Cosela
trilaciclib
Species
RatDog
Longest study
1 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Dogs were treated for seven days by iv injection followed by a 2-week drug-free recovery period.”
Species: general tox
Rat and dog: pivotal iv studies plus oral studies up to 28 days (rat) and 14 days (dog)
“day iv toxicity studies were considered the pivotal toxicity studies which cover the clinical dosing route and duration. Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing.”
Species: DART
Not conducted (short duration of clinical use, patient population needs)
“No developmental or reproductive toxicity (DART) studies were conducted, consistent with the short duration of clinical use and therapeutic needs of the patient population”
Species: carcinogenicity
Not conducted
“Carcinogenic potential of trilaciclib has not been assessed in animals.”
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
1 (7-day rat and dog iv)
“day iv toxicity studies were considered the pivotal toxicity studies which cover the clinical dosing route and duration.”
Pivotal GLP studies
7-day iv studies plus additional oral rat (up to 28-day) and dog (up to 14-day) studies
“Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing. Dose-limiting toxicity in the 14-day and 28-day studies was consistent with exaggerated pharmacology and generally similar to the 7-day iv toxicity study results.”
Route in tox
Intravenous (30-min infusion)
“Seven-day iv (30 min infusion) pilot toxicity in dogs with a two-week drug-free recovery phase.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; negative for clastogenicity in human fibroblasts; increased micronuclei in human lymphocytes in vitro
“Trilaciclib was negative for mutagenic potential in the Ames assays and negative for clastogenic potential in primary human fibroblasts. Trilaciclib increased micronucleus formation in human peripheral blood lymphocytes in vitro, suggesting clastogenic activity.”
Carcinogenicity
Not conducted
“Carcinogenic potential of trilaciclib has not been assessed in animals.”
Reproductive & developmental
Not conducted (no fertility, developmental or reproductive toxicity studies)
“No fertility, developmental, or reproductive toxicity studies were conducted in animals.”
Safety pharmacology
Low-potency hERG inhibition (IC50 ≈20 μM) and increased heart rate in dogs; no QT prolongation in animal studies
“There were signals for potential cardiovascular effects of trilaciclib based on a low potency in vitro signal for hERG inhibition (IC50 ≈ 20 μM) and increased heart rate in dogs. In vitro hERG inhibition is a biological marker of QT prolongation but no QT prolongation was observed in animal studies.”
Genotox: Ames
Negative
“Trilaciclib was negative for mutagenic potential in the Ames assays and negative for clastogenic potential in primary human fibroblasts.”
Genotox: in vitro mammalian
Micronucleus in human peripheral blood lymphocytes: positive (confounded by cell-cycle arrest); H2AX in human fibroblasts: negative
“Trilaciclib increased micronucleus formation in human peripheral blood lymphocytes in vitro, suggesting clastogenic activity. However, lymphocytes were shown to be very sensitive to the intended pharmacologic effect of G1 cell cycle by trilaciclib, so the increase in micronuclei seen in HPBL cells was confounded by direct drug-related effects on lymphocyte proliferation.”
Genotox: in vivo
Not conducted
“Genetic toxicity was not assessed in any in vivo assay (e.g., rat liver micronucleus formation in vivo to assess clastogenic potential).”
Carcinogenicity model
Not conducted: patients with SCLC already receiving chemotherapy
“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”
Carcinogenicity timing
Not required (patients with SCLC receiving chemotherapy)
“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”
hERG / QT
hERG IC50 ~20 µM (low potency); no QT prolongation in dog studies
“There were signals for potential cardiovascular effects of trilaciclib based on a low potency in vitro signal for hERG inhibition (IC50 ≈ 20 μM) and increased heart rate in dogs. In vitro hERG inhibition is a biological marker of QT prolongation but no QT prolongation was observed in animal 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 Cosela 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: Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d (FDA pharmacology/toxicology review, p. 50)
NOAEL / key findings
Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d
“Drug-related effects in the low dose were limited to slight hematology changes and hematology changes in the 10 mg/kg/d were considered of insufficient magnitude to be adverse to the animals. Marked reductions in neutrophils (↓ 60%, mean count <600/μL) and lymphocytes ((↓ 77%, mean count <60/μL) at 25 mg/kg/d were considered adverse.”
