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.”
Species: general tox
Rat (up to 6-month) and dog (up to 9-month), 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.”
Species: DART
Rat (oral EFD) and rabbit (intravenous EFD)
“No lenacapavir-related effects on embryo-fetal development (EFD) occurred at doses up to 30 mg/kg lenacapavir when orally administered to rats once daily from gestation day (GD) 6 to 17 at exposures 16-fold the RHD. In the rabbit EFD study, lower body weight gains at doses up to 20 mg/kg correlated to a dose-dependent decrease in food intake following intravenous administration of lenacapavir.”
Species: carcinogenicity
Tg rasH2 mouse (26-week) and Wistar Hannover rat (2-year), subcutaneous
“The carcinogenicity potential of lenacapavir is being evaluated in a 26-week study (single subcutaneous injection given once every 13 weeks for a total of two doses) in 001178-T (hemizygous) RasH2 mice and a 2-year study (single subcutaneous injection given once every 13 weeks for a total of eight doses) in Wister Hanover rats.”
Surrogate used in
No surrogate used; lenacapavir tested directly
“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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Human peripheral lymphocyte clastogenicity assay: negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
26-week Tg rasH2 mouse and 2-year rat, subcutaneous every 13 weeks
“The carcinogenicity potential of lenacapavir is being evaluated in a 26-week study (single subcutaneous injection given once every 13 weeks for a total of two doses) in 001178-T (hemizygous) RasH2 mice and a 2-year study (single subcutaneous injection given once every 13 weeks for a total of eight doses) in Wister Hanover rats.”
Carcinogenicity timing
6-month Tg rasH2 mouse and 2-year rat studies in progress at the marketing application
“A 6-month transgenic mouse (TgRasH2) and a 2-year rat carcinogenicity studies with lenacapavir are stated to be in progress becoming available between end of 2021 and early 2023).”
hERG / QT
Not conducted: lenacapavir formed a suspension at ≥0.1 µM in the patch-clamp vehicle
“As lenacapavir became a suspension at concentrations ≥ 0.1 µM in the DMSO/buffer vehicle used for the patch clamp technique no GLP hERG assay was performed.”
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.”
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
- Immune Reconstitution Syndrome
- Long-Acting Properties and Potential Associated Risks with SUNLENCA
- Injection Site Reactions
Hypersensitivity & infusion reactions
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Dog subcutaneous study, dosed every 4 weeks for up to 37 weeks, with 2- or 13-week recovery
“Animals were dosed once every 4 weeks for up to 37 weeks then sacrificed after a 2- or 13-week recovery period.”
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.”
DART package
Species: DART
Rat (oral EFD) and rabbit (intravenous EFD)
“No lenacapavir-related effects on embryo-fetal development (EFD) occurred at doses up to 30 mg/kg lenacapavir when orally administered to rats once daily from gestation day (GD) 6 to 17 at exposures 16-fold the RHD. In the rabbit EFD study, lower body weight gains at doses up to 20 mg/kg correlated to a dose-dependent decrease in food intake following intravenous administration of lenacapavir.”
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”
PPND / ePPND: when
PPND in rat (single subcutaneous dose) completed before the marketing application
“For the assessment of long-term development toxicity effects from prenatal exposure, a prenatal and postnatal development (PPND) rat study was conducted.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week) and Wistar Hannover rat (2-year), subcutaneous
“The carcinogenicity potential of lenacapavir is being evaluated in a 26-week study (single subcutaneous injection given once every 13 weeks for a total of two doses) in 001178-T (hemizygous) RasH2 mice and a 2-year study (single subcutaneous injection given once every 13 weeks for a total of eight doses) in Wister Hanover rats.”
Carcinogenicity model
26-week Tg rasH2 mouse and 2-year rat, subcutaneous every 13 weeks
“The carcinogenicity potential of lenacapavir is being evaluated in a 26-week study (single subcutaneous injection given once every 13 weeks for a total of two doses) in 001178-T (hemizygous) RasH2 mice and a 2-year study (single subcutaneous injection given once every 13 weeks for a total of eight doses) in Wister Hanover rats.”
Carcinogenicity timing
6-month Tg rasH2 mouse and 2-year rat studies in progress at the marketing application
“A 6-month transgenic mouse (TgRasH2) and a 2-year rat carcinogenicity studies with lenacapavir are stated to be in progress becoming available between end of 2021 and early 2023).”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL 6- to 8-fold human exposure at RHD in 6-month rat (32-fold in 2-month rat)
“Based on systemic exposure, at the no observed adverse effect level (NOAEL), lenacapavir was 32-fold the human exposure at the recommended human dose (RHD) in the 2-month rat study and 6- to 8-fold in the 6-month rat study.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cell-culture antiviral activity in human MT-4 T-cell line (EC50 0.19 nM)
“In MT-4 cells, LEN demonstrated antiviral activity with an EC50 value of 0.19nM and a selectivity index (CC50 value/EC50 value) of 140,000.”
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: preclinical characterisation of antiviral activity appropriate; novel mechanism established
“The preclinical characterisation of antiviral activity is appropriate. The mechanism of action is novel and has been established.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a condition
No completed carcinogenicity studies at submission; rasH2 mouse and 2-year rat studies ongoing, submitted post-approval
Why: Intended patient population allows post-approval submission; no clear warning signals for oncogenicity · Within the guideline · Weight of evidence
“No carcinogenicity studies have been submitted except a dose-range finding transgenic RasH2 study (which did not find any signs of neoplasia).”
“As the intended patient population allows the option of post-approval submission, and there are no clear warnings signals for oncogenicity, the post-approval submission approach is acceptable.”
Safety pharmacologyAcceptedBeyond the letter
No GLP hERG assay because lenacapavir precipitated in the patch clamp vehicle
Why: No cardiovascular effects in dogs at 20-fold clinical free Cmax; negative human thorough QT study · Human data · Weight of evidence
“As lenacapavir became a suspension at concentrations ≥ 0.1 µM in the DMSO/buffer vehicle used for the patch clamp technique no GLP hERG assay was performed.”
“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.”
OtherCriticised but acceptedBeyond the letter
Toxicology program mostly not run with the exact clinical subcutaneous formulation; several vehicle variations used
Why: All subcutaneous formulations produced more or less the same toxicity findings · Weight of evidence
“It should be noted that the toxicological programme has in most cases not been conducted with the exact clinical formulations - especially the SC formulation (lenacapavir sodium 26.46% [w/w], PEG300 50.13% [w/w] and water) where several variations have been used in the toxicological studies (containing variations of combinations of PEG200, PEG300, P188, ethanol and/or NaOH).”
“This is considered a weakness but still acceptable as all SC exposure independent of exact formulation generated more or less the same toxicity findings.”
DARTCriticised but acceptedBeyond the letter
Rat embryofetal study by oral route with low bioavailability; only rabbit achieved higher systemic exposure
Why: Absence of adverse DART signals · Weight of evidence
“With regard to the DART studies, the choice of conducting repeated oral exposure in rat (which has low bioavailability) and IV exposure in rabbit means that, in practice, a setup where only one animal model has achieved a higher systemic exposure (i.e., rabbit).”
“It is agreed that the there is an absence of adverse DART signals.”
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