Romvimza
vimseltinib
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeat-dose toxicology studies were conducted in rats (4-weeks, 13-weeks, and 26-weeks) and dogs (4-weeks, 13-weeks, and 39-weeks).”
Why that species
Rat, rabbit, dog and mouse selected for high protein homology (up to 96%) of the pharmacologic target
“Rats, rabbits, dogs, and mice were selected as relevant species in the toxicology studies based on high protein homology (up to 96%) of the pharmacologic target of vimseltinib.”
Surrogate molecule
No surrogate; the clinical compound was tested
“GLP repeat-dose toxicity studies were conducted with vimseltinib in rats and dogs up to 26 and 39 weeks of duration, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“GLP repeat-dose toxicity studies were conducted with vimseltinib in rats and dogs up to 26 and 39 weeks of duration, respectively.”
Pivotal GLP studies
4-, 13- and 26-week rat and 4-, 13- and 39-week dog studies
“Repeat-dose toxicology studies were conducted in rats (4-weeks, 13-weeks, and 26-weeks) and dogs (4-weeks, 13-weeks, and 39-weeks).”
Route in tox
Oral gavage, once daily
“Vimseltinib was given by oral gavage once a day, as this is the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in vivo rat bone marrow micronucleus and liver DNA strand-break assays; overall negative for genotoxicity
“In vivo, vimseltinib administered to rats at doses up to 200 mg/kg/day did not increase bone marrow micronucleated polychromatic erythrocytes, nor did vimseltinib increase liver DNA strand breaks. The overall assessment was that vimseltinib was negative for genotoxicity.”
Carcinogenicity
6-month transgenic mouse: negative up to 12.5 mg/kg/day; 104-week rat study ongoing as PMR
“In a 6-month transgenic mouse carcinogenicity study at doses up to 12.5 mg/kg/day, vimseltinib was negative for carcinogenic findings. The Applicant is currently conducting a 104-week carcinogenicity study in Sprague Dawley rats to be submitted as a PMR.”
Reproductive & developmental
Rat EFD: skeletal variations at ≥2.5 mg/kg/day and cardiac malformations at 15 mg/kg/day
“Structural abnormalities (skeletal variations) occurred at ≥2.5 mg/kg/day (approximately 3 times the exposure at the recommended dose based on AUC). Additional structural abnormalities (cardiac malformations) were observed at the highest dose of 15 mg/kg/day”
Safety pharmacology
No ECG, QTcF, heart rate or blood pressure effects in dogs up to 15 mg/kg
“In the dog cardiovascular (CV) safety pharmacology study, no vimseltinib-related qualitative electrocardiogram (ECG) effects or quantitative changes in PR interval, QRS duration, QT interval, QT interval corrected by Fridericia’s formula (QTcF) interval, heart rate (HR), arterial pressure, or body temperature were seen at doses up to 15 mg/kg.”
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 Romvimza 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: Inflammation, hematologic, hepatic, renal, bone and GI toxicities consistent with CSF1R inhibition (FDA multi-discipline review, p. 38)
NOAEL / key findings
Inflammation, hematologic, hepatic, renal, bone and GI toxicities consistent with CSF1R inhibition
“The vimseltinib toxicity profile is characterized by inflammation, hematologic, hepatic, renal, bone, and gastrointestinal toxicities, and is generally consistent with CSF1R inhibition.”
Risksopen answer page →
Immune & cytokine safety
Rat: bone marrow suppression and lymphoid tissue hypocellularity/necrosis at the highest 28-day dose
“In rats, dose-limiting toxicity included bone marrow suppression, lymphoid tissue hypocellularity and/or necrosis at the highest dose tested in the 28-day study leading to termination of all animals for welfare reasons.”
Biodistribution & persistence
Rat QWBA: prolonged retention in uveal tract, eye and meninges to 672 h, suggesting melanin binding
“Radioactivity was cleared from most tissues by 168 hours post dose, but was still quantifiable in the meninges, eye uveal tract, eye(s), and eye vitreous humour at 672 hours, suggesting melanin binding.”
Modality-specific risk
Hepatotoxicity
“While plausible, the totality of the nonclinical data for vimseltinib do not fully rule out the risk for hepatotoxicity in humans.”