Kainova bigs up EP4 antagonism

Domain Therapeutics started 2026 by rebranding itself as Kainova, and now it’s trying to gain more traction with investors through a very limited data reveal from a trial of its lead project, the EP4 receptor antagonist DT-9081, in solid tumours.

However, despite this study having ended last July, Kainova is still apparently unable to say anything concrete about the antitumour efficacy DT-9081 might have shown. One possibility, given the track record of other EP4 antagonists, is that DT-9081 is inactive as monotherapy; Kainova won't want to lose momentum, having last month closed a $24m series B financing round.

The financing will in part go towards moving DT-9081 through clinical development, but for now all Kainova was able to say about its phase 1 solid tumour trial is that it showed favourable safety, robust pharmacokinetic data and “early signs of antitumuor activity”.

Combination promise?

If indeed DT-9081 has failed to yield any responses as monotherapy that might not be disastrous, given the logic behind this mechanism. EP4 antagonism is said to reverse PGE2-mediated immunosuppression in the tumour microenvironment, something that seems more ripe for a combination approach to boost anti-PD-(L)1 activity.

Indeed, Kainova says it sees DT-9081’s role as being to improve responses to immune checkpoint blockade. That would fit with the experience of other EP4 antagonist projects on which reported clinical data make for unhappy reading as monotherapy.

At ASCO in 2024 Shanghai Yuyao reported no responses among 14 solid tumour patients given its EP4 contender YY01 in a phase 1 trial. Undeterred, the company heralded the positive safety signals YY01 had shown, and said it would move into phase 2 in combination with immune checkpoint blockade; this has yet to begin, however.

ASCO’s gastrointestinal cancers symposium that year revealed phase 1 data on Ono’s ONO-4578 in combination with Opdivo. Despite the combo approach this could only manage two partial responses among 51 patients with metastatic colorectal cancer.

ASCO 2025 saw data from Rottapharm’s vorbipiprant, in combination with Agenus’s anti-PD-1 MAb balstilimab. There was promising efficacy in PD-L1-high tumours, with three of nine gastric cancer patients responding, though outside gastric cancer, and at lower PD-L1 expression levels, vorbipiprant activity was disappointing.

Then at ESMO came data for NXE0039732 from Nxera, a biotech formerly known as Sosei Heptares. There was no activity seen among 13 patients given monotherapy, while two of 22 subjects given a Tecentriq combo (one with renal cancer and the other with microsatellite-stable colorectal cancer) responded. The first patient in the phase 2 portion of this trial was dosed last September.

And an early study of palupiprant, a molecule licensed by Adlai Nortye from Eisai, showed 20% clinical complete response rate and 16% pathological CR rate in neoadjuvant rectal cancer when combined with chemoradiotherapy, based on which the molecule was taken into the phase 2 Artemis study in this setting.

Clinical-stage projects with activity on EP4

Source: OncologyPipeline.

Artemis was to have yielded data last year, but no results were announced, and Adlai’s latest presentation noted only that the trial was now due to undergo a futility analysis in the current quarter.

There have been other disappointments, with ONO-4578 having previously been licensed to Bristol Myers Squibb, but Bristol giving up on it in 2021. Ikena discontinued grapiprant in a portfolio review the following year. Medibiofarma completed a trial of MBF-362 but hasn’t reported data.

That said, several EP4-inhibiting projects remain in play, including two – Keythera’s KF-0210 and Shenzhen Ionova’s INV-1120 – being combined with PD-(L)1 blockade in phase 1. Notable recent entrants into human studies include Oscotec’s OCT-598, the subject of a collaboration with Kanaph, and Owkin’s OKN4395.