Palupiprant (AN0025)

Palupiprant, also known as AN0025 (Eisai code E7046), is an oral small-molecule EP4 receptor antagonist that Adlai Nortye licensed from Eisai in May 2018 [1]. The linked trial NCT04432857 is a Phase Ib basket study of palupiprant plus Merck's pembrolizumab in advanced solid tumors (bladder, breast, colorectal, endometrial, non-small cell lung cancer), on the theory that blocking EP4 signaling will rescue cancers that do not respond to checkpoint inhibitors alone [2]. In parallel, Adlai Nortye is running the ARTEMIS Phase II study of AN0025 plus chemoradiation in locally advanced rectal cancer, with a futility analysis expected by Q1 2026 [3]. The class - EP4 antagonists as immune-oncology adjuvants - has solid preclinical rationale but a thin clinical record. Bristol Myers Squibb / Ono (BMS-986310/ONO-4578) and Rottapharm Biotech (vorbipiprant/CR6086) have run EP4-antagonist combination trials with PD-1 inhibitors over the past several years without producing a registration-quality dataset [4][5]. For Adlai Nortye, palupiprant is one of several immune-oncology assets and recent investor communications continue to feature it but do not flag a near-term registrational path.

Novel compound. Never approved anywhere. Eisai discovered the molecule as E7046 and completed two early-phase studies before out-licensing: a first-in-human Phase 1 in advanced cancers (NCT02540291) and a Phase 1b combination with radiotherapy or chemoradiotherapy in locally advanced rectal cancer (NCT03152370) [6][7]. Eisai out-licensed the program to Adlai Nortye in 2018 (deal terms have not been publicly disclosed in detail), and Adlai Nortye renamed it AN0025 [1]. The active development footprint today is two trials: the linked Phase Ib basket with pembrolizumab (NCT04432857) [2], and the ARTEMIS Phase 2 study in locally advanced rectal cancer with chemoradiation, with futility analysis expected Q1 2026 [3]. ChEMBL records a Phase 2 maximum stage across the broader development history; structured_data.phase is set to 1 to reflect the linked trial (NCT04432857 is Phase Ib dose escalation/expansion), not the parallel ARTEMIS Phase 2. No FDA breakthrough therapy, fast track, orphan drug, or accelerated approval designations have been disclosed. Expected next readout: ARTEMIS futility analysis Q1 2026 [3]; no public guidance on the pembrolizumab basket. The molecule's commercial trajectory depends on Adlai Nortye choosing to fund a registrational program, which would require a Phase 2 efficacy signal it has not yet publicly delivered.

PGE2 (prostaglandin E2) is a lipid signaling molecule that tumors produce in large amounts. Cancer cells turn on COX-2, the same enzyme that ibuprofen blocks, and pump PGE2 into the tumor microenvironment, where it does several unhelpful things. PGE2 binds the EP4 receptor (gene PTGER4, UniProt P35408) [8] on immune cells and tells them to back off. Myeloid-derived suppressor cells and tumor-associated macrophages expand and become more immunosuppressive; cytotoxic T cells, the ones that would otherwise kill tumor cells, become exhausted and less infiltrative [9]. The net effect: the tumor turns into a friendly zone for cancer rather than a hostile one. Blocking EP4 with palupiprant should remove this brake on anti-tumor immunity. The biological case is solid, supported by EP4 knockout mice with stronger anti-tumor T-cell responses and preclinical combination studies showing EP4 antagonism plus PD-1 blockade work better than either alone [9]. The clinical case is thinner. Multiple EP4 antagonists have entered solid-tumor trials over the past decade - Bristol Myers Squibb/Ono's BMS-986310 (ONO-4578) [4], Eisai's own E7046 [6], and Rottapharm Biotech's vorbipiprant (CR6086) [5] - without producing a registrational efficacy signal. Grapiprant, the only marketed EP4 antagonist, treats osteoarthritis in dogs. Useful for the animal-health market, but a long way from oncology.

NCT04432857 is an open-label, multicenter, single-arm Phase Ib study of palupiprant plus pembrolizumab in patients with locally advanced or metastatic solid tumors [2]. The therapeutic areas covered (bladder, breast, colorectal, endometrial, non-small cell lung cancer) indicate a basket design enrolling patients across cancer types. Primary endpoints are safety, tolerability, and recommended Phase 2 dose; secondary endpoints include objective response rate (ORR) and disease control rate. No comparator arm. No head-to-head against pembrolizumab monotherapy. The design is appropriate for a first-look Phase Ib, but the absence of biomarker selection limits what the data can tell you. EP4 signaling matters differently across these tumor types, and PGE2 levels, COX-2 expression, and MDSC infiltration are not being used to select patients. A positive overall response could be diluted by tumor types where the mechanism does not apply, and a null result is hard to interpret. Enrollment was projected around 150 patients; current recruitment status is not publicly tracked in detail, and Adlai Nortye has not provided recent enrollment updates. Prior clinical proof-of-concept for the molecule comes from the Eisai-era studies: the first-in-human Phase 1 in advanced cancers reported manageable tolerability with best response of stable disease (≥18 weeks) in several heavily pretreated patients - no objective responses [6]. The E7046 + radiotherapy/chemoradiotherapy Phase 1b in locally advanced rectal cancer (NCT03152370) was reported as well tolerated with encouraging preliminary efficacy at ESMO 2019, and motivated the ongoing ARTEMIS Phase 2 [7][3]. Without a single-indication expansion in NCT04432857 showing ORR above checkpoint monotherapy in a defined population, the basket trial alone will not move palupiprant toward registration.

