RegulationPriority Review (US), Breakthrough Therapy (US), Orphan Drug (US), Priority Review (CN), Orphan Drug (KR), Orphan Drug (AU), Conditional marketing approval (EU)

Structure/Sequence

Molecular FormulaC17H12F3NO4S

InChIKeyLOMMPXLFBTZENJ-ZACQAIPSSA-N

CAS Registry1672668-24-4

Clinical Trials associated with Belzutifan

NCT06677190

/ RecruitingPhase 2IIT

A Phase II Trial of Belzutifan in Patients with Recurrent or Persistent Clear Cell Carcinoma of the Ovary

The purpose of this research study is to see if the study drug Belzutifan is effective and safe for participants with ovarian cancer.
The name of the study drug involved in this study is:
- Belzutifan (a type of Hypoxia-Inducible Factor-2 alpha (HIF-2a) inhibitor)

Start Date01 Dec 2024

Sponsor / Collaborator

Dana-Farber Cancer Institute, Inc.

[+1]

NCT06428396

/ RecruitingPhase 2

A Phase 2, Randomized, Active-controlled, Open-label, Multicenter Study of Belzutifan Plus Fulvestrant in Participants With Estrogen Receptor Positive, HER2 Negative Unresectable Locally Advanced or Metastic Breast Cancer After Progression on Previous Endocrine Therapy (LITESPARK-029)

The purpose of this study is to assess the efficacy and safety of belzutifan (MK-6482) plus fulvestrant compared to everolimus plus endocrine therapy (ET) (investigator's choice of fulvestrant or exemestane) in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) unresectable metastatic breast cancer. There is no formal hypothesis testing in this study.

Start Date27 Nov 2024

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT06554730

/ WithdrawnNot Applicable

Non-interventional Post-authorization Study of Belzutifan in Adult Patients With Von Hippel-Lindau Disease-associated Renal Cell Carcinoma, Pancreatic Neuroendocrine Tumor and/or Central Nervous System Hemangioblastoma (MK-6482-026)

This is a prospective observational cohort study evaluating the effectiveness and safety of belzutifan treatment in routine clinical practice.
This study has been registered and will be maintained through close out on the RWD Catalogues Observational Registry - https://catalogues.ema.europa.eu/ under the EU PAS number:
EUPAS108114

Start Date30 Jun 2024

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Belzutifan

100 Translational Medicine associated with Belzutifan

100 Patents (Medical) associated with Belzutifan

165

Literatures (Medical) associated with Belzutifan

05 Feb 2025·ACS Applied Materials & Interfaces

Sustained Release of HIF-2α Inhibitors Using Biodegradable Porous Silicon Carriers for Enhanced Immunogenic Cell Death of Malignant Merkel Cell Carcinoma

Article

Author: Kim, Minju ; Yoo, Jounghyun ; Seong, Juyoung ; Mack, David L. ; Lee, Jung Hyun ; Joo, Jinmyoung

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with limited treatment options, often associated with Merkel cell polyomavirus (MCPyV) and marked by hypoxic tumor microenvironments that promote resistance to therapies. Belzutifan, an FDA-approved hypoxia-inducible factor-2α (HIF-2α) inhibitor, has shown promise in inhibiting tumor growth; however, its clinical efficacy is hindered by its low solubility, rapid clearance, and limited bioavailability. In this study, we present a strategy using porous silicon (pSi) microparticles and nanoparticles as carriers for the sustained delivery of benzoate to MCC cells. The pSi carriers were engineered to securely encapsulate and gradually release belzutifan, overcoming the limitations of free drug administration. Microparticles provided sustained extracellular release, while nanoparticles enabled efficient intracellular delivery, enhancing HIF-2α inhibition. Moreover, the use of biodegradable silicon particles enables long-term consistent release of belzutifan over 10 days in vitro with a single dose administration in the tumor microenvironment, while free belzutifan is rapidly deactivated within 1 day postadministration. In vitro studies demonstrated significant immunogenic cell death (ICD) in MCC cells, marked by the cytosolic localization of HMGB1 and elevated expression of pro-inflammatory cytokines as well as strong upregulation of TLR9. Particularly, the increased TLR9 expression in both MCC cell lines with pSi carrier treatment reinforces immune activation through toll-like receptor signaling, enhancing both innate and adaptive immune responses within the tumor microenvironment. These findings indicate that pSi carriers not only enhance belzutifan's stability and release profile but also amplify antitumor immune responses within the tumor microenvironment. Our results suggest that belzutifan-loaded pSi carriers offer a potent and targeted therapeutic strategy for MCC, potentially addressing key challenges in cancer immunotherapy by combining HIF-2α inhibition with robust immune activation. This platform highlights the universal utility of pSi-based delivery systems to advance MCC treatment with implications for broader cancer therapies.

01 Feb 2025·Expert Review of Clinical Pharmacology

Targeting HIF-2α: the role of belzutifan in clear cell renal carcinoma management

Review

Author: Rojas, Carlos ; González-Montero, Jaime ; Valdés, Alejandro ; Burotto, Mauricio ; Pizarro, Gonzalo

INTRODUCTION:

Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. It targets the von Hippel-Lindau protein (pVHL)-HIF-vascular endothelial growth factor (VEGF) pathway, which is crucial in cellular responses to hypoxia. By inhibiting HIF-2α, belzutifan disrupts the transcription of genes involved in tumor growth and angiogenesis.

AREAS COVERED:

In this review, we describe the pVHL-HIF-VEGF pathway and how it led to the development of HIF inhibitors, including belzutifan. A search was conducted for trials involving Belzutifan, including phase I-III trials. We describe the relevant toxicity, with emphasis on hypoxia and anemia.

EXPERT OPINION:

Belzutifan is a relatively safe drug, with manageable adverse events, including anemia and hypoxia as on-target toxicity. Ongoing trials are studying its benefit in overall survival for RCC in first-line treatment and its potential in other malignancies. 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.

06 Jan 2025·CURRENT CANCER DRUG TARGETS

The Clinical Role of Hypoxia Inducible Factor (HIF) Inhibition in Renal Cancer: A Focus on Belzutifan

Article

Author: Ciccarese, Chiara ; Iacovelli, Roberto ; Strusi, Alessandro ; Beccia, Viria ; Scala, Alessandro ; Pedone, Romina Rose ; Sardaro, Valeria ; Arduini, Daniela ; Tortora, Giampaolo

Systemic therapy for metastatic Renal Cell Carcinoma (mRCC) has dramatical-ly improved in the last years because of the use of immunotherapy with checkpoint inhibi-tor combinations with or without targeted therapies against the Vascular Endothelial Growth Factor Receptors (VEGFR). As a result, patients with mRCC have prolonged sur-vival time, but they ultimately develop resistance and the disease progresses, which high-lights the critical need for novel treatment options. The Hypoxia-inducible Factor (HIF) pathway is central to the pathophysiology of ccRCC and von Hippel-Lindau (VHL) disease. As part of the VHL-HIF-VEGF axis, the HIF-2α inhibition has been identified as a rationale target for mRCC treatment. Indeed, one such agent called belzutifan is already approved for VHL-associated RCC and other VHL-associated neoplasms, and a series of trials have indicated encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan into the mRCC treatment armamentarium either as a single agent or as combination therapy could cover the lack of therapeutic options as well as the need for a new combination in mRCC; therefore, this drug has the potential to be largely used in mRCC. In this review, we have recapitulated the clinical data supporting the use of belzutifan in mRCC as monotherapy and the background for combination with other agents as well as its safety profile.

News (Medical) associated with Belzutifan

19 Feb 2025

·pipelinereview.com

WELIREG® (belzutifan) Receives First European Commission Approval for Two Indications

WELIREG is the first and only oral hypoxia-inducible factor-2 alpha inhibitor approved in the European Union RAHWAY, NJ, USA I February 18, 2025 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the European Commission (EC) has conditionally approved WELIREG ® (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, as monotherapy for: The EC approval of these two indications is based on results from the LITESPARK-004 and LITESPARK-005 trials, respectively, and follows the positive recommendation from the Committee for Medicinal Products for Human Use adopted in December 2024 . This marks the first approval for WELIREG in the European Union (EU). WELIREG is now approved in over 30 countries for certain adult patients with previously treated advanced RCC and in more than 40 countries for adult patients with certain eligible VHL disease-associated tumors. “The approval of WELIREG in the EU introduces the first and only systemic treatment option for adult patients with certain VHL disease-associated tumors for whom localized procedures are unsuitable, and offers a new option for adult patients with advanced clear cell renal cell carcinoma that progressed following a PD-1 or PD-L1 inhibitor and at least two VEGF targeted therapies,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “This is an important moment, and we are pleased that WELIREG, a first-in-class HIF-2α inhibitor, can now potentially help these patients in need.” This approval allows marketing of WELIREG for these indications in all 27 EU member states, as well as Iceland, Liechtenstein and Norway. The conditional approval of WELIREG will be valid for one year, subject to yearly renewal, pending additional clinical data from LITESPARK-004 and another ongoing Phase 2 trial of WELIREG in patients with certain VHL disease-associated tumors. Timing for commercial availability of WELIREG in individual EU countries will depend on multiple factors, including the completion of national reimbursement procedures. Results in Patients With Certain Eligible VHL Disease-associated Tumors (LITESPARK-004) WELIREG is now the first and only systemic therapy for the treatment of VHL disease-associated tumors in the EU. The approval in adult patients with certain eligible VHL disease-associated tumors is based on objective response rate (ORR) and duration of response (DOR) results from the LITESPARK-004 trial. WELIREG was approved in the U.S. in August 2021 for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas or pNET not requiring immediate surgery based on the results from LITESPARK-004. In patients with VHL disease-associated RCC (n=61), WELIREG showed an ORR of 49% (95% CI, 36-62) (n=30/61); all responses were partial responses (PR). Median DOR for these patients was not reached, with ongoing responses ranging from 2.8+ to 22+ months; among responders, 56% (n=17/30) maintained a response for at least 12 months. Among these 61 patients, the study also evaluated response rates in other common disease-associated tumors including CNS hemangioblastomas and pNET. In patients with VHL disease-associated CNS hemangioblastomas (n=24) in this trial, WELIREG showed an ORR of 63% (95% CI, 41-81) (n=15/24), with a complete response (CR) rate of 4% (n=1/24) and a PR rate of 58% (n=14/24). Median DOR for these patients was not reached, with ongoing responses ranging from 3.7+ to 22+ months; among responders, 73% (n=11/15) maintained a response for at least 12 months. In patients with VHL disease-associated pNET (n=12) in this trial, WELIREG showed an ORR of 83% (95% CI, 52-98) (n=10/12), with a CR rate of 17% (n=2/12) and a PR rate of 67% (n=8/12). Median DOR for these patients was not reached, with ongoing responses ranging from 11+ to 19+ months; among responders, 50% (n=5/10) maintained a response for at least 12 months. Results in Certain Patients With Previously Treated Advanced RCC (LITESPARK-005) The approval in adult patients with advanced clear cell RCC that progressed following two or more lines of therapy, including a PD-1 or PD-L1 inhibitor and at least two VEGF targeted therapies, is based on progression-free survival (PFS) and ORR results from the LITESPARK-005 trial, which was the first trial in advanced RCC to specifically evaluate patients who progressed following these treatments. WELIREG was approved in the U.S. in December 2023 for the treatment of adult patients with advanced RCC following both a PD-1 or PD-L1 inhibitor and a VEGF-tyrosine kinase inhibitor based on the results from LITESPARK-005. In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus. Median PFS was 5.6 months (95% CI, 3.9-7.0) for WELIREG versus 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for WELIREG was 22% (n=82) (95% CI, 18-27), with a CR rate of 3% (n=10) and a PR rate of 19% (n=72), and the ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients achieving a CR and a PR rate of 4% (n=13). About LITESPARK-004 LITESPARK-004 is an open-label Phase 2 trial (ClinicalTrials.gov, NCT03401788 ) evaluating WELIREG for the treatment of patients with VHL disease who had at least one measurable solid tumor localized to the kidney and who did not require immediate surgery. The study enrolled 61 patients who received WELIREG (120 mg orally once daily) until disease progression or unacceptable toxicity. The primary endpoint is ORR in VHL disease-associated RCC. Secondary endpoints include, DOR, time to response, PFS, time to surgery and safety. Additionally, this study evaluated response rates in other common VHL disease-associated tumors including pNET and CNS hemangioblastomas. About LITESPARK-005 LITESPARK-005 is an open-label, randomized, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT04195750 ) evaluating WELIREG compared to everolimus for the treatment of patients with unresectable, locally advanced or metastatic clear cell RCC that progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies either in sequence or in combination. The trial enrolled 746 patients who were randomized to receive WELIREG (120 mg orally once daily) or everolimus (10 mg orally once daily). The dual primary endpoints are PFS and overall survival. Secondary endpoints include ORR, DOR and safety. About von Hippel-Lindau disease Von Hippel-Lindau disease is a rare genetic disease, which impacts an estimated 200,000 people worldwide and an estimated 10,000 to 15,000 people in Europe. Patients with VHL disease are at risk for recurrent, benign blood vessel tumors as well as some cancerous ones. One of the most commonly occurring tumors is RCC, a form of kidney cancer, which occurs in about 70% of patients with VHL disease. About renal cell carcinoma Renal cell carcinoma is by far the most common type of kidney cancer. Clear cell RCC is considered the most common form of RCC, representing about 70% of all cases. In 2020, more than 130,000 new cases of RCC were diagnosed in Europe. Renal cell carcinoma is about twice as common in men than in women. Approximately 30% of patients with kidney cancer are diagnosed at an advanced stage. About WELIREG ® (belzutifan) 40 mg tablets, for oral use Indications in the U.S. Certain von Hippel-Lindau (VHL) disease-associated tumors WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Selected Safety Information for WELIREG Warning: Embryo-Fetal Toxicity Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective. Anemia WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG. In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs. Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. In LITESPARK-004, hypoxia occurred in 1.6% of patients. In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months). Embryo-Fetal Toxicity Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Adverse Reactions In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%). WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%). Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%). Drug Interactions Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended. Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose. Females and Males of Reproductive Potential WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG. Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown. Pediatric Use Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established. Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www-merck-com.libproxy1.nus.edu.sg/research/oncology/ . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . SOURCE: Merck

