Retevmo
selpercatinib
Species
RatPig
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 Göttingen minipig
“To assess the safety of selpercatinib, Loxo conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and Gottingen mini pigs.”
Why that species
Relevant rodent and non-rodent species based on pharmacokinetic and metabolic considerations
“Rats (Sprague-Dawley) and minipig (Göttingen) were chosen as relevant rodent and non-rodent species for toxicology program based on pharmacokinetic and metabolic considerations.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 13-week study in minipigs, male and female animals received selpercatinib at doses of 2, 5, or 15 mg/kg/day for 13 weeks via oral gavage.”
Species: general tox
Sprague Dawley rat and Göttingen minipig (up to 13 weeks)
“To assess the safety of selpercatinib, Loxo conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and Gottingen mini pigs.”
Species: DART
Rat only (fertility, EFD); second species not warranted given high fetal toxicity near human exposure
“Because of high fetal toxicity at doses resulting exposures similar to the human exposure at the 160 mg twice daily clinical dose, studies in a second species were not warranted.”
Species: carcinogenicity
Rat (2-year) and rasH2 transgenic mouse (6-month)
“Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”
Surrogate used in
No surrogate used; selpercatinib tested directly
“In a 13-week study in minipigs, male and female animals received selpercatinib at doses of 2, 5, or 15 mg/kg/day for 13 weeks via oral gavage.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“To assess the safety of selpercatinib, Loxo conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and Gottingen mini pigs.”
Pivotal GLP studies
13-week GLP oral gavage studies in rats and minipigs, with 4-week recovery
“Due to sex-specific differences in exposure, in the 13-week toxicology study male rats received selpercatinb at doses of 2, 7.5, or 20 mg/kg while females received 7.5, 25, or 75 mg/kg daily via oral gavage, followed by a 4-week recovery.”
Route in tox
Oral gavage
“In a 13-week study in minipigs, male and female animals received selpercatinib at doses of 2, 5, or 15 mg/kg/day for 13 weeks via oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vitro micronucleus; positive in rat in vivo micronucleus at high doses
“In the standard genotoxicity battery, selpercatinib was negative in both the Ames and the in vitro micronucleus assay regardless of metabolic activation. In the in vivo micronucleus assay in rats, selpercatinib did cause increases in micronuclei at high dose levels”
Carcinogenicity
2-year rat and 6-month rasH2 mouse: not carcinogenic
“not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”
Reproductive & developmental
Rat EFD: embryolethality and malformations at maternal exposures approximately equal to human exposure
“Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily.”
Safety pharmacology
hERG IC50 1.1 µM; QT prolongation in female minipigs at 5 and 12 mg/kg in 28-day study
“LOXO-292 inhibited the hERG potassium current with IC50 of 1.1 μM in the GLP in vitro hERG assay studies, respectively, suggesting low potential for QTc prolongation. In the 28-day minipig study, statistically significant QT prolongation was observed in females administered 5 and 12 mg/kg LOXO-292 when compared to controls”
Genotox: Ames
Negative with or without metabolic activation
“Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation.”
Genotox: in vitro mammalian
In vitro micronucleus in human peripheral lymphocytes: negative
“Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation.”
Genotox: in vivo
Rat micronucleus: positive at >7 times human Cmax
“Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the C max at the human dose of 160 mg twice daily.”
Carcinogenicity model
2-year rat and 6-month rasH2 mouse; not carcinogenic
“Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”
Carcinogenicity timing
Rat and mouse carcinogenicity studies: postmarketing requirements at US approval (MTC indication)
“however, as the MTC indication includes patients who can have a prolonged life expectancy, FDA has requested carcinogenicity studies for selpercatinib as postmarketing requirements (PMRs).”
hERG / QT
hERG IC50 1.1–2.79 µM (low potential), but QT prolongation in female minipigs at 5 and 12 mg/kg
“Though hERG potassium current assays demonstrated low potential for LOXO-292 to cause QTc prolongation, with IC50s of 1.1 or 2.79 μM, respectively, female mini pigs in the 4-week study that received 5 or 12 mg/kg selpercatinib for 28 days had statistically significant QT prolongation compared to controls.”
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 Retevmo 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: Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure (FDA multi-discipline review, p. 80)
NOAEL / key findings
Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure
“Minipigs were exquisitely sensitive to selpercatinib and was the most sensitive species. Major toxicological findings that occurred in the minipig were at doses that induced moribundity/lethality with exposures below therapeutic exposures in human.”
Risksopen answer page →
Immune & cytokine safety
Hematopoietic and lymphoid system changes
“Similar findings included: changes in hematopoietic, lymphoid, and GIT systems, liver and altered inorganic phosphorus levels (hyperphosphatemia).”
Biodistribution & persistence
Rat QWBA: highest in uveal tract, eyes, Harderian gland, meninges and melanin-containing skin
“Tissues from male rats that received 10 mg/kg [14C]-labeled selpercatinib showed the highest levels in uveal tract (24 hours post-dose), eyes (24 hr), Harderian gland (2 hr), meninges (72 hr), and pigmented (melanin-containing) skin (8 hr).”