Our model puts this drug's chance of eventual approval at 9%. That figure starts from the historical approval rate for Phase 2 drugs in this area - about 13% - then adjusts based on ten facts about the trial and its sponsor. The estimate is nudged up by the trial's non-randomized design and open-label setup, but pulled down by the sponsor's thin approval track record and weak earlier-phase results. The remaining factors land close to average, so they leave the final number near where the base rate started.

Efficacy risk dominates. The class has not delivered. BMS-986310/ONO-4578 ran a monotherapy and nivolumab-combination Phase 1/1b in advanced solid tumors (NCT03155061, NCT03661632); both have completed without an announced key next step [4]. Rottapharm's vorbipiprant + balstilimab Phase Ib/IIa in chemorefractory MSS metastatic colorectal cancer was published in Clinical Cancer Research in 2025: well tolerated, but median progression-free survival was only 2 months, with no breakout ORR signal that would justify a Phase 3 on its own [5]. Possible explanations: PGE2-EP4 signaling is one of many immunosuppressive pathways in tumors, and blocking it alone is not enough; or current trials enroll patients where this pathway is not load-bearing. A basket design in unselected solid tumors is unlikely to find a signal that earlier studies missed. Safety risk is moderate. EP4 receptors regulate renal hemodynamics, intestinal transport, and uterine function, so systemic blockade can produce GI side effects, fluid retention, and dose-limiting toxicity [8]. Eisai's prior Phase 1 work with E7046 reported manageable tolerability at therapeutic doses with no objective responses [6], and the rectal cancer Phase 1b was well tolerated in combination with radiation [7], but a larger pembrolizumab-combination dataset will test this more thoroughly. Execution risk is real. Adlai Nortye reported US$44.1 million in cash and cash equivalents at June 30, 2025, down from US$60.9 million at year-end 2024, with a US$18.3 million H1 2025 net loss; R&D spending was cut 41.4% year-on-year [11]. At the current burn rate the company has roughly 12 months of runway without new financing, partnership inflows, or further R&D cuts - palupiprant is not its only program (AN4005 oral PD-L1, AN8025, AN9025 pan-RAS, AN4035 ADC are also in development), and the pembrolizumab basket could be deprioritized or out-licensed. Commercial risk: even with approval, palupiprant plus pembrolizumab would need to clearly beat pembrolizumab alone (or pembrolizumab plus chemotherapy) to win payer coverage, and the bar is high in indications where checkpoint inhibitors already work.

Watch but do not lean in. Palupiprant is the right kind of biological hypothesis (EP4 blockade should make tumors more visible to the immune system) but it sits in a class with a poor clinical conversion record and inside a small sponsor with limited resources to push it through. The single data point that would change the picture: a specific indication cohort showing ORR meaningfully above what pembrolizumab delivers on its own. Pembrolizumab monotherapy ORR baselines for the basket indications anchor the bar: ~45% in first-line non-small cell lung cancer with PD-L1 tumor proportion score ≥50% (KEYNOTE-024); ~21% in second-line urothelial bladder cancer (KEYNOTE-045); ~21% in PD-L1+ triple-negative breast cancer monotherapy (KEYNOTE-119); ~44% in microsatellite-instability-high (MSI-H) colorectal cancer (KEYNOTE-177) but essentially 0-2% in microsatellite-stable (MSS) colorectal cancer; and ~50%+ in MSI-H endometrial cancer with much lower activity in MSS endometrial disease. A 30%+ ORR in MSS colorectal disease or in non-PD-L1-high NSCLC would be a real signal; the same 30% in PD-L1-high NSCLC would not be. For colorectal cancer in particular - where MSS tumors make up roughly 85% of cases and do not respond to checkpoint inhibitors - a positive signal in MSS would be genuinely interesting and would justify a serious follow-up trial. The vorbipiprant Phase Ib/IIa in MSS mCRC set a reference: well tolerated but median PFS of only 2 months, so palupiprant needs to clear that bar [5]. Check back at the ARTEMIS Q1 2026 futility analysis [3] and within 12 to 18 months for any pembrolizumab-basket cohort readout from NCT04432857. Either Adlai Nortye reports data, at which point the signal is either there or it is not, or the program goes quiet, which is itself a signal. Watch for any Adlai Nortye press release tagged AN0025 or palupiprant, any abstract submitted to ASCO or ESMO with the trial number, and any indication of partnership or out-licensing. Adlai Nortye trades on the Hong Kong exchange as 9606.HK and on Nasdaq as ANL; meaningful pipeline disclosures usually appear in their interim and annual results [11].