Clinical ResultDrug ApprovalPhase 2Phase 3Accelerated Approval

19 Feb 2025

·pmlive.com

Merck’s Welireg granted EC approval for von Hippel-Lindau disease and kidney cancer

Merck & Co’s – known as MSD outside of the US and Canada – Welireg (belzutifan) has been conditionally approved by the European Commission (EC) as a monotherapy for certain patients with von Hippel-Lindau (VHL) disease and renal cell carcinoma (RCC). Welireg has been authorised for use in adults with VHL disease who require therapy for associated, localised RCC, central nervous system haemangioblastomas, or pancreatic neuroendocrine tumours, and for whom localised procedures are unsuitable. The drug has also been approved to treat adults with advanced clear cell RCC that has progressed following at least two lines of therapy that included a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and two or more vascular endothelial growth factor (VEGF) targeted therapies. Up to 15,000 people in Europe are living with VHL disease, which occurs when a mutation in the VHL gene causes cells to grow abnormally. This can lead to cysts or tumours developing in different parts of the body, including the kidneys and pancreas, that can impair function or become cancerous. RCC is far more common, with more than 130,000 new cases of the kidney cancer diagnosed in Europe in 2020 alone. The disease disproportionately affects men and approximately 30% of patients are diagnosed at an advanced stage. Merck gained access to Welireg in 2019 through its $1.1bn buyout of Peloton Therapeutics. The drug is taken orally and is designed to inhibit the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α), which regulates cellular proliferation, angiogenesis and tumour growth. The EC’s decision on the two indications follows a recent recommendation from the European Medicines Agency’s human medicines committee and was supported by positive results from the phase 2 LITESPARK-004 trial in VHL disease and the phase 3 LITESPARK-005 study in RCC. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, said: “The approval of Welireg in the EU introduces the first and only systemic treatment option for adult patients with certain VHL disease-associated tumours for whom localised procedures are unsuitable, and offers a new option for adult patients with advanced clear cell RCC that progressed following a PD-1 or PD-L1 inhibitor and at least two VEGF targeted therapies. “This is an important moment, and we are pleased that Welireg, a first-in-class HIF-2α inhibitor, can now potentially help these patients in need.”

Drug ApprovalPhase 2Phase 3Clinical Result

18 Feb 2025

·endpts.com

Arcus touts early kidney cancer data as Gilead declines option

Arcus Biosciences presented new Phase 1/1b data for a kidney cancer program over the weekend and picked a dose to move forward into additional studies. At the same time, Gilead passed on its option to license the program, which is expected to eventually compete with Merck’s approved drug Welireg in the same kidney cancer setting. Gilead has a roughly 33% equity stake in Arcus and participated in a $150 million public offering from the biotech. Arcus’ stock price $RCUS was down about 15% after Arcus executives held a conference call discussing the program’s data and development plans on Tuesday morning. Arcus presented the results at the ASCO Genitourinary Cancers Symposium in San Francisco on Saturday. The update came from a study called ARC-20, testing the experimental drug casdatifan in metastatic clear cell renal cell carcinoma (ccRCC). As of a Jan. 3 cutoff date, Arcus had data from 87 patients across three dosing cohorts: 50 mg twice per day, 50 mg once per day and 100 mg once per day. The company will move forward with the 100 mg once-daily dose. In that cohort, nine out of 27 patients experienced a partial response with a median follow-up of five months, good for a 33% overall response rate. Progression-free survival was not yet reached in this arm, or in the 50 mg once-a-day cohort. In the 50 mg twice-daily trial arm, however, patients experienced a median progression-free survival of 9.7 months after a median follow-up of 15 months. All of the patients in the study had previously been treated with PD-1 immunotherapy. Each of the three arms produced similar ORRs numerically — 25% in 50 mg twice a day, 32% in 50 mg once a day, and the 33% mark from the 100 mg once-daily cohort — prompting analysts to ask Arcus why they selected the 100 mg dose for Phase 2 studies. CEO Terry Rosen noted the 100 mg had reached those levels despite the follow-up being much shorter, and said it suggests the 100 mg once-daily dose will have the best long-lasting effects. “Even though it’s early, you can play out the movie because you have enough data from the 50 milligram and 100 milligram,” Rosen said. Before the conference call, Leerink analyst Daina Graybosch wrote in a note that the 100 mg data “already surpass our most comparable” Welireg benchmarks and “could widen” in casdatifan’s favor given how responses for this drug class deepen in longer follow-ups — echoing Rosen’s comments. Both casdatifan and Welireg are HIF-2a inhibitors. Graybosch also added that questions remain about the class’ overall survival impact and likely won’t be answered until at least the next Merck readout for a trial called LITESPARK-011. The estimated primary completion date for the study is in February 2026, according to the government’s clinical trials online database. Arcus is still testing casdatifan in combination with Cabometyx and plans to launch a Phase 3 study looking at that combo against Cabometyx alone in the second quarter for the same kidney cancer setting. The company also plans to examine the drug’s effects in combination with AstraZeneca’s volrustomig, an anti-CTLA-4/anti-PD-1 bispecific, in patients who have not previously received immunotherapy in ccRCC. A trial is slated to begin in the middle of this year. More monotherapy data from the Phase 1/1b study will also be released this fall, Arcus projected. Gilead’s decision not to license casdatifan came as a surprise to analysts, given its close working relationship with Arcus. The move prompted Arcus to launch the $150 million offering so the biotech could fund the program’s continuing development. Nonetheless, Rosen said during Tuesday’s call that Arcus is “thrilled” to be able to develop casdatifan on its own. He didn’t comment on why Gilead declined to pick up its option (“It’s best to ask Gilead,” he told analysts), but said Arcus now has more flexibility to develop the combination therapies. “We couldn’t have been happier about this,” Rosen said. “Given the value of this asset, given the opportunity, given the ability to control our own destiny with development, and then, most importantly, the strategic optionality that that provides us.” Gilead spokespeople didn’t immediately respond to a request for comment.

