Sunlenca (lenacapavir): what was done before first-in-human, and what came after?

Precedia/Small molecules/Sunlenca/Tox package

Sunlenca: what was done before first-in-human, and what came after?

lenacapavir · HIV-1 capsid

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.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

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)

Full method, every step sourced →

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.”

✓ VerifiedFDA integrated review, p. 358Source ↗

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.”

✓ VerifiedFDA integrated review, p. 270Source ↗

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.”

✓ VerifiedFDA integrated review, p. 271Source ↗

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”

✓ VerifiedUS prescribing informationSource ↗

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.”

✓ VerifiedEMA assessment report, p. 27Source ↗

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.”

✓ VerifiedFDA integrated review, p. 271Source ↗

Carcinogenicity model

26-week Tg rasH2 mouse and 2-year rat, subcutaneous every 13 weeks

✓ VerifiedFDA integrated review, p. 271Source ↗

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).”

✓ VerifiedEMA assessment report, p. 34Source ↗

Summary across all 211 small molecules →

Sunlenca: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other small molecules