Protagonist waits to find out the meaning of trial failure

Having canned the phase IIb trial of its lead asset, PTG-100, in ulcerative colitis after a futility analysis, Protagonist Therapeutics is now forced to pin its hopes on the interleukin-23 blocker PTG-200, a project in phase I for Crohn’s disease.

The two have different mechanisms of action – PTG-100 is an alpha-4 beta-7 integrin antagonist – but there are similarities, not least that both are based on Protagonist’s oral peptide technology. It is hard to judge whether the failure of ’100 might bode ill for ’200, but with a share price fall of nearly 60% yesterday it certainly bodes ill for Protagonist.

An analysis of the first 65 patients in the 240-patient Propel trial showed an unusually high placebo response, Protagonist said, suggesting that the study would not show an effect on clinical remission, its primary endpoint. This came despite a trial design intended to limit placebo response, with an objective definition of clinical remission and a 12-week duration – the same as the Oasis trial of Arena Pharmaceuticals’ etrasimod, and longer than the Touchstone trial of Celgene’s ozanimod (Arena takes the ulcerative colitis fight to Celgene, March 20, 2018).

The extent of PTG-100’s failure in ulcerative colitis will become clearer when full data on Propel are released in a month or so. This will determine PTG-100’s future in another indication: Protagonist had also been planning to start a phase II/III trial of it in chronic pouchitis, and was waiting for a positive outcome of the Propel futility analysis before going ahead. Pouchitis development is now on hold.

Reading the runes

Unless PTG-100 can somehow be revived Protagonist is reliant on the other compounds, all of which are based on its peptide technology. Its next most advanced candidate is PTG-200 for Crohn’s disease and potentially ulcerative colitis.

While PTG-100 had a novel mechanism, PTG-200’s pharmacology is more familiar. As an IL-23 peptide receptor antagonist it has a similar action to J&J’s Stelara, an anti-IL-12 and 23 antibody that was approved for Crohn’s in late 2016 and which is forecast to have sales of $2bn in this indication in 2022 according to EvaluatePharma’s consensus. J&J is also the licensee of PTG-200, having paid $50m for worldwide rights to all indications last May.

PTG-200 is in its first human trial, a double-blind, placebo-controlled, dose-escalation study in 80 volunteers comparing tablet and capsule formulations. Being phase I this is a safety study so, while ’200’s pharmacokinetics and maximum tolerated dose will be made public when the study reports in the second half, no clue to efficacy – or whether it too might fall prey to an unexpectedly high placebo response – will be available until phase II. A global phase II study in Crohn’s is expected to start in the second half of this year.

The end of 2018 might also see Protagonist’s third candidate hit phase II. PTG-300 is a subcutaneous hepcidin for the treatment of underlying anaemia in orphan diseases, including beta-thalassaemia and myelodysplastic syndromes.

Shuttering Propel might at least mean that Protagonist has the cash to see ’200 and ’300 through phase II – just as well since its stock price crash will leave little opportunity for fund-raising.

A clearer picture of the prospects for these two molecules will be available when the Propel post-mortem concludes next month. If the trial’s failure is related to Protagonist’s peptide platform hope for PTG-200 in particular grows dim; PTG-300 might have a better chance owing to its different route of administration and non-GI indications.

It is PTG-200 that Protagonist needs to succeed, though: the licence to J&J provides for milestones worth up to $940m and double-digit royalties. Analysts from Stifel Nicolaus give both PTG-200 and ’300 a 10% probability of success. Perhaps shareholders cannot be blamed for not liking these odds.

To contact the writer of this story email Elizabeth Cairns in London at [email protected] or follow @LizVantage on Twitter

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