Welireg (belzutifan)

P2, N=32, Not yet recruiting, Dana-Farber Cancer Institute

P2, N=120, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.

No abstract available

These include the treatment of ADPKD with Tolvaptan, which has now been in use for 10 years. Recently, exciting, and completely new approaches have been added, such as the first siRNA therapies in nephrology for primary hyperoxaluria type 1, the targeted treatment of hyperphagia in Bardet-Biedl syndrome, the therapy of APOL1-associated kidney disease or the use of the HIF-2 antagonist Belzutifan for renal cell carcinoma associated with Von-Hippel-Lindau syndrome...This also applies to the further training of colleagues in the field. In Germany, the National Action Alliance for People with Rare Diseases (NAMSE) and the nationwide establishment of - to date - 36 centers for rare diseases play an important role in this regard.

Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.

Four patients experienced grade 1-2 anemia and two patients required a dose reduction. Our report suggests that belzutifan can be an effective therapy for pediatric, adolescent, and young adult patients with VHL-associated hemangioblastomas.

In response to these challenges, a hypoxia-responsive polymer (Poly(4,4'-azobisbenzenemethanol-PMDA)-mPEG5k, P-APm) encapsulating both a HIF-2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF...Moreover, this treatment effectively transforms the immunosuppressive microenvironment from "immune-cold" to "immune-hot", thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC.

P2, N=120, Not yet recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Jan 2027 --> May 2027

In a heavily pretreated cohort of patients with sporadic, metastatic ccRCC, belzutifan had meaningful clinical activity and was well tolerated. These real-world results add to the results of LITESPARK-005 and support the use of belzutifan after progression on ICT and VEGFR-TKIs.

Further analysis via ensemble machine learning uncovered important and distinct interchain residue interactions modified by G323E and pT324. These findings reveal a molecular mechanism of G323E-induced drug resistance and suggest that pT324 may also affect the efficacy of HIF-2 drug binding interactions via allosteric effects.

The efficacy of belzutifan was similar between the 120-mg dose and the 200-mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

The drug belzutifan shows great promise for controlling RHs and preventing vision loss in patients with VHL. Further work needs to address the optimal dose, role of the drug as a neoadjuvant therapy, and long-term efficacy and tolerability of the drug in a larger cohort of patients with ocular tumors.

P=N/A, N=100, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=120, Not yet recruiting, Merck Sharp & Dohme LLC | Trial completion date: May 2028 --> Sep 2028 | Trial primary completion date: Jun 2027 --> Jan 2027

Results indicate that Belzutifan effectively stabilizes disease, reduces tumor progression, and achieves significant therapeutic responses, although side effects like anemia and fatigue were noted.

The case was notable for reporting a not-yet described adverse event during treatment with belzutifan plus lenvatinib, the etiology of which was of unobvious determination given the pre-exposure to pembrolizumab, a known cause of drug-related myocarditis. We surmise that myocarditis was a delayed adverse event related to pembrolizumab (8 months after treatment interruption), although we emphasize that only attentive monitoring of cardiac adverse events of patients exposed to belzutifan and lenvatinib in the context of large clinical trials may rule out any causal implication of these drugs.

P1/2, N=180, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Mar 2027 --> Sep 2028 | Trial primary completion date: Mar 2027 --> Sep 2028

One of the most common adverse effect of this drug is anemia; however, it is treatment is not well known. This review summarizes role of the VHL-HIF pathway in ccRCC aroused the interest of targeting HIF activity, the history of belzutifan development and their relationship to anemia as well as propose a management algorithm.

P3, N=708, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Dec 2024 --> Feb 2026 | Trial primary completion date: Dec 2024 --> Feb 2026

P3, N=755, Active, not recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Sep 2025 --> Apr 2024

P3, N=249, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2027 --> Dec 2026 | Trial primary completion date: Jun 2027 --> Dec 2026

Analyses of PDB holdings, the scientific literature, and related documents for each drug-target combination revealed that the impact of structural biologists and public-domain 3D biostructure data was broad and substantial, ranging from understanding target biology (100% of all drug targets), to identifying a given target as likely druggable (100% of all targets), to structure-guided drug discovery (>80% of all new small-molecule drugs, made up of 50% confirmed and >30% probable cases). In addition to aggregate impact assessments, illustrative case studies are presented for six first-in-class small-molecule anti-cancer drugs, including a selective inhibitor of nuclear export targeting Exportin 1 (selinexor, Xpovio), an ATP-competitive CSF-1R receptor tyrosine kinase inhibitor (pexidartinib,Turalia), a non-ATP-competitive inhibitor of the BCR-Abl fusion protein targeting the myristoyl binding pocket within the kinase catalytic domain of Abl (asciminib, Scemblix), a covalently-acting G12C KRAS inhibitor (sotorasib, Lumakras or Lumykras), an EZH2 methyltransferase inhibitor (tazemostat, Tazverik), and an agent targeting the basic-Helix-Loop-Helix transcription factor HIF-2α (belzutifan, Welireg).

P1, N=110, Active, not recruiting, Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Nov 2024 --> Nov 2026

Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for >2 years while on treatment.

P2, N=120, Not yet recruiting, Merck Sharp & Dohme LLC

Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

P2, N=730, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Aug 2026 --> Mar 2027 | Trial primary completion date: Aug 2026 --> Mar 2027

P1, N=14, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P3, N=1800, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

Several clinical trials are currently ongoing, which should help in identifying this promising drug's role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.

P1/2, N=400, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

When the tumors have metastasized, systemic therapy with protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, and tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, and stem cell factor growth factor receptors (VEGFR, PDGFR, FGFR, MET, and Kit) were prescribed after 2005. The monoclonal antibody immune checkpoint inhibitor nivolumab (targeting PD1) was approved for the treatment of RCCs in 2015. It is usually used now in combination with ipilimumab (targeting CTLA-4) or cabozantinib (a multikinase blocker). Other combination therapies include pembrolizumab (targeting programed cell death protein 1) and axitinib (a VEGFR and PDGFR blocker) or lenvatinib (a multikinase inhibitor). Since the KEYNOTE-426 clinical trial, the use of immune checkpoint inhibitors in combination with protein-tyrosine kinase inhibitors is now the standard of care for most patients with metastatic renal cell carcinomas and monotherapies are used only in those individuals who cannot receive or tolerate immune checkpoint inhibitors.

P1, N=14, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P2, N=0, Withdrawn, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=30 --> 0 | Not yet recruiting --> Withdrawn

P3, N=249, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1, N=80, Recruiting, HiberCell, Inc. | Not yet recruiting --> Recruiting

P3, N=1653, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs...MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Separation of diastereomeric mixtures at two different stages of the synthesis proved advantageous in ease of separation. The X-ray structure of belzutifan was determined.

In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.