casdatifan (AB521)

P3, N=1116, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1, N=14, Completed, Arcus Biosciences, Inc. | Active, not recruiting --> Completed

P3, N=720, Recruiting, Arcus Biosciences, Inc. | Not yet recruiting --> Recruiting

P1, N=14, Active, not recruiting, Arcus Biosciences, Inc. | Recruiting --> Active, not recruiting

P3, N=1116, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

Casdatifan, after single and multiple dosing in healthy participants, was safe and tolerable. Linear PK was associated with a mean maximum erythropoietin reduction of 85% following a single dose and multiple doses of casdatifan, demonstrating a promising exposure-biological activity profile.

We discuss the major key inhibitors, with focus on belzutifan and review the various trials investigating its efficacy in monotherapy as well as in combination therapies in RCC...We also highlight emerging HIF-2α inhibitors currently in clinical trials, namely casdatifan, NKT-2152, and DFF332. Finally, we address the major toxicities and management of these inhibitors.

P1, N=25, Terminated, Exelixis | Phase classification: P1/2 --> P1 | Trial completion date: Jan 2027 --> May 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2026 --> May 2025; The study was terminated prior to starting the Phase 2 portion due to a business decision.

P3, N=720, Not yet recruiting, Arcus Biosciences, Inc.

P3, N=1116, Not yet recruiting, AstraZeneca

AB521 is a potent, selective and orally bioavailable HIF-2α inhibitor, with favourable pharmacological properties, that is being explored clinically for the treatment of ccRCC.

HIF-2α inhibition represents a breakthrough in targeting the fundamental pathobiology of clear cell RCC, with belzutifan demonstrating significant clinical benefit in both von Hippel-Lindau disease and sporadic RCC...ADCs have become a cornerstone of UC treatment, with enfortumab vedotin plus pembrolizumab now approved as first-line therapy. Multiple human epidermal growth factor receptor 2 (HER2)-directed ADCs have shown efficacy in HER2-expressing UC, including trastuzumab deruxtecan, which recently received tumor-agnostic approval. While ADC development in RCC faces unique challenges, novel approaches including immunostimulatory payloads and bispecific antibodies are being explored. The integration of these advances in molecular imaging and therapeutics offers opportunities for more personalized treatment approaches in RCC and UC.