Sunlenca
lenacapavir
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
“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”
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
“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”
Pivotal GLP studies
GLP oral and subcutaneous studies up to 6 months in rats and 9 months in dogs
“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”
Route in tox
Oral and subcutaneous
“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and in vivo rat micronucleus assays
“Lenacapavir was negative for mutagenesis in the in vitro reverse mutation assay, negative for clastogenicity in the in vitro assay using human peripheral lymphocytes, and negative for genotoxicity in the in vivo micronucleus assay in rats.”
Carcinogenicity
Rat SC study: injection-site malignant sarcoma (males) and fibroma/fibrosarcoma (females) at 927 mg/kg
“A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg).”
Reproductive & developmental
Rat and rabbit reproduction studies: no adverse developmental effects at ≥16x human exposure
“In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA”
Safety pharmacology
No hERG assay; no adverse cardiovascular effects in dogs at 20-fold clinical free Cmax
“As no adverse cardiovascular effects were observed in dogs at exposures 20-fold the clinical free Cmax and a human thorough QT study without significant effects at supratherapeutic doses of lenacapavir is available, the lack of a hERG study is however considered acceptable.”
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 Sunlenca 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: Injection site in both species; liver, gall bladder, kidneys and stomach in 9-month dog studies (FDA integrated review, p. 270)
NOAEL / key findings
Injection site in both species; liver, gall bladder, kidneys and stomach in 9-month dog studies
“However, repeat-dose studies up to 9 months in dogs identified the liver, gall bladder, kidneys, and stomach as targeted organs of toxicity.”
Risksopen answer page →
Immune & cytokine safety
Positive in two of three in vitro skin sensitisation assays; negative in vivo
“Using in vitro skin models, lenacapavir was not considered corrosive but was considered positive in two of three skin sensitization assays. However, in the in vivo assessment, lenacapavir was considered negative for sensitization potential.”
Biodistribution & persistence
Rat QWBA: distribution restricted by blood-brain and blood-testes barriers
“No quantifiable or low levels of radioactivity were detected in brain and testes, respectively, suggesting that distribution of [14C]-lenacapavir-derived radioactivity was restricted by the blood to brain and blood-to-testes barriers.”
Modality-specific risk
Injection-site reactions from the subcutaneous depot
“The most common toxicity noted among all of the toxicology studies was injection site reactions.”