Risksopen answer page →
Immune & cytokine safety
Failure to clear catheter-related bacterial infections, suggesting compromised immune response from leukocyte suppression
“The bacterial infections likely originated from indwelling catheters but the failure to clear the infections suggest a compromised immune response, consistent with trilaciclib-mediated leukocyte and thrombocyte suppression during treatment.”
Biodistribution & persistence
Highest in thyroid, kidney, harderian, adrenal and lacrimal glands, spleen and liver; eye uveal tract and meninges in pigmented rats
“Highest radioactivity, representing drug or metabolite tissue distribution, was seen in thyroid, kidney, harderian gland, adrenal gland, lacrimal glands, spleen, and liver in non-pigmented rats with additional distribution in eye/eye uveal tract and meninges in pigmented rats.”
Modality-specific risk
Major human metabolite M8 not covered in animals (<1% in rat plasma, absent in dog plasma)
“Negligible levels of M8 (<1%) were detected in rat plasma and none were detected in dog plasma, so animals were not exposed to M8 at expected clinical exposure levels in toxicology studies.”
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
- Injection-Site Reactions, Including Phlebitis and Thrombophlebitis
- Acute Drug Hypersensitivity Reactions
- Interstitial Lung Disease/Pneumonitis
- Embryo-Fetal Toxicity
Thrombosis & embolismHypersensitivity & infusion reactionsImmune-mediated reactionsPulmonary toxicityEmbryo-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 Cosela 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: Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d (FDA pharmacology/toxicology review, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day oral gavage rat study with 3-week drug-free recovery
“Rats were treated with 0, 1, 3, or 10 mg/kg trilaciclib in 5% dextrose by oral gavage (5 mL/kg) for 28-days followed by a 3-week drug-free recovery period.”
Pivotal GLP studies
7-day iv studies plus additional oral rat (up to 28-day) and dog (up to 14-day) studies
“Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing. Dose-limiting toxicity in the 14-day and 28-day studies was consistent with exaggerated pharmacology and generally similar to the 7-day iv toxicity study results.”
DART package
Species: DART
Not conducted (short duration of clinical use, patient population needs)
“No developmental or reproductive toxicity (DART) studies were conducted, consistent with the short duration of clinical use and therapeutic needs of the patient population”
Reproductive & developmental
Not conducted (no fertility, developmental or reproductive toxicity studies)
“No fertility, developmental, or reproductive toxicity studies were conducted in animals.”
PPND / ePPND: when
Not conducted: no DART studies, given short duration of clinical use and patient population needs
“No developmental or reproductive toxicity (DART) studies were conducted, consistent with the short duration of clinical use and therapeutic needs of the patient population”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenic potential of trilaciclib has not been assessed in animals.”
Carcinogenicity model
Not conducted: patients with SCLC already receiving chemotherapy
“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”
Carcinogenicity timing
Not required (patients with SCLC receiving chemotherapy)
“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”
Safety marginopen answer page →
Safety margin at NOAEL
Pivotal iv dog study: NOAEL 5 mg/kg = 0.5x MRHD; LOAEL 15 mg/kg = 1x MRHD
“NOAEL = 5 mg/kg (0.5X MRHD) [LOAEL = 15 mg/kg (1X MRHD; consistent with exaggerated pharmacologic effect)]”
NOAEL / key findings
Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d
“Drug-related effects in the low dose were limited to slight hematology changes and hematology changes in the 10 mg/kg/d were considered of insufficient magnitude to be adverse to the animals. Marked reductions in neutrophils (↓ 60%, mean count <600/μL) and lymphocytes ((↓ 77%, mean count <60/μL) at 25 mg/kg/d were considered adverse.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vivo mouse studies of protection from chemotherapy-induced myelosuppression and of tumor protection
“The sponsor conducted numerous in vitro and in vivo pharmacology studies to investigate both intended protection from chemotherapy-induced myelosuppression as well as unintended tumor cell protection from chemotherapy-induced cytotoxicity.”
