Welireg (belzutifan)

P2, N=322, Recruiting, Merck Sharp & Dohme LLC | N=170 --> 322

P2, N=50, Active, not recruiting, Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Mar 2026 --> Apr 2027 | Trial primary completion date: Mar 2026 --> Apr 2027

The belzutifan treatment effect is large compared with the ECA, supporting belzutifan efficacy in VHL RCC. Although residual confounding is possible, the large effect is unlikely due to chance.

Compared with the HIF-2-selective inhibitors belzutifan and PT2385, dual HIF-1/2 inhibitor 1.21S9N showed superior activity against breast and colorectal cancer models, respectively. PT2385 caused breathing abnormalities, whereas 1.21S9N did not. The drugs are orally bioavailable, and no safety concerns were identified even after extended or supratherapeutic dosing.

P2, N=322, Recruiting, Merck Sharp & Dohme LLC | N=171 --> 322

Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

A slight but measurable improvement in visual acuity was also observed, despite the overall structural stability of the RH. These findings support the potential value of early radiological and functional assessment in selected patients receiving HIF-2α inhibitors.

Resistance to HIF-2α inhibitors such as Belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC)...Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1-STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.

P3, N=758, Not yet recruiting, Merck Sharp & Dohme LLC

P3, N=450, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P3, N=904, Recruiting, Merck Sharp & Dohme LLC

Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003-2025), prioritizing mechanistic and translational studies on hypoxia-HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer.