Welireg
belzutifan
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
Why that species
Pharmacokinetic profile similar to humans, especially in dogs
“It can be concluded that especially dogs and to a lesser extent rats exhibit a similar pharmacokinetic profile of belzutifan compared to humans and are therefore appropriate for toxicological assessment of belzutifan.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
Species: general tox
Rat and dog (up to 3 months)
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
Species: DART
Rat only (pilot EFD); rabbit studies not pursued after rat EFD findings
“No further rabbit studies were conducted based on the identified risk in the rat embryo-fetal development study”
Species: carcinogenicity
Tg rasH2 mouse (6-month) completed; 2-year rat study not required for the MAA
“The applicant justified in depth why the results of the 2-year carcinogenicity study in rats would not be required for this MAA, and presented the results of the 6-month Tg. rasH2 mouse carcinogenicity study with belzutifan at doses up to 600 mg/kg/day.”
Surrogate used in
No surrogate used; clinical compound tested in rats and dogs
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
Pivotal GLP studies
3-month (13-week) oral studies in rats and dogs
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
Route in tox
Oral (gavage)
“A 13-week oral gavage toxicity study followed by 28-day and 26-week recovery period in rats”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat bone marrow micronucleus assays
“Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro micronucleus assay in human peripheral blood lymphocytes or the in vivo bone marrow erythrocyte micronucleus test in rats.”
Carcinogenicity
6-month rasH2 mouse up to 600 mg/kg/day: no neoplastic findings
“presented the results of the 6-month Tg. rasH2 mouse carcinogenicity study with belzutifan at doses up to 600 mg/kg/day. The results indicate no belzutifan-related neoplastic findings at any dose level and no carcinogenic risk were identified in the study.”
Reproductive & developmental
Pilot rat EFD only: post-implantation loss at ≥60 mg/kg/day
“The Applicant conducted a pilot embryo-fetal development study in rats. Oral administration of belzutifan at doses up to 200 mg/kg/day to pregnant rats during the period of organogenesis caused embryo-fetal lethality (post-implantation loss) at ≥ 60 mg/kg/day”
Safety pharmacology
Low-potency hERG blocker (IC50 >50 µM); no QTc effect in dogs up to 30 mg/kg/day for 3 months
“Belzutifan was a low-potency hERG blocker in vitro (IC50 > 50 µM) and did not influence QTc in dogs dosed up to 30 mg/kg/day for 3 months.”
Genotox: Ames
Negative
“Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro micronucleus assay in human peripheral blood lymphocytes or the in vivo bone marrow erythrocyte micronucleus test in rats.”
Genotox: in vitro mammalian
In vitro micronucleus assay in human peripheral blood lymphocytes: negative
“Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro micronucleus assay in human peripheral blood lymphocytes or the in vivo bone marrow erythrocyte micronucleus test in rats.”
Genotox: in vivo
Rat bone marrow erythrocyte micronucleus test: negative
“Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro micronucleus assay in human peripheral blood lymphocytes or the in vivo bone marrow erythrocyte micronucleus test in rats.”
Carcinogenicity model
26-week Tg rasH2 mouse and 104-week rat, initiated April 2023 (not conducted for FDA NDA)
“A 26-week carcinogenicity study in rasH2 transgenic mice and a 104-week carcinogenicity study in WH rats have been initiated in April 2023.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies not conducted before approval; postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
hERG / QT
Low-potency hERG blocker (IC50 >50 µM); no QTc effect in dogs up to 30 mg/kg/day for 3 months
“Belzutifan was a low-potency hERG blocker in vitro (IC50 > 50 µM) and did not influence QTc in dogs dosed up to 30 mg/kg/day for 3 months.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Welireg don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Reversible decreases in red blood cell parameters at ≥2 mg/kg/day in rats and ≥1 mg/kg/day in dogs, below human exposure (FDA multi-discipline review, p. 34)
NOAEL / key findings
Reversible decreases in red blood cell parameters at ≥2 mg/kg/day in rats and ≥1 mg/kg/day in dogs, below human exposure
“Belzutifan caused reversible decreases in red blood cell parameters at ≥ 2 mg/kg/day in rats and ≥ 1 mg/kg/day in dogs (approximately ≥ 0.05 times the human exposure at the recommended human dose of 120 mg daily).”
Risksopen answer page →
Immune & cytokine safety
No immunosuppression in repeat-dose toxicity studies
“belzutifan does not show off-target activity, did not induce proliferative changes or potential endocrine/hormonal perturbations, or immunosuppression in repeat-dose toxicity studies”
Biodistribution & persistence
Mainly excretory organs and GI tract in rats; no melanin binding
“Distribution studies showed distribution of belzutifan to mostly excretory organs and the GI tract in rats. No gender differences were observed and no melanin binding was evident.”