Clinical ResultImmunotherapyPhase 3Phase 2ASCO

100 Deals associated with Belzutifan

External Link

KEGG	Wiki	ATC	Drug Bank
D11954	-	-	DB15463

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Locally Advanced Clear Cell Renal Cell Carcinoma	EU	Merck & Co., Inc.	18 Feb 2025
Locally Advanced Clear Cell Renal Cell Carcinoma	IS	Merck & Co., Inc.	18 Feb 2025
Locally Advanced Clear Cell Renal Cell Carcinoma	LI	Merck & Co., Inc.	18 Feb 2025
Locally Advanced Clear Cell Renal Cell Carcinoma	NO	Merck & Co., Inc.	18 Feb 2025
Advanced Renal Cell Carcinoma	US	Merck & Co., Inc.	14 Dec 2023
Hemangioblastoma	AU	Merck Sharp & Dohme (Australia) Pty Ltd.	22 Dec 2022
Neuroendocrine tumor of pancreas	AU	Merck Sharp & Dohme (Australia) Pty Ltd.	22 Dec 2022
Renal Cell Carcinoma	CA	Merck Canada, Inc.	11 Jul 2022
Von Hippel-Lindau Disease	US	Merck Sharp & Dohme Corp.	13 Aug 2021

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ovarian clear cell carcinoma	Phase 2	US	Merck Sharp & Dohme Corp.	01 Dec 2024
ER-positive/HER2-negative Breast Cancer	Phase 2	US	Merck Sharp & Dohme Corp.	27 Nov 2024
ER-positive/HER2-negative Breast Cancer	Phase 2	AR	Merck Sharp & Dohme Corp.	27 Nov 2024
ER-positive/HER2-negative Breast Cancer	Phase 2	CL	Merck Sharp & Dohme Corp.	27 Nov 2024
ER-positive/HER2-negative Breast Cancer	Phase 2	KR	Merck Sharp & Dohme Corp.	27 Nov 2024
ER-positive/HER2-negative Breast Cancer	Phase 2	GB	Merck Sharp & Dohme Corp.	27 Nov 2024
Metastatic breast cancer	Phase 2	US	Merck Sharp & Dohme Corp.	27 Nov 2024
Metastatic breast cancer	Phase 2	AR	Merck Sharp & Dohme Corp.	27 Nov 2024
Metastatic breast cancer	Phase 2	CL	Merck Sharp & Dohme Corp.	27 Nov 2024
Metastatic breast cancer	Phase 2	KR	Merck Sharp & Dohme Corp.	27 Nov 2024

