Ogsiveo
nirogacestat
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 toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Why that species
Rat and dog chosen based on nirogacestat PK and metabolism compared across species
“The rat and dog were selected as the toxicology species based on nirogacestat PK and metabolism properties compared across species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats received up to 25 mg/kg (50 mg/kg/day) oral nirogacestat, twice per day, for 3 months, resulting in mean exposure levels (AUC) up to 3.4 times the AUC of 6740 ng.h/mL in patients with desmoid tumors at the 150 mg BID dose.”
Species: general tox
Rat and dog (3-month studies)
“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Species: DART
Rat only (two fertility studies and a preliminary EFD study)
“The developmental and reproductive toxicology assessment of nirogacestat consisted of two separate fertility studies in male and female rats and a preliminary embryo-foetal toxicity study in pregnant rats.”
Species: carcinogenicity
Tg rasH2 mouse (26-week); no rat study
“The carcinogenicity of nirogacestat was assessed in a 6‐month repeat dose study in transgenic rasH2 mice (20174162).”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Pivotal GLP studies
GLP 3-month repeat-dose studies in rats and dogs
“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Route in tox
Oral
“The oral route of exposure was selected for these studies since the oral route is the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human chromosome aberration and in vivo rat bone marrow micronucleus assays
“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
rasH2 mouse: non-significant increase in hemangiosarcomas in 100 mg/kg/day males; negative in females
“The results showed an increased incidence of whole body hemangiosarcomas in 100 mg/kg/day males that was above the historical control value for the test facility but did not reach statistical significance for trend and pairwise comparisons. The study was negative for drug‐related neoplasms in female mice.”
Reproductive & developmental
Preliminary rat EFD: decreased fetal weight, post-implantation loss and fetal subcutis edema at ≥20 mg/kg/day
“Daily oral administration of nirogacestat to pregnant rats resulted in decreased fetal body weights, post‐ implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the exposure in patients with desmoid tumors based on AUC at the 150 mg BID dose).”
Safety pharmacology
No CNS, respiratory or cardiovascular effects up to 500 mg/kg; hERG IC50 1 µM, >100x free human Cmax
“There were no nirogacestat‐related adverse effects on the central nervous system, pulmonary function, or the cardiovascular system at single doses up to 500 mg/kg. Nirogacestat blocked the hERG channel with an IC50 of 1 μM; however, this IC50 is greater than 100 times the free Cmax in humans at the 150 mg BID dose.”
Genotox: Ames
Negative
“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
In vitro human chromosome aberration assay: negative
“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
26-week Tg rasH2 mouse (negative overall); 2-year rat study not conducted
“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”
Carcinogenicity timing
26-week Tg rasH2 mouse completed before the marketing application; 2-year rat waived
“In the 6‐month carcinogenicity study (Study 20174162), a significant increase in hemangiosarcomas was noted in both male and female transgenic mice with the incidence above historical control values of the test facility. Therefore, SpringWorks requested a waiver for the 2‐year carcinogenicity study in rats”
hERG / QT
hERG IC50 1 µM, >100x free human Cmax at 150 mg BID; no QT effect clinically or in vivo
“Nirogacestat blocked the hERG channel with an IC50 of 1 μM; however, this IC50 is greater than 100 times the free Cmax in humans at the 150 mg BID dose. Consistent with these findings, nirogacestat did not have effects on QT prolongation clinically or in in vivo nonclinical studies.”
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 Ogsiveo 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: No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day) (EMA assessment report, p. 35)
NOAEL / key findings
No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day)
“Due to oocyte mineralization at the lowest dose in the 3-month dog study, a NOAEL was not identified. The lowest dose in the dog was 2 mg/kg/day (human equivalent dose of 70 mg/day).”
Risksopen answer page →
Immune & cytokine safety
Decreased cellularity of gut-associated lymphoid tissue and mesenteric lymph nodes in rats
“In the 3‐month rat study, ovarian atrophy, alterations in the estrous cycle and decreased cellularity in gut‐associated lymphoid tissue (GALT) in females, and decreased cellularity of mesenteric lymph nodes in males and females at 5 mg/kg/day was observed.”
