Inpefa
sotagliflozin
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
“This includes a single-dose rat study, a battery of definitive repeat-dose general toxicity studies in rats (up to 26 weeks) and dogs (up to 39 weeks), a full battery of genetic toxicity studies, mouse and rat carcinogenicity studies”
Why that species
All species used are pharmacologically relevant
“Repeat-dose toxicity studies were performed in rats and dogs. Carcinogenicity evaluation was performed in mice and rats. Embryofetal development studies were performed in rats and rabbits. All species are pharmacologically relevant.”
Surrogate molecule
No surrogate; the clinical compound was tested
“the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“a battery of definitive repeat-dose general toxicity studies in rats (up to 26 weeks) and dogs (up to 39 weeks)”
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“Sotagliflozin did not impair fertility or alter early embryonic development in the rat at doses up to 300 mg/kg/day, the highest dose evaluated. Embryo-fetal development was evaluated in rats and rabbits.”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study.”
Surrogate used in
No surrogate used; all toxicology species pharmacologically relevant
“Repeat-dose toxicity studies were performed in rats and dogs. Carcinogenicity evaluation was performed in mice and rats. Embryofetal development studies were performed in rats and rabbits. All species are pharmacologically relevant.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“This includes a single-dose rat study, a battery of definitive repeat-dose general toxicity studies in rats (up to 26 weeks) and dogs (up to 39 weeks), a full battery of genetic toxicity studies, mouse and rat carcinogenicity studies”
Pivotal GLP studies
26-week rat and 39-week dog oral studies (with 4-week recovery), plus 13-week rat and dog studies
“13-week repeat dose studies (with 4 weeks recovery) in the rat and the dog, 26-week repeat dose study (with 4 weeks recovery) in the rat, and 39-week repeat dose study (with 4 weeks recovery) in the dog.”
Route in tox
Oral
“Seven oral GLP toxicology studies have been completed”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration and in vivo rat bone marrow micronucleus assays
“A standard battery of GLP genetic toxicology studies including an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in CHO cells, and an in vivo rat bone marrow micronucleus assay were completed with sotagliflozin. Sotagliflozin was neither mutagenic nor clastogenic in the three valid assays.”
Carcinogenicity
rasH2 mouse and rat: no treatment-related, statistically significant neoplasms
“Sotagliflozin did not cause any treatment-related, statistically significant neoplasms in transgenic RasH2 (Tg.RasH2) mice or the rat in either sex.”
Reproductive & developmental
Not teratogenic in rats (100 mg/kg) or rabbits (200 mg/kg); maternal and fetal toxicity with malformations in rats at 350 mg/kg
“Sotagliflozin was not teratogenic in the rat at 100 mg/kg (40X MHRD) or in the rabbit at 200 mg/kg (9X MHRD). In rats, a higher dose (350 mg/kg; 161X MHRD) caused both maternal and fetal toxicity including significant reduction in maternal weight gain, embryo-lethality, reduced fetal weights, altered sex ratio, and cardiovascular and skeletal malformations.”
Safety pharmacology
hERG IC50 >23.5 µM; no QT/QTc effect in dog telemetry up to 500 mg/kg
“Sotagliflozin has an IC50 >23.5 µM in the human ether-a-go-go related gene (hERG) assay. A cardiac telemetry study in Beagle dogs showed that sotagliflozin had no significant effect on QT or QTc interval (corrected with the Fridericia method) at dose levels up to 500 mg/kg.”
Genotox: Ames
Negative
“A standard battery of GLP genetic toxicology studies including an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in CHO cells, and an in vivo rat bone marrow micronucleus assay were completed with sotagliflozin. Sotagliflozin was neither mutagenic nor clastogenic in the three valid assays.”
Genotox: in vitro mammalian
Negative: chromosomal aberration test in CHO cells
“A standard battery of GLP genetic toxicology studies including an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in CHO cells, and an in vivo rat bone marrow micronucleus assay were completed with sotagliflozin. Sotagliflozin was neither mutagenic nor clastogenic in the three valid assays.”
Genotox: in vivo
Negative: rat bone marrow micronucleus
“A standard battery of GLP genetic toxicology studies including an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in CHO cells, and an in vivo rat bone marrow micronucleus assay were completed with sotagliflozin. Sotagliflozin was neither mutagenic nor clastogenic in the three valid assays.”
Carcinogenicity model
26-week Tg rasH2 mouse; 2-year rat
“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 2-year rat completed before the marketing application; ECAC judged both adequate
“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study. The Executive Carcinogenicity Committee (ECAC) concluded that both studies adequately addressed the carcinogenicity of sotagliflozin”
hERG / QT
hERG IC50 >23.5 µM; no QT/QTc effect in dog telemetry up to 500 mg/kg
“Sotagliflozin has an IC50 >23.5 µM in the human ether-a-go-go related gene (hERG) assay. A cardiac telemetry study in Beagle dogs showed that sotagliflozin had no significant effect on QT or QTc interval (corrected with the Fridericia method) at dose levels up to 500 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 Inpefa 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: 26-week rat NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day (FDA integrated review, p. 260)
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day
“the low-observed-adverse level (LOAEL) for male rats and No-observed adverse level (NOAEL) for female rats in 26-week oral sotagliflozin were 30 and 30 mg/kg/day, respectively; the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No significant CNS accumulation; no selective association with melanin-containing tissues
“There was no significant accumulation of radioactivity in the central nervous system (CNS), and radioactivity was not selectively associated with the melanin-containing tissues or red blood cells.”
Modality-specific risk
Prostate inflammation in rats of unclear clinical relevance
“Clinical implication of prostate inflammation observed in rats is unclear and may become apparent with post-market experience.”
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
- Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
- Volume Depletion
- Genitourinary Infections, including Urosepsis, Pyelonephritis Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
- Positive Urine Glucose Test
- Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Metabolic & endocrineNephrotoxicityInfections
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 Inpefa 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: 26-week rat NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day (FDA integrated review, p. 260)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog oral study with 4-week recovery (26-week rat also with 4-week recovery)
“26-week repeat dose study (with 4 weeks recovery) in the rat, and 39-week repeat dose study (with 4 weeks recovery) in the dog.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies (with 4-week recovery), plus 13-week rat and dog studies
“13-week repeat dose studies (with 4 weeks recovery) in the rat and the dog, 26-week repeat dose study (with 4 weeks recovery) in the rat, and 39-week repeat dose study (with 4 weeks recovery) in the dog.”
DART package
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“Sotagliflozin did not impair fertility or alter early embryonic development in the rat at doses up to 300 mg/kg/day, the highest dose evaluated. Embryo-fetal development was evaluated in rats and rabbits.”
Reproductive & developmental
Not teratogenic in rats (100 mg/kg) or rabbits (200 mg/kg); maternal and fetal toxicity with malformations in rats at 350 mg/kg
“Sotagliflozin was not teratogenic in the rat at 100 mg/kg (40X MHRD) or in the rabbit at 200 mg/kg (9X MHRD). In rats, a higher dose (350 mg/kg; 161X MHRD) caused both maternal and fetal toxicity including significant reduction in maternal weight gain, embryo-lethality, reduced fetal weights, altered sex ratio, and cardiovascular and skeletal malformations.”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In a prenatal and postnatal development study in pregnant and lactating rats, sotagliflozin was administered at oral doses up to 100 mg/kg/day from gestation Day 6 through to lactation Day 20 (weaning).”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study.”
