Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the National Medical Products Administration (NMPA) in China has approved WELIREG® (belzutifan), 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. WELIREG is a first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor and is the first and only approved HIF-2α inhibitor in China. This approval is based on objective response rate (ORR) and median duration of response (DOR) results from the Phase 2 LITESPARK-004 trial and is the 17th approval of WELIREG for these patients globally.
“This approval of WELIREG brings the first and only systemic therapy to adult patients in China with certain VHL disease-associated tumors who, to date, have not had access to a non-surgical treatment option to help manage manifestations of VHL disease,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We are committed to bringing innovative treatment options to patients in need around the world and are proud to offer eligible adult patients in China a first-in-class HIF-2α inhibitor as a possible treatment option.”
In August 2021, WELIREG was approved in the U.S. for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas or pNET, not requiring immediate surgery. The efficacy of WELIREG was evaluated in LITESPARK-004, an open-label clinical trial in 61 patients with VHL-associated RCC. In the LITESPARK-004 trial, WELIREG showed an ORR of 49% (95% CI, 36-62) in patients with VHL-associated RCC (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 22.3+ months; among responders, 56% (n=17/30) maintained a response for at least 12 months.
Patients enrolled in LITESPARK-004 had other VHL-associated tumors, including CNS hemangioblastomas and pNET. In patients with VHL-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 22.3+ months; among responders, 73% (n=11/15) maintained a response for at least 12 months. In patients with VHL-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 10.8+ to 19.4+ months; among responders, 50% (n=5/10) maintained a response for at least 12 months.
WELIREG is also approved in the U.S. for the treatment of adult patients with advanced 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), based on results from the Phase 3 LITESPARK-005 trial. Merck is evaluating WELIREG in advanced RCC and other tumor types through a broad clinical development program, including in Phase 2 and 3 trials evaluating WELIREG as monotherapy and in combination with other medicines.
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 in RCC tumors include disease control rate, DoR, time to response, progression-free survival, time to surgery and safety. Additionally, this study evaluated response rates in other common VHL disease-associated tumors including pNET and CNS hemangioblastomas.
About von Hippel-Lindau disease
Von Hippel-Lindau disease is a rare genetic disease that impacts an estimated 200,000 people worldwide. Patients with VHL disease are at risk for recurrent, benign blood vessel tumors as well as some cancerous ones. The most commonly occurring tumor is renal cell carcinoma, a form of kidney cancer, which occurs in about 70% of patients with VHL disease.
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/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.
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Please see Prescribing Information, including information for the Boxed Warning about embryo-fetal toxicity, for WELIREG (belzutifan) at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf and Medication Guide for WELIREG at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf.
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