However, additional research is required to sustain HIF-1α inhibition while maintaining anticancer activity. The FDA approval of Belzutifan provided researchers with an opportunity to conduct broader HIF-2 studies.

The LITESPARK-005 trial reported the benefit of belzutifan in progression-free survival (PFS) compared to everolimus in later lines of treatment, with improvement in quality-of-life outcomes. Given its different mechanism of action to currently available treatments, belzutifan is expected to play a prominent role in the treatment of clear cell renal carcinoma and other cancers.

P2, N=322, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Feb 2027 --> Jun 2029 | Trial primary completion date: Feb 2027 --> Jun 2029

P=N/A, N=0, Withdrawn, Merck Sharp & Dohme LLC | N=100 --> 0 | Trial completion date: May 2029 --> Dec 2030 | Initiation date: Jan 2025 --> Jun 2024 | Not yet recruiting --> Withdrawn | Trial primary completion date: May 2027 --> Dec 2030

P1, N=52, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jul 2025 --> Jul 2026

The phase 3 clinical trial LITESPARK-005-belzutifan (HIF-2α inhibitor) demonstrated improvement in progression-free survival compared with everolimus in heavily pretreated patients unselected for somatic/germline VHL alterations (an objective response rate of 23% and a median time on therapy of 7.6 months in the belzutifan cohort), resulting in U.S. FDA approval for patients with advanced RCC. Both patients had an excellent clinical response (partial remissions ongoing at >12 and >20 months). Future studies should assess the merits of biomarker selection for belzutifan treatment.

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

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

P2, N=172, Active, not recruiting, NiKang Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Sep 2026 --> Jun 2026 | Trial primary completion date: Jun 2026 --> Jun 2025

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.

P1/2, N=128, Active, not recruiting, NiKang Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2024 --> May 2025

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.

Furthermore, Se-Met alleviated heat-induced activation of p-p38MAPK/p38MAPK (HE-C vs. HE-S: 1.79-fold, p < 0.05) and p-HSPB1/HSPB1 (HE-C vs. HE-S: 2.72-fold, p < 0.05). In conclusion, p38MAPK/HSPB1 might be involved in Se-Met-mediated alleviation of heat-induced cell apoptosis, cell viability and testosterone secretion impairments in sheep LCs.

The structure of the mitochondria, mRNA, protein expression levels, and the content of proinflammatory factors in mice from the FParkin-/- and F + SeMetParkin-/- groups closely resembled those in the F + SeMetWT group. Overall, the above results indicated that SeMet could alleviate fluoride-triggered inflammation and apoptosis in mice liver via blocking Parkin-mediated mitophagy.

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

P1, N=60, Recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd.

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.

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

The control diet was a basal diet added with: 0.2 mg/kg Sodium Selenite (SS-control), 0.2 mg/kg Selenium nano-particles (Nano-Se), 0.2 mg/kg Selenomethionine (SeMet), and 0.2 mg/kg Selenocysteine (Sec) as the treatments...In conclusion, our study demonstrated that Nano-Se and SeMet are better at improving the intestinal health of 21-day-old broilers. Additionally, Nano-Se demonstrated superior antioxidant and anti-inflammatory effects, promoting the development of intestinal goblet cells by modifying the NLRP3 signaling pathway.

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

The INC comprised a diverse array of additives, including water-soluble and fat-soluble vitamins, Selenomethionine, and active dry Saccharomyces cerevisiae...Results indicate that supplementation with INC in peripartum dairy cows could be a major strategy to improve immune response, decrease inflammation, maintain antioxidant stress status in transition dairy cows, and have merit in their calves. In conclusion, this study underlines the benefits of INC supplementation during the transition period, as it improved anti-inflammatory capacity, could positively impact antioxidative stress capacity, and eventually enhanced the production performance of dairy cows and the health and growth of calves.

NASeLM could clearly increase caspase-3 activity in both cell types, Jurkat or MTC-SK cells, and thus induce cell death. NALM and NASeLM showed a reduction in cell growth and mitochondrial activity in both cell lines: While NALM and NASeLM showed almost identical measurements on Jurkat cells, NASeLM was much more effective on MTC-SK than the non-selenium-containing carrier, indicating that it has additional anti-chemoprotective effects.

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

Using a redox-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we show that both selenoamino acids shifted the ER redox balance towards an even more oxidizing environment. These results suggest that alteration of the redox state of the ER may disrupt protein folding and cause ER stress-induced apoptosis in MCF-10A cells exposed to selenoamino acids.

P1, N=56, Active, not recruiting, University of Auckland, New Zealand | Trial completion date: Mar 2024 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

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