Protagonist “delighted” with trial failure
Development of the ulcerative colitis project PN-943 continues.
Protagonist Therapeutics reckons it has a winner in PN-943 because the ulcerative colitis project’s phase 2 trial showed an advantage with the lower of the two trial doses in a subgroup within a subgroup. Unfortunately the claimed significance for this faint efficacy signal is nominal because of one glaring fact: the trial missed its primary endpoint.
In other words, the study was pretty much a total bust, and Protagonist’s insistence on pushing into phase 3 with the oral α4β7 integrin inhibitor treads the line between optimism and foolhardiness. The company’s stock is down 52% so far today.
On a conference call Dinesh Patel, Protagonist’s chief executive, professed himself “delighted” with the topline data from the Ideal trial. He should not be: the high, 450mg twice-daily dose did not show a significant improvement over placebo in the number of patients achieving clinical remission after 12 weeks’ treatment, Ideal’s primary endpoint.
Nothing of significance
The lower dose, 150mg twice daily, missed this mark too. But Protagonist has sieved the data finely, and claims to have come up with a couple of hints of an efficacy signal with this lower dose. This yielded a placebo-adjusted improvement of 13 points in the modified intent-to-treat (mITT) group, which excluded 10 subjects from trial sites in Russia and Ukraine who had not completed week 12.
| Topline Ideal (NCT04504383) results | |||
|---|---|---|---|
| mITT | |||
| PN-943 450mg bid | PN-943 150mg bid | Placebo | |
| N | 51 | 53 | 55 |
| Clinical remission (%) | 15.1 | 27.5 | 14.5 |
| Delta vs placebo (% points) | 0.6 | 13.0 | |
| Nominal (not statistically significant) p value vs placebo | Not given | 0.081 | |
| mITT, biologic-naive | |||
| PN-943 450mg bid | PN-943 150mg bid | Placebo | |
| N | 47 | 46 | 45 |
| Clinical remission (%) | 17.0 | 30.2 | 14.0 |
| Delta vs placebo (% points) | 3.0 | 16.2 | |
| Nominal (not statistically significant) p value vs placebo | Not given | 0.035 | |
| Per protocol enrolment: 169 patients. Source: company release. | |||
Even here the nominal p value is above the traditional 0.05 limit for significance, so it is hard to construe a way of considering this a win.
The other cohort in which Protagonist claims the lower dose of PN-943 to have scored a hit was in patients in the mITT group who had not previously been treated with biologicals.
In this group Protagonist claimed a p value of 0.04, which was of course not statistically significant since the trial whiffed on its primary endpoint.
Moreover, biologics – including Takeda’s Entyvio, an intravenous α4β7-specific integrin inhibitor – are increasingly prescribed first line for ulcerative colitis, so how much of a market Protagonist could snare here is unclear, even assuming that this faint glimmer of efficacy is borne out in future studies.
Onwards
Unconcerned by the lack of a dose response, in a trial in which both doses failed, Protagonist has big plans for phase 3.
“The intent would be to run towards the study as fast as we can with the 150mg dose,” said Mr Patel on the call. The group will not look for a partner first, but will consider any non-dilutive sources of cash as well as “the regular financing options that may come our way” to fund the new study. It had $305m in cash at the end of last month.
That said, Protagonist clearly plans on partnering or selling PN-946 at some point. “The reality is that this is an asset that … belongs in the hands of a large pharma company,” Mr Patel said. Any interested parties, please make yourselves known.