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
Low HSPC proliferation and efficient trilaciclib-mediated arrest may contribute to myeloprotection; tumor cells stay chemosensitive
“Results were consistent with tumor cells having high rates of cell proliferation and being sensitive to cytotoxic chemotherapeutic agents, and the overall low rate of proliferation and high efficacy of trilaciclib-mediated cell cycle arrest on HSPC and blood cells may contribute to myeloprotective effects of trilaciclib (Figure 12).”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
No fertility, embryo-fetal or pre/postnatal development studies despite ovary and estrus-cycle findings in rats
Why: Short duration of clinical use and patient needs; CDK4/6 inhibitor class labels already describe reproductive toxicity · Class precedent · Serious disease
“No developmental or reproductive toxicity (DART) studies were conducted, consistent with the short duration of clinical use and therapeutic needs of the patient population, but there was no additional data to inform potential endocrine/reproductive toxicity.”
“Labels for other US-listed CDK4/6 inhibitors show endocrine/reproductive toxicity in the class and potential risks can be described in the label for trilaciclib.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity assessment in animals
Why: Patients already receive chemotherapy for existing small cell lung cancer, so little to gain · Serious disease
“Carcinogenic potential of trilaciclib has not been assessed in animals.”
“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”
GenotoxicityAcceptedBeyond the letter
No in vivo genotoxicity assay; in vitro micronucleus increase in human lymphocytes
Why: Patients with SCLC are already treated with genotoxic chemotherapy, so further genotoxicity testing is not needed · Serious disease
“Genetic toxicity was not assessed in any in vivo assay (e.g., rat liver micronucleus formation in vivo to assess clastogenic potential).”
“The proposed indicated use in SCLC patients being treated with genotoxic chemotherapeutic agents also obviates a need for any further genotoxicity of trilaciclib or trilaciclib metabolites (e.g., M8) for the proposed use.”
Impurity or metaboliteAccepted with a condition
Major human metabolite M8 not formed in rat or dog and not qualified (genotoxicity unknown)
Why: M8 pharmacologically inactive; ICH S9 for advanced cancer; sponsor to submit ongoing M8 investigations · Within the guideline · Pharmacology or kinetics · Serious disease
“Given that M8 is not pharmacologically active, and consistent with ICH S9 guidance for anticancer pharmaceuticals, further qualification of M8 is not recommended for patients with advanced cancer.”
“The sponsor agreed to update the NDA with results from ongoing nonclinical investigations related to the major human metabolite, M8.”
Safety marginVerdict not stated
Pivotal IV dog study NOAEL 5 mg/kg at 0.5 times the MRHD
“NOAEL = 5 mg/kg (0.5X MRHD) [LOAEL = 15 mg/kg (1X MRHD; consistent with exaggerated pharmacologic effect)]”
Similar precedents
InrebicSmall molecules · fedratinib · JAK2Rodent + dog or minipig · 39 wkOjjaaraSmall molecules · momelotinib · JAK1/JAK2/ACVR1Rodent + dog or minipig · 39 wkVonjoSmall molecules · pacritinib · JAK2/FLT3Rodent + dog or minipig · 39 wkWayrilzSmall molecules · rilzabrutinib · BTK (reversible covalent)Rodent + dog or minipig · 39 wkOxbrytaSmall molecules · voxelotor · HbS polymerisationMonkey + rodent · 39 wkPyrukyndSmall molecules · mitapivat · Pyruvate kinase (activator)Monkey + rodent · 39 wk