Chemical formula: C₄₁H₃₆ClF₈N₇O₅S₂ Molecular mass: 968.28 g/mol PubChem compound: 133082658
Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (CA) subunits. Lenacapavir inhibits HIV-1 replication by interfering with multiple, essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of CA subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).
The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes. The EC50 and selectivity (CC50/EC50) values ranged from 30 to 190 pM and 140,000 to >1,670,000, respectively, for wild-type (WT) HIV-1 virus. The protein-adjusted EC95 for lenacapavir was 4 nM (3.87 ng per mL) in the MT-4 T-cell line for wild-type HIV-1 virus.
In a study of lenacapavir in combination with representatives from the main classes of antiretroviral agents (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs], integrase strand-transfer inhibitors [INSTIs], and protease inhibitors [PIs]), synergistic antiviral effects were observed. No antagonism was observed for these combinations.
Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G, H.
Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.
HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. In vitro resistance selections with lenacapavir identified 7 mutations in CA: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination. Phenotypic susceptibility to lenacapavir was reduced 4- to >3,226-fold, relative to WT virus. HIV-1 variants with >10-fold reduction in susceptibility to lenacapavir compared to WT virus displayed diminished replication capacity in primary human CD4+ T lymphocytes and macrophages (0.03–28% and 1.9–72% of WT virus, respectively).
In GS-US-200-4625 (‘CAPELLA’), 29% (21/72) of heavily treatment experienced-patients met the criteria for resistance analyses through Week 52 (HIV-1 RNA ≥50 copies/mL at confirmed virologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit]) and were analysed for lenacapavir-associated mutation emergence. Lenacapavir-associated capsid mutations were found in 11.1% (n=8) of these patients. The M66I CA mutation was observed in 8.3% (n=6) of patients, alone or in combination with other lenacapavir-associated capsid mutations including N74D, Q67Q/H/K/N, K70K/N/R/S, T107T/C, and T107A. One patient had a K70H CA mutation emerging along with T107T/N, and one patient had emergence of both Q67H and K70R in CA.
Phenotypic analyses indicated that the M66I and K70H mutations were associated with an average decrease in lenacapavir susceptibility of 234-fold and 265-fold, respectively, when compared to WT. The Q67H + K70R CA resistance pattern was associated with a 15-fold decrease in lenacapavir susceptibility.
The in vitro antiviral activity of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the 4 main classes of antiretroviral agents (NRTIs, NNRTIs, INSTIs and PIs; n=58), as well as to viruses resistant to maturation inhibitors (n=24), and to viruses resistant to the entry inhibitors (EI) class (fostemsavir, ibalizumab, maraviroc, and enfuvirtide; n=42). These data indicated that lenacapavir remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms.
In a parallel-design thorough QT/QTc study, lenacapavir had no clinically relevant effect on the QTcF interval. At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of lenacapavir), the predicted mean (upper 90% confidence interval) increase in QTcF interval was 2.6 (4.8) msec, and there was no association (p=0.36) between observed lenacapavir plasma concentrations and change in QTcF.
Lenacapavir exposures (AUCtau, Cmax and Ctrough) were 29% to 84% higher in heavily treatment experienced patients with HIV-1 infection as compared to subjects without HIV-1 infection based on population pharmacokinetics analysis.
Lenacapavir is completely absorbed following subcutaneous administration. Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex with peak plasma concentrations occurring 84 days postdose.
Lenacapavir is absorbed following oral administration with peak plasma concentrations occurring approximately 4 hours after administration of lenacapavir. Absolute bioavailability following oral administration of lenacapavir is low (approximately 6 to 10%). Lenacapavir is a substrate of P-gp.
Lenacapavir AUC, Cmax and Tmax were comparable following administration of a low fat (~400 kcal, 25% fat) or high fat (~1000 kcal, 50% fat) meal relative to fasted conditions. Oral lenacapavir can be administered without regard to food.
Simulated steady state exposures of lenacapavir following recommended dosing regimen in heavily treatment experienced patients with HIV are provided in the following table.
Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration:
| Parameter Mean (%CV)a | Day 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC) | ||
|---|---|---|---|
| Day 1 to Day 15 | Day 15 to end of month 6 | Steady state | |
| Cmax (ng/mL) | 69.6 (56) | 87 (71.8) | 97.2 (70.3) |
| AUCtau (h•ng/mL) | 15,600 (52.9) | 250,000 (66.6) | 300,000 (68.5) |
| Ctrough (ng/mL) | 35.9 (56.8) | 32.7 (88) | 36.2 (90.6) |
CV = Coefficient of Variation; SC = subcutaneous
a Simulated exposures utilizing population PK analysis.
Lenacapavir steady state volume of distribution was 976 litres in heavily treatment experienced patients with HIV-1 infection based on population pharmacokinetic analysis.
Lenacapavir is highly bound to plasma proteins (approximately 99.8%, based on in vivo data).
Following a single intravenous dose of radiolabelled-lenacapavir to healthy subjects, 76% of the total radioactivity was recovered from feces and <1% from urine. Unchanged lenacapavir was the predominant moiety in plasma (69%) and feces (33%). Metabolism played a lesser role in lenacapavir elimination. Lenacapavir was metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A4 and UGT1A1. No single circulating metabolite accounted for >10% of plasma drug-related exposure.
The median half-life following oral and subcutaneous administration ranged from 10 to 12 days, and 8 to 12 weeks, respectively. Lenacapavir clearance was 3.62 L/h in heavily treatment experienced patients with HIV-1 infection based on population pharmacokinetic analysis.
The single dose pharmacokinetics of lenacapavir after oral administration are non-linear and less than dose proportional over the dose range of 50 to 1800 mg.
The single dose pharmacokinetics of lenacapavir after subcutaneous injection (309 mg/mL) are dose proportional over the dose range of 309 to 927 mg.
Population PK analyses using data from adult trials, including a limited number of elderly patients (n=5; ≥65 to 78 years), did not identify any clinically relevant differences in the exposure of lenacapavir due to age, gender, race/ethnicity or weight.
The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated Phase 1 trial in subjects with moderate hepatic impairment (Child-Pugh Class B). Lenacapavir mean exposures (total and unbound) were 1.47- to 2.84-fold and 2.61- to 5.03-fold higher for AUCinf and Cmax, respectively in patients with moderate hepatic impairment (Child-Pugh B) compared to subjects with normal hepatic function. However, this increase is not considered clinically relevant based on lenacapavir exposure-response. The pharmacokinetics of lenacapavir have not been studied in patients with severe hepatic impairment (Child-Pugh C).
The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated study in subjects with severe renal impairment (estimated creatinine clearance ≥15 and <30 mL/minute). Lenacapavir exposures were increased (84% and 162% for AUCinf and Cmax, respectively) in subjects with severe renal impairment compared with subjects with normal renal function; however, the increase was not considered clinically relevant. The pharmacokinetics of lenacapavir have not been studied in patients with end-stage renal disease, including those on dialysis. As lenacapavir is approximately 99.8% protein bound, dialysis is not expected to alter exposures of lenacapavir.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.
Lenacapavir was not mutagenic or clastogenic in conventional genotoxicity assays.
Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 300 mg/kg/dose once every 13 weeks, which resulted in exposures approximately 60 times the exposure in humans at the recommended human dose. A 2-year rat carcinogenicity study is ongoing.
In offspring from rat and rabbit dams treated with lenacapavir during pregnancy, there were no toxicologically significant effects on developmental endpoints.
In rats, male and female fertility was not affected at lenacapavir exposures up to 8 times the human exposure at the recommended human dose (RHD). In rats and rabbits, embryofoetal development was not affected at exposures up to 21 and 172 times the human exposure, respectively, at the RHD. In rats, pre- and postnatal development was not affected at exposures up to 7 times the human exposure at the RHD.
Transfer of lenacapavir from maternal to neonatal rats was observed in a prenatal and postnatal development study, but it is not known whether the transport occurred via the placenta or the milk; therefore the potential for lenacapavir to pass into the placenta or be excreted into milk in humans is not known.
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