Carcinogenicity model
26-week Tg rasH2 mouse; 2-year rat
“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 2-year rat completed before the marketing application; ECAC judged both adequate
“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study. The Executive Carcinogenicity Committee (ECAC) concluded that both studies adequately addressed the carcinogenicity of sotagliflozin”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 26-week NOAEL 30 mg/kg/day (males) ~8x human AUC at MRHD
“Study Type Species Sex NOEL/NOAEL (mg/kg/day) AUC0-24h (ng*hr/mL) MOEa 26-Week Repeat-dose Rat M 30 15 077 8x”
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day
“the low-observed-adverse level (LOAEL) for male rats and No-observed adverse level (NOAEL) for female rats in 26-week oral sotagliflozin were 30 and 30 mg/kg/day, respectively; the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”
Efficacy evidenceopen answer page →
Efficacy evidence
Metabolic rat model of HFpEF: improved diastolic dysfunction markers (LVEDP, left atrial remodeling, IVRT)
“In conclusion, chronic treatment with sotagliflozin in a metabolic rat model of HFpEF improved strong in vivo surrogate markers of diastolic dysfunction including left ventricular end-diastolic pressure, left atrial remodeling, and isovolumetric relaxation time.”
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
FDA: HFpEF rat model improved cardiac surrogate markers, but without an SGLT2-inhibitor control SGLT1 vs SGLT2 contribution cannot be distinguished
“The in vivo pharmacology study using a rat model of heart failure with preserved ejection fraction (HFpEF) showed significant improvement in surrogate markers of cardiac function following treatment with sotagliflozin for 6 weeks. However, a concurrent control with a SGLT2 inhibitor was not included in the study and the contribution by SGLT2 vs. SGLT1 inhibition cannot be distinguished.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAcceptedBeyond the letter
Major human metabolite sotagliflozin-3-O-glucuronide not qualified in animal studies (formed at much lower levels in rodents, absent in dog)
Why: Experience with other glucuronides; metabolite has minimal SGLT1/SGLT2 activity and is not an acyl glucuronide · Class precedent · Pharmacology or kinetics
“The main human metabolite sotagliflozin-3-O-glucuronide was formed in rats and mice at much lower levels than in humans and was not found in dog. Whereas this metabolite is not qualified in these animal studies it is not considered a safety concern, based on experience with other glucuronides.”
“However, the toxicological concern of sotagliflozin-3-Oglucuronide is minimal as the metabolite demonstrated minimal pharmacological activity at SGLT1 and SGLT2 and it is not an acyl glucuronide. Additional evaluation was not considered necessary.”
OtherAcceptedBeyond the letter
NOAELs set without treating pharmacological glucosuria as adverse
Why: Glucosuria is the desired clinical effect, so a NOAEL based on it would not be meaningful · Pharmacology or kinetics
“While it is generally not acceptable to disregard an adverse effect that is related to primary pharmacology, and glucosuria would normally be considered an adverse effect, in this case such NOAEL determination would not be meaningful. Glucosuria is the desired effect in the clinical situation.”
“The NOAEL values proposed by the applicant are endorsed.”
Efficacy modelQuestioned
HFpEF rat model lacked a concurrent SGLT2-inhibitor control, so SGLT1 vs SGLT2 contribution cannot be distinguished
“However, a concurrent control with a SGLT2 inhibitor was not included in the study and the contribution by SGLT2 vs. SGLT1 inhibition cannot be distinguished.”
Similar precedents
BrenzavvySmall molecules · bexagliflozin · SGLT2Monkey + rodent · 39 wkCardamystSmall molecules · etripamil · L-type calcium channelMonkey + rodent · 26 wkAlyftrekSmall molecules · vanzacaftor, tezacaftor and deutivacaftor · CFTRRodent + dog or minipig · 39 wkAttrubySmall molecules · acoramidis · Transthyretin (stabiliser)Rodent + dog or minipig · 39 wkAzstarysSmall molecules · serdexmethylphenidate and dexmethylphenidate · Dopamine/norepinephrine reuptakeRodent + dog or minipig · 26 wkBylvaySmall molecules · odevixibat · IBATRodent + dog or minipig · 39 wk