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.”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”