Biodistribution & persistence
Highest in uveal tract, liver, adrenal, spleen, pituitary; binds melanin in pigmented ocular tissues
“Excluding excreta, the highest Cmax levels of radiolabeled [14C] nirogacestat were uveal tract, liver, adrenal gland, spleen, and pituitary gland. Radiolabeled [14C] nirogacestat exhibited an affinity for pigmented ocular tissues containing melanin.”
Modality-specific risk
Notch-mediated ovarian toxicity (degeneration, atrophy, oocyte mineralization)
“Regarding ovarian dysfunction in humans, ovarian degeneration/necrosis/atrophy and oocyte mineralization occurred in animals administered nirogacestat and was consistent with Notch regulation of mammalian folliculogenesis (Vanorny and Mayo, 2014).”
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
- Diarrhea
- 2 Ovarian Toxicity
- 3 Hepatotoxicity
- 4 Non-Melanoma Skin Cancers
- 5 Electrolyte Abnormalities
- Hypersensitivity Reactions
- 7 Embryo-Fetal Toxicity
GastrointestinalHepatotoxicitySecondary malignancySkin reactionsMetabolic & endocrineHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 Ogsiveo 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: No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day) (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and 3-month dog (oral, GLP), each with 1-month recovery
“Nirogacestat was administered to rats and dogs in repeat dose general toxicology studies up to 3 months in duration followed by a 1‐month recovery.”
Pivotal GLP studies
GLP 3-month repeat-dose studies in rats and dogs
“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
DART package
Species: DART
Rat only (two fertility studies and a preliminary EFD study)
“The developmental and reproductive toxicology assessment of nirogacestat consisted of two separate fertility studies in male and female rats and a preliminary embryo-foetal toxicity study in pregnant rats.”
Reproductive & developmental
Preliminary rat EFD: decreased fetal weight, post-implantation loss and fetal subcutis edema at ≥20 mg/kg/day
“Daily oral administration of nirogacestat to pregnant rats resulted in decreased fetal body weights, post‐ implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the exposure in patients with desmoid tumors based on AUC at the 150 mg BID dose).”
PPND / ePPND: when
Not conducted: rat PPND waived given severe embryo-fetal effects in the rat dose-range finding study
“Based on the severity of the embryo‐fetal development (EFD) effects of nirogacestat observed in the dose‐range finding study in rats (Study 01214026) and the importance of the gamma‐ secretase pathway in embryo implantation and development, SpringWorks requested a waiver for conducting the definitive EFD study in rat, the range finding and definitive EFD studies in rabbits, as well as the pre‐ and post‐natal development (PPND) study in rats.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week); no rat study
“The carcinogenicity of nirogacestat was assessed in a 6‐month repeat dose study in transgenic rasH2 mice (20174162).”
Carcinogenicity model
26-week Tg rasH2 mouse (negative overall); 2-year rat study not conducted
“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”
Carcinogenicity timing
26-week Tg rasH2 mouse completed before the marketing application; 2-year rat waived
“In the 6‐month carcinogenicity study (Study 20174162), a significant increase in hemangiosarcomas was noted in both male and female transgenic mice with the incidence above historical control values of the test facility. Therefore, SpringWorks requested a waiver for the 2‐year carcinogenicity study in rats”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: NOAEL/LOAEL exposures in 1- and 3-month studies below human exposure at 150 mg BID
“The exposures at the NOAEL or lowest observed adverse effect level in the 1 and 3‐month studies were below the human steady state exposures after administration of nirogacestat at 150 mg BID.”
NOAEL / key findings
No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day)
“Due to oocyte mineralization at the lowest dose in the 3-month dog study, a NOAEL was not identified. The lowest dose in the dog was 2 mg/kg/day (human equivalent dose of 70 mg/day).”
