Protagonist Verifies Takeda’s interest

Around a year ago Takeda took a punt on Protagonist Therapeutics’ hepcidin mimetic rusfertide ahead of a key phase 3 readout – and now that trial has come in positive. The partners released topline data on Monday from the Verify trial, testing rusfertide in patients with polycythemia vera not well controlled by standard of care, including phlebotomy.

The study met its primary endpoint, showing a 77% response rate in the rusfertide arm versus 33% with control. Still, the companies will not be filing until the fourth quarter, with Protagonist noting during a conference call that 52-week data were needed to submit rusfertide to the FDA, though apparently there is "no particular bar" to hit in terms of durability.

Takeda paid $300m up front to license rusfertide, and Protagonist will earn another $25m milestone on the Verify results. The partners have estimated that the asset could make peak sales of $2bn, and Protagonist execs hinted that this figure might be raised given the latest results. “I can almost guarantee there will be no downward guidance,” said its chief executive, Dinesh Patel.

This appeared to scotch doubts about rusfertide’s potential market, raised when recruitment into Verify was delayed, initially from the first half to the second half of 2023, then until the first quarter of 2024, before Takeda finally confirmed full enrolment in October 2024.

Any lingering questions here could help explain why Protagonist rose just 4% on the news, although the company’s valuation also looks relatively rich, at $2.5bn.

Polycythemia vera, which is thought to affect around 100,000 US patients, involves the overproduction of red blood cells. Treatment includes phlebotomy (blood removal) and cytoreductive agents like hydroxyurea, interferon and Novartis/Incyte’s Jakafi.

By mimicking hepcidin, the primary regulator of iron homeostasis, rusfertide is designed to reduce red blood cell production. According to OncologyPipeline there are no other hepcidin mimetics in active clinical development. Protagonist also plans to nominate a new oral hepcidin candidate by the end of this year.

Placebo response

One curious finding from Verify is a higher than expected placebo response, at 33%. In the study response was defined as no phlebotomy, or phlebotomy eligibility between weeks 20 and 32, and completion of weeks 0-32 – with the latter also encompassing a dose-titration period.

Previously, the phase 2 Revive study found response rates of 60% and 17% with rusfertide and placebo respectively. Protagonist said this difference could be explained by a shift from a smaller, US-centric phase 2 to a larger and longer global phase 3 with greater patient heterogeneity, including those at an earlier stage of disease.

In any case the reason seems academic, as Verify still hit its primary endpoint.

Verify also prevailed on a key secondary, phlebotomy rate, the preferred endpoint for EU regulators. The mean number of phlebotomies per patient was 0.5 with rusfertide, versus 1.8 with control during weeks 0-32 (p<0.0001). And 73% of patients receiving rusfertide received no phlebotomies before week 32, compared with 22% with control.

Protagonist and Takeda also said the study hit other secondary endpoints, including haematocrit control and patient-reported outcomes, although the partners are saving these data for an upcoming medical meeting.

On safety, the companies said rusfertide was generally well tolerated with no new safety findings, adding that there was no evidence of an increased cancer risk. Cancer concerns were previously raised, including animal data that led to a clinical hold.

Protagonist appears to be positioning rusfertide as an intermediate-stage therapy for polycythemia vera, suggesting that it could fit between phlebotomy and Jakafi, which tends to be used in more advanced patients, the company noted.

Under the Takeda deal Protagonist can choose to opt out of a 50/50 profit share, and is due to make a decision by mid-2026.