Nxera Pharma Co., Ltd. and Cancer Research UK have announced the dosing of the first patient in a Phase 2a clinical trial evaluating HTL0039732 (NXE0039732), a novel oral EP4 antagonist immunotherapy for advanced solid tumors. The milestone follows successful completion of the Phase 1 portion of the trial, which identified a safe and well-tolerated dose of the investigational drug in combination with checkpoint inhibitor atezolizumab.
Phase 1 Results Show Early Promise
The Phase 1 trial enrolled participants with advanced solid tumors that were resistant or refractory to standard therapy. The study demonstrated encouraging early efficacy, including two confirmed partial responses in two distinct tumor types when HTL0039732 was administered in combination with atezolizumab. The trial successfully identified a dose that achieves good engagement of the intended target EP4 without significantly engaging EP2.
Results from the Phase 1 trial will be presented at the European Society for Medical Oncology Congress (ESMO) 2025 in October.
Mechanism of Action and Therapeutic Rationale
HTL0039732 is an oral small molecule drug candidate that blocks signaling through the prostaglandin E2 (PGE2)-type prostanoid receptor 4 (EP4). PGE2 acts in the tumor microenvironment to trigger cancer cells to evade the immune system. By targeting EP4 to block the effects of PGE2, HTL0039732 increases the ability of the immune system to detect and control cancer cells, making it a potential candidate to treat patients with cancers that generally do not respond well to current immunotherapies.
Phase 2a Trial Design and Patient Populations
The Phase 2a trial will expand to four cohorts of patients with specific cancer types:
- Microsatellite stable colorectal cancer (MSS CRC)
- Gastric or gastroesophageal junction (GOJ) adenocarcinoma
- Clear cell renal cell carcinoma
- Metastatic castration-resistant prostate cancer
Cancer Research UK's Centre for Drug Development is sponsoring and managing the trial, which is led by Chief Investigator Dr. Bristi Basu from the University of Cambridge and Co-Chief Investigator Dr. Debashis Sarker from King's College London. The trial's lead site is Addenbrooke's Hospital, Cambridge, with recruitment open across several sites in the Experimental Cancer Medicine Centre (ECMC) network.
Industry Perspectives
Dr. Matt Barnes, Chief Scientific Officer and President of Nxera Pharma UK, stated: "We are proud to reach this important milestone in the development of HTL0039732 and to continue our productive collaboration with Cancer Research UK. The initiation of the Phase 2a trial marks a significant step forward in our efforts to bring this promising drug to patients with difficult-to-treat cancers."
Dr. Bristi Basu, Chief Investigator at the University of Cambridge, commented: "It is exciting to move to the next phase of assessing this new inhibitor of an important receptor EP4, which is implicated in suppression of the antitumor immune response. We hope that by combining it with immunotherapy, we will build on some of the promising early data we have seen in patients treated in the Phase 1 trial."
Dr. Lars Erwig, Director of the Centre for Drug Development at Cancer Research UK, emphasized the collaboration's significance: "The dosing of the first patient in the Phase 2a trial of HTL0039732 is a significant step forward in the Centre for Drug Development's collaboration with Nxera Pharma, which exemplifies the power of partnership in accelerating the development of groundbreaking therapies. The need for novel immunotherapies is more pressing than ever, as many cancers continue to evade current treatments."
Development Partnership and Licensing
Nxera Pharma holds a license to the results generated under the trial to continue the clinical development and commercialization of HTL0039732. The collaboration represents part of Cancer Research UK's broader drug development efforts, which have taken over 170 potential new anti-cancer agents into clinical trials over 30 years, with six agents reaching market including temozolomide for brain cancer, abiraterone for prostate cancer, and rucaparib for ovarian cancer.