Efficacy evidenceopen answer page →
Efficacy evidence
Patient-derived desmoid tumor cell lines in vitro; in vivo only in non-desmoid Notch-driven xenografts (e.g., T-ALL)
“Nirogacestat also demonstrated growth inhibition in various Notch expressing patient‐derived desmoid tumor cell lines in vitro with IC50s of 4‐160 µM. Nirogacestat exhibited anti‐tumor activity in numerous Notch‐driven tumor xenograft models in mice but did not induce tumor growth inhibition in a non‐Notch‐driven tumor xenograft model.”
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: mechanism in desmoid tumors not well defined nonclinically; some efficacy evidence from patient-derived culture models
“While this mechanism is not well defined by non-clinical evaluations to date, some evidence of nirogacestat-mediated antitumour efficacy in DT has been established using patient-derived culture models.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No 2-year rat carcinogenicity study; only 26-week Tg rasH2 mouse study plus weight-of-evidence assessment
Why: Skin cancers already reported in humans; achievable rat exposures below human exposure due to poor tolerance · Human data · Pharmacology or kinetics · Weight of evidence
“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”
“It is accepted not to perform a 2-year rat carcinogenicity study since the results of such study would not add to the clinical safety assessment.”
DARTAcceptedBeyond the letter
No definitive rat or rabbit embryo-fetal studies and no pre- and postnatal study; preliminary rat EFD study plus weight of evidence
Why: Severe embryo-fetal toxicity in the preliminary rat study; Notch required for embryonic development · Weight of evidence · Pharmacology or kinetics
“Based on the severity of the embryo‐fetal toxicities, and the known requirement for the Notch pathway for normal embryo implantation and development, the weight of evidence provides justification for not conducting the definitive embryo‐fetal toxicity studies in rats and in rabbits, as well as not conducting the rat peri‐ and post‐natal development study.”
“Further embryo-foetal toxicity studies in rats and rabbits as well as a pre- and post-natal development (PPND)-study in the rat is not warranted.”
Study lengthAcceptedBeyond the letter
No chronic studies: 6-month rat and 9-month dog studies not conducted
Why: Very low animal exposures versus clinical exposure; longer studies would not add to the clinical safety assessment · Pharmacology or kinetics
“Conduct of additional general toxicology studies were not required based on FDA feedback received at the end‐of‐Phase 1 meeting; therefore, the 6‐month rat and 9‐month dog studies with nirogacestat were not conducted.”
“Considering the toxicological findings in multiple organs across all tested species at no exposure margins to the clinical exposure further non-clinical toxicity studies of longer duration is not considered to add to the clinical safety assessment.”
Safety marginAcceptedBeyond the letter
No exposure margins: NOAEL/LOAEL exposures in all repeat-dose, reproductive and carcinogenicity studies well below 1
Why: Relevant findings already identified for human risk assessment; human safety endpoints rather than more animal studies · Human data
“The exposure margins based on NOAEL/LOAEL observed in all repeat-dose studies performed in the rat, dog and mouse, reproductive toxicity studies performed in the rat, as well as the carcinogenicity study performed in the TgRasH2 mouse are considerable below 1, indicating a lack of safety margins to the adverse effects observed in the non-clinical studies.”
“It is agreed that additional studies in animals are not warranted as significant findings relevant for risk assessment and risk mitigation in humans already is identified.”
Impurity or metaboliteAcceptedBeyond the letter
Nitrosamine impurities above the M3 acceptable intake; product-specific higher intake limit accepted
Why: Unmet need in a severe condition; long-term treatment unlikely; low mutagenic potential; excess cancer risk near or below acceptable · Rare disease / unmet need · Serious disease · Weight of evidence
“Considering the clinical context (unmet medical need for a severe condition with a beneficial clinical profile), the clinical judgement that long term treatment is unlikely, that both impurities are considered to have relatively low mutagenic potential, a product specific acceptable intake limit of 20 μg/day (corresponding to 66,667 ppb/day based on a maximum daily dose of 300 mg) for the sum of ASYM-136911 and ASYM-136912 was proposed.”
“The NcWP has been consulted on the product specific limit proposed by the applicant and concluded that the theoretical excess cancer risk (TECR) for total NDSRI (ASYM 136911 + ASYM 136912) levels is near or below the acceptable TECR of 1:100,000 for 7 years of treatment duration or less.”
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