Cancer drug resistance remains one of the most significant unmet needs in modern oncology. The World Health Organization reported approximately 20 million new cancer cases and 9.7 million deaths globally in 2022, a burden that continues to accelerate with population growth and aging. Despite revolutionary advances in immuno-oncology, more than 75% of all cancer patients fail anti-PD-1/PD-L1 immunotherapy. For microsatellite stable (MSS) tumors, including most ovarian, pancreatic, and many other cancers, immunotherapy is not even approved, leaving patients with few or no viable options after standard-of-care failure.

Endothelin B receptor (ETBR) expression is the best-identified predictor of non-response to anti-PD1 drugs. This suggests a key role of the ETBR in anti-PD1 resistance and highlights the importance of ETBR blockade in overcoming resistance. ENB Therapeutics is a clinical-stage oncology company developing ENB-003, the world’s first selective endothelin B receptor (ETBR) inhibitor to reach clinical trials in cancer. ENB-003 overcomes anti-PD1 resistance and restores immune cell access to otherwise immunologically ‘cold’ tumors. ENB-003 overcomes immunotherapy resistance by acting throughout the tumor microenvironment, restoring T-cell and B-cell infiltration, inducing tertiary lymphoid organ (TLO) formation, and blocking ETBR-driven metastasis. It is a small-molecule suitable for subcutaneous or intravenous administration.

Clinical findings to date are highly promising: a completed Phase 1 study with no dose-limiting toxicities across 46 patients; a 40% objective response rate (ORR) and 80% disease control rate (DCR) in microsatellite stable, platinum refractory/ resistant ovarian cancer patients not expected to respond to immunotherapy; and durable responses including a 20-month progression-free survival in a sixth-line patient. The therapy is supported by issued composition of matter and method of use patents through 2039, pharma collaborations with Merck and Coherus, and institutional backing from the MD Anderson Cancer Focus Fund and the Cancer Research Institute.

This expanded evidence summary draws on peer-reviewed literature to contextualise ENB-003’s clinical significance within the global landscape of unmet need. HITLAB has evaluated the available clinical, scientific, and patient-centric evidence and concludes that ENB-003 represents an emerging and highly promising direction in oncology innovation, one that addresses a fundamental and so-far unsolved barrier to effective cancer immunotherapy.