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04195750 (LITESPARK-005, ASCO_GU2025) Manual	Phase 3	Renal Cell Carcinoma	-	Belzutifan 120 mg QD (Bone mets, yes)	ahfnespytj(riyqhldypk) = hktlsdtomz uawizknscu (edmbtjrsga ) View more	Positive	13 Feb 2025
				Everolimus 10 mg QD (Bone mets, yes)	ahfnespytj(riyqhldypk) = rgggwxcpzf uawizknscu (edmbtjrsga ) View more
NCT03634540 (LITESPARK-003, ASCO_GU2025)	Phase 2	Renal Cell Carcinoma ECOG performance status of 0 or 1	-	Belzutifan 120 mg + Cabozantinib 60 mg	lpzylavvkj(ullzextekc) = qurzcvhipk lolkjufnwp (csydozqrod, 55 - 82) View more	Positive	13 Feb 2025
ASCO_GU2025	Not Applicable	Familial Renal Cell Carcinoma HIF-2a	-	belzutifan (sporadic renal cell carcinoma (spRCC))	zggwtzmcrl(pixxwmbbhw) = gusmhztfhy fazbtxjkqf (ohilbunnae ) View more	-	13 Feb 2025
				belzutifan (VHL-syndrome-associated renal cell carcinoma (VHL-RCC))	zggwtzmcrl(pixxwmbbhw) = uosyxxiojc fazbtxjkqf (ohilbunnae ) View more
NCT04995484 (MK-6482-020, CTgov)	Phase 1	Liver Injury	17	Belzutifan (Moderate Hepatic Impairment)	bbdihijold(tybbiladkk) = jccjdcwjuf uwdwvxcjyg (rfdtbgibaj, ejfsdsuamn - egwxhhrewr) View more	-	13 Jan 2025
				Belzutifan (Healthy)	bbdihijold(tybbiladkk) = ouvxdztrmy uwdwvxcjyg (rfdtbgibaj, bugjwvozsz - hwromwbgzj) View more
NCT03634540 (LITESPARK-003, Pubmed \| Lancet Oncol)	Phase 2	Locally Advanced Clear Cell Renal Cell Carcinoma First line	50	Belzutifan 120 mg + Cabozantinib 60 mg	yplcszikju(nfvnkctxdp) = pfjsnevahv zxfnqqvzvp (acglgodhlp, 55 - 82) View more	Positive	01 Jan 2025
NCT04489771 (LITESPARK-013, Pubmed \| Ann Oncol)	Phase 2	Renal Cell Carcinoma VHL disease \| anti-PD-(L)1 regimen	154	Belzutifan 120 mg	kdmpjlcpnj(ygwdneamju) = vqrkdxaqoh akiossdvwn (pitywidlpu, -0.5% [-14.0 - 12.9]) View more	Positive	01 Dec 2024
				Belzutifan 200 mg	kdmpjlcpnj(ygwdneamju) = egbeoxqaud akiossdvwn (pitywidlpu ) View more
NCT03401788 (LITESPARK-004, BusinessWire) Manual	Phase 2	Von Hippel-Lindau Disease	24	WELIREG (belzutifan) (VHL-associated CNS hemangioblastomas)	ziwccbpent(mzquubftjj) = ocrgcfqufi bxdksnvqpr (wwkcweqqnh, 41 - 81) View more	Positive	22 Nov 2024
				WELIREG (belzutifan) (VHL-associated pNET)	ziwccbpent(mzquubftjj) = zdojijssog bxdksnvqpr (wwkcweqqnh, 52 - 98) View more
CTNI-82 (SNO2024)	Not Applicable	-	-	Belzutifan	ooqtbzyfqu(szzmkfvjdg) = 4 patients ejuosafxxt (xjmqlfdcrr ) View more	Positive	11 Nov 2024
P20.05.B (EANO2024)	Not Applicable	-	9	Belzutifan	huvncjkjre(mwnrjfjsba) = 4 patients experienced anemia ljekxdemdr (unfoqmeczf ) View more	Positive	17 Oct 2024
Pubmed Manual	Not Applicable	Von Hippel-Lindau Disease \| Hemangioblastoma	5	Belzutifan	vevaexerud(mypthumaqn) = Three patients were started on belzutifan due to vision loss from progressive retinal hemangioblastomas. Within one year of treatment, all three patients had improvement in hemangioblastoma size and visual acuity. rbungfhopk (pxtavtsqzp ) View more	Positive	16 Oct 2024

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