise looked at risk of being undermined by the failure of the Propel study. Takeda has shown that blocking α4β7 integrin works in IBD, so PTG-100 should have shown activity.

As it turned out, it was mistakes made by a single reader of endoscopies that threw the trial. Unusually high responses in the placebo arm raised suspicions, and Protagonist called in a new CRO to conduct a fresh, blinded analysis of the dataset.

A 24% remittance rate in the placebo arm dropped to 5% in the new analysis – much closer to historic norms – while a dose response with therapy also appeared to emerge.

Still, these results only come from a small set of patients who have progressed after taking TNFs and steroids, and at the time of the interim analysis only 65 of a planned 190 patients had been enrolled.

This weakens Protagonist’s claim that these results put PTG-100’s efficacy in line with mechanistically similar projects, given that most of the examples it cited – Roche’s etrolizumab and Shire’s SHP647, for example – have generated more robust evidence from larger mid-stage trials.

The new analysis could at least help erase some fears that the failure of Propel signalled deeper problems with Protagonist’s platform. And a deal with J&J over a second project shows that the group’s approach is being taken seriously – PTG-200 is a peptide version of the pharma giant’s blockbuster psoriasis therapy Stelara.

But the setback with PTG-100 serves as a reminder of just how far Protagonist still has to go – particularly when considering the huge pivotal programmes that its rivals already have under way. For any hope of competing here, Protagonist needs PTG-100 to emerge as much more than a convenient version of Entyvio.