Modality-specific risk
Embryo-fetal toxicity, warranting a boxed warning given chronic use in younger patients
“given the chronic use of belzutifan in a younger population than other targeted oncology drugs, the review team recommended the label contain a boxed warning for embryo-fetal toxicity.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
Boxed warning: Embryo-fetal toxicity
- Anemia
- Hypoxia
- Cardiac Dysfunction with Concomitant Use of WELIREG and Lenvatinib
- Embryo-Fetal Toxicity
Embryo-fetal toxicityCytopeniasCardiovascular
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human dose-escalation study 001
“FFP formulation was initially developed used in the FIH dose escalation study 001, Phase 2 efficacy study MK-6482-004, and food effect study MK-6482-002.”
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Welireg don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Reversible decreases in red blood cell parameters at ≥2 mg/kg/day in rats and ≥1 mg/kg/day in dogs, below human exposure (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week oral GLP studies in rat (28-day and 26-week recovery) and dog (28-day recovery)
“PT2977: A 13-week oral gavage toxicity study followed by 28-day and 26-week recovery periods in Sprague-Dawley rats / TT187809”
Pivotal GLP studies
3-month (13-week) oral studies in rats and dogs
“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”
DART package
Species: DART
Rat only (pilot EFD); rabbit studies not pursued after rat EFD findings
“No further rabbit studies were conducted based on the identified risk in the rat embryo-fetal development study”
Reproductive & developmental
Pilot rat EFD only: post-implantation loss at ≥60 mg/kg/day
“The Applicant conducted a pilot embryo-fetal development study in rats. Oral administration of belzutifan at doses up to 200 mg/kg/day to pregnant rats during the period of organogenesis caused embryo-fetal lethality (post-implantation loss) at ≥ 60 mg/kg/day”
PPND / ePPND: when
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month) completed; 2-year rat study not required for the MAA
“The applicant justified in depth why the results of the 2-year carcinogenicity study in rats would not be required for this MAA, and presented the results of the 6-month Tg. rasH2 mouse carcinogenicity study with belzutifan at doses up to 600 mg/kg/day.”
Carcinogenicity model
26-week Tg rasH2 mouse and 104-week rat, initiated April 2023 (not conducted for FDA NDA)
“A 26-week carcinogenicity study in rasH2 transgenic mice and a 104-week carcinogenicity study in WH rats have been initiated in April 2023.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies not conducted before approval; postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 30 mg/kg/day (no testicular findings) ~1-fold human AUC; rat testis degeneration at 0.13-fold
“The seminiferous tubule degeneration was observed at ≥6 mg/kg/day (0.13-fold human AUC) in SD rats but not in dogs with 10 times higher exposure (30 mg/kg/day, 1-fold human AUC).”
NOAEL / key findings
Reversible decreases in red blood cell parameters at ≥2 mg/kg/day in rats and ≥1 mg/kg/day in dogs, below human exposure
“Belzutifan caused reversible decreases in red blood cell parameters at ≥ 2 mg/kg/day in rats and ≥ 1 mg/kg/day in dogs (approximately ≥ 0.05 times the human exposure at the recommended human dose of 120 mg daily).”
Efficacy evidenceopen answer page →
Efficacy evidence
VHL-deficient 786-O ccRCC xenograft and patient-derived ccRCC xenograft in immunodeficient mice
“The anti-tumour activity of belzutifan was evaluated in a VHL-deficient tumour xenograft model derived from the human ccRCC cell line 786-O implanted in SCID/Beige mice.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: proof of concept sufficiently demonstrated; relevant for VHL-deficient RCC
“Overall, the proof of concept of belzutifan has been sufficiently demonstrated. The presented in vivo results are considered relevant for patients with VHL that exhibit RCC tumours and for the ccRCC patients who exhibit VHL deficiency or hypoxic tumours.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before US approval for chronic use in VHL disease; mouse and rat studies required postmarketing
Why: Preliminary weight-of-evidence assessment did not adequately address carcinogenicity for chronic use; studies required postmarketing
“Given the indication, the long-life expectancy and prolonged treatment, it is important to address the carcinogenicity potential of belzutifan for chronic use. Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
“During the review cycle, the Applicant submitted a preliminary weight-of-evidence assessment, which did not adequately address the carcinogenicity potential of belzutifan for chronic use.”
DARTAccepted
No confirmatory second-species (rabbit) embryo-fetal study; rat pilot study only
Why: ICH S5(R3): teratogenic and embryotoxic potential already shown in the rat study · Within the guideline
“As belzutifan showed teratogenic and embryotoxic potential in the pEFD rat study, a confirmatory study in a second species (rabbit) was not performed and is not required in accordance with ICH S5 (R3).”
Safety marginVerdict not stated
Rat seminiferous tubule degeneration at 0.13-fold human AUC (no margin); not seen in dogs at 1-fold
“The seminiferous tubule degeneration was observed at ≥6 mg/kg/day (0.13-fold human AUC) in SD rats but not in dogs with 10 times higher exposure (30 mg/kg/day, 1-fold human AUC).”
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