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.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“Repeat-dose toxicology studies were conducted in rats (4-weeks, 13-weeks, and 26-weeks) and dogs (4-weeks, 13-weeks, and 39-weeks).”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD dose-range study only)
“Developmental and reproductive toxicology studies comprised studies on male and female fertility and early embryonic development, in rats, embryo-foetal development, in rats and rabbits (only dose range study in the rabbit), and pre- and post-natal development, in rats.”
Species: carcinogenicity
Transgenic mouse (6-month) and Sprague Dawley rat (104-week, ongoing)
“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.”
Surrogate used in
No surrogate used; vimseltinib tested directly
“Repeat-dose toxicology studies were conducted in rats (4-weeks, 13-weeks, and 26-weeks) and dogs (4-weeks, 13-weeks, and 39-weeks).”
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.”
Genotox: Ames
Negative (Ames)
“Vimseltinib was not mutagenic in the bacterial reverse mutation assay (Ames).”
Genotox: in vitro mammalian
In vitro micronucleus: positive (increased micronuclei after 24-hour incubation without metabolic activation)
“In an in vitro micronucleus assay, vimseltinib increased micronuclei after a 24-hour incubation in the absence of metabolic activation.”
Genotox: in vivo
In vivo rat bone marrow micronucleus and liver DNA strand-break assays: negative
“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.”
Carcinogenicity model
6-month transgenic mouse (negative); 104-week Sprague Dawley rat (ongoing)
“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.”
Carcinogenicity timing
26-week RasH2 mouse completed; 104-week Sprague Dawley rat study ongoing at approval, final report as PMR
“The Applicant is conducting a 104-Week rat carcinogenicity study of vimseltinib in Sprague Dawley rats (DCC-3014-04-0025, eCTD 2.6.7 Table 21).”
hERG / QT
hERG IC50 not calculable; 17% or less inhibition at solubility-limited maximum concentrations
“In the in vitro human ether-à-go-go-related gene (hERG) study, the half maximal inhibitory concentration (IC50) values for inhibition of the hERG potassium current by vimseltinib and DP-7005 could not be calculated due to 17% or less inhibition at the maximum concentrations that could be tested at the solubility limits of the two compounds”
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)
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: 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.”
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
- Hepatotoxicity
- Embryo-Fetal Toxicity
- Allergic Reactions to FD&C Yellow No.5 (Tartrazine) and No. 6 (Sunset Yellow FCF)
- Increased Creatinine without Affecting Renal Function
HepatotoxicityEmbryo-fetal toxicityHypersensitivity & infusion reactionsNephrotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
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 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)
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: Inflammation, hematologic, hepatic, renal, bone and GI toxicities consistent with CSF1R inhibition (FDA multi-discipline review, p. 38)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral) with 4-week recovery
“In the 39-week repeat-dose dog toxicology study (Study No. 8413879) with a 4-week recovery phase, vimseltinib was administered once daily by oral gavage at 0, 2, 4, or 8 mg/kg/day.”
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).”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD dose-range study only)
“Developmental and reproductive toxicology studies comprised studies on male and female fertility and early embryonic development, in rats, embryo-foetal development, in rats and rabbits (only dose range study in the rabbit), and pre- and post-natal development, in rats.”
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”
PPND / ePPND: when
Rat PPND completed before the marketing application
“The Applicant also performed a pre- and post-natal study (Study No. DCC-3014-04-0029) to observe the effects of oral administration of vimseltinib from the period of implantation to lactation.”
Carcinogenicity
Species: carcinogenicity
Transgenic mouse (6-month) and Sprague Dawley rat (104-week, ongoing)
“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.”
Carcinogenicity model
6-month transgenic mouse (negative); 104-week Sprague Dawley rat (ongoing)
“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.”
Carcinogenicity timing
26-week RasH2 mouse completed; 104-week Sprague Dawley rat study ongoing at approval, final report as PMR
“The Applicant is conducting a 104-Week rat carcinogenicity study of vimseltinib in Sprague Dawley rats (DCC-3014-04-0025, eCTD 2.6.7 Table 21).”
Safety marginopen answer page →
Safety margin at NOAEL
No exposure margin at the 13-week dog NOAEL; rat NOAEL margin around 4
“It is important to notice that no margins of exposure were observed in the 13-week dog study at NOAEL (for free and total vimseltinib) whereas in rats, margins of exposure were around 4 at NOAEL.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
CSF1R-dependent in vivo primary PD models; no TGCT models
“The models employed in the in vivo primary PD studies are CSF1R-dependent but not TGCT models.”
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: potent selective CSF1R inhibitor in vitro and in vivo, but efficacy in TGCT rests on clinical data only (no TGCT animal models)
“Vimseltinib has been demonstrated to be a potent and selective CSF1R inhibitor in vitro and in vivo. However, information on its efficacy in the proposed indication can only be taken from clinical data as no animal models of TGCT were employed in the non-clinical development of vimseltinib.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study ongoing at approval; report deferred to post-marketing
Why: Agreed at a pre-submission meeting as a post-marketing commitment
“A long–term rat 2-year carcinogenicity study in rats is ongoing and will be submitted post-marketing. During a Pre-submission meeting held on 17 April 2024, the rapporteur agreed that it is acceptable to submit the report of the 2-year rat carcinogenicity study as a post-marketing commitment.”
“The Applicant is currently conducting a 104-week carcinogenicity study in Sprague Dawley rats to be submitted as a PMR.”
DARTAccepted
No definitive rabbit embryo-fetal study; rabbit dose-range-finding study only
Why: Rabbit maternal toxicity and abortions plus rat teratogenicity; consistent with ICH S5(R3) · Within the guideline · Weight of evidence
“Based on maternal toxicity and abortions observed at ≥2.5 mg/kg and ≥5 mg/kg, respectively, following administration of vimseltinib in New Zealand White rabbits, and in conjunction with teratogenicity observed in rats at 15 mg/kg/day, a definitive EFD assessment was not conducted in rabbits, consistent with ICH S5(R3) guidance.”
“The package of developmental and reproductive toxicology studies is considered adequate.”
Safety marginVerdict not stated
No exposure margin at the 13-week dog NOAEL (free and total vimseltinib)
“It is important to notice that no margins of exposure were observed in the 13-week dog study at NOAEL (for free and total vimseltinib) whereas in rats, margins of exposure were around 4 at NOAEL.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal studies
Why: Product-specific paediatric waiver for all subsets · Other reason
“The lack of juvenile animal studies is acceptable. The medicinal product has been granted a product-specific waiver for all subsets of the paediatric population.”
Efficacy modelVerdict not stated
No tenosynovial giant cell tumour animal model; efficacy in the indication rests on clinical data
“However, information on its efficacy in the proposed indication can only be taken from clinical data as no animal models of TGCT were employed in the non-clinical development of vimseltinib.”
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