Modality-specific risk
QTc prolongation (labeled warning)
“The label includes a warning for QTc prolongation.”
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
- Interstitial Lung Disease/Pneumonitis
- Hypertension
- QT Interval Prolongation
- Hemorrhagic Events
- Hypersensitivity
- Tumor Lysis Syndrome
- Risk of Impaired Wound Healing
- Hypothyroidism
- Embryo-Fetal Toxicity
- Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients
HepatotoxicityImmune-mediated reactionsPulmonary toxicityCardiovascularBleedingHypersensitivity & infusion reactionsSecondary malignancyMetabolic & endocrineEmbryo-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
28-day rat and minipig repeat-dose studies submitted with the original IND
“Dr. Brian Cholewa reviewed the 28-day repeat-dose toxicology studies in rats and minipigs under the original IND submission (IND 133193).”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Retevmo 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: Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure (FDA multi-discipline review, p. 80)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and minipig oral gavage studies, each with 4-week recovery
“A 13-Week Daily Oral Gavage Toxicity and Toxicokinetic Study of LOXO-292 in Gottingen Minipigs with a 4-Week Recovery Phase”
Pivotal GLP studies
13-week GLP oral gavage studies in rats and minipigs, with 4-week recovery
“Due to sex-specific differences in exposure, in the 13-week toxicology study male rats received selpercatinb at doses of 2, 7.5, or 20 mg/kg while females received 7.5, 25, or 75 mg/kg daily via oral gavage, followed by a 4-week recovery.”
DART package
Species: DART
Rat only (fertility, EFD); second species not warranted given high fetal toxicity near human exposure
“Because of high fetal toxicity at doses resulting exposures similar to the human exposure at the 160 mg twice daily clinical dose, studies in a second species were not warranted.”
Reproductive & developmental
Rat EFD: embryolethality and malformations at maternal exposures approximately equal to human exposure
“Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily.”
PPND / ePPND: when
Not conducted: severe EFD findings near human exposure made PPND uninformative
“Given the severity of the findings at the human equivalent exposure level, an additional PPND is unlikely to provide information that would significantly affect the human risk assessment and such a study is not warranted either to support approval in either of the proposed indications or as a postmarketing requirement.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and rasH2 transgenic mouse (6-month)
“Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”
Carcinogenicity model
2-year rat and 6-month rasH2 mouse; not carcinogenic
“Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”
Carcinogenicity timing
Rat and mouse carcinogenicity studies: postmarketing requirements at US approval (MTC indication)
“however, as the MTC indication includes patients who can have a prolonged life expectancy, FDA has requested carcinogenicity studies for selpercatinib as postmarketing requirements (PMRs).”
Safety marginopen answer page →
Safety margin at NOAEL
91-day minipig HNSTD/NOAEL 5 mg/kg/day: ~0.2–0.3x human AUC
“In the 91-day study in minipig, the HNSTD and NOAEL was 5 mg/kg/day (175 mg/m2/day) and exposure at this dose corresponded to approximately 0.2 to 0.3 times the human geometric mean AUC at the recommended clinical dose.”
NOAEL / key findings
Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure
“Minipigs were exquisitely sensitive to selpercatinib and was the most sensitive species. Major toxicological findings that occurred in the minipig were at doses that induced moribundity/lethality with exposures below therapeutic exposures in human.”
Efficacy evidenceopen answer page →
Efficacy evidence
TT medullary thyroid carcinoma and LC-2/ad lung adenocarcinoma xenografts in mice
“Using these cell lines in in vivo studies, investigators observed selpercatinib dose-dependent reduction in tumor growth in mice implanted with TT human thyroid medullary carcinoma and human LC-2/ad human lung adenocarcinoma.”
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: good potency and selectivity against RET, RET fusions and RET mutants
“Selpercatinb inhibits RET, RET fusions, and multiple RET mutants with a good potency and selectivity.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a condition
No carcinogenicity studies before approval although MTC patients can live long; rat and mouse studies required postmarketing
Why: Slow-growing MTC follows ICH S9 principles, but prolonged life expectancy warrants carcinogenicity studies after approval · Within the guideline
“however, as the MTC indication includes patients who can have a prolonged life expectancy, FDA has requested carcinogenicity studies for selpercatinib as postmarketing requirements (PMRs).”
“FDA agrees that while drugs intended for the treatment of patients with often slow growing tumors such as MTC can be developed following the principles of ICH S9, additional studies, such as a full battery of reproductive toxicology studies and carcinogenicity studies may be warranted to support further development in these patient populations.”
Safety marginVerdict not stated
No exposure margin at the 91-day minipig HNSTD/NOAEL (0.2-0.3 times human AUC)
“In the 91-day study in minipig, the HNSTD and NOAEL was 5 mg/kg/day (175 mg/m2/day) and exposure at this dose corresponded to approximately 0.2 to 0.3 times the human geometric mean AUC at the recommended clinical dose.”
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