Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
Pharmacotherapeutic group: Antivirals for systemic use, other antivirals
ATC code: J05AX31
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 EC 95 for lenacapavir was 4 nM (3.87 ng per mL) in the MT-4 T-cell line for wild-type HIV-1 virus.
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.
There were 2 incident infections (infections that occurred after starting lenacapavir for HIV-1 PrEP) among participants in the lenacapavir group of the PURPOSE 1 trial. Both infections occurred after the time of the primary analysis. Genotyping of virus in one of the participants revealed no lenacapavir resistance-associated capsid substitutions. The second participant had viral loads that were too low for genotyping.
There were 3 incident infections among participants in the lenacapavir group of the PURPOSE 2 trial. One of the infections occurred after the time of the primary analysis. Lenacapavir resistance-associated substitutions were detected in viruses from the 3 participants, 2 with N74D, and 1 with Q67H/K70R.
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=32), 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 (16-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.
The efficacy and safety of lenacapavir in preventing the acquisition of HIV-1 were evaluated in two randomised, double-blind, active-controlled, multinational trials (PURPOSE 1 and PURPOSE 2).
This study was conducted in sexually active cisgender women. Participants were randomised to receive lenacapavir per the recommended dosing schedule (see Table 1, section 4.2; n=2134), once daily FTC/TAF (n=2136), or once daily FTC/TDF (n=1068) in a 2:2:1 ratio.
The median age of participants was 21 years (range, 16-26); and 99.9% were Black. Baseline characteristics in the randomised participants were similar to the screened population.
The efficacy of lenacapavir was established by comparing the HIV-1 incidence in the lenacapavir group to the HIV-1 incidence in the FTC/TDF group. Incident HIV-1 infections were observed in none (0%) of the participants in the lenacapavir group compared to 16 (1.5%) participants in the FTC/TDF group. Lenacapavir demonstrated superiority with a 100% reduction in the risk of HIV-1 acquisition over FTC/TDF (Table 3).
Table 3. Overall HIV-1 Infection Outcomes in PURPOSE 1:
| Lenacapavir n=2134 | FTC/TDF n=1068 | Rate Ratio (95% CI) | |
|---|---|---|---|
| Person-years | 1939 | 949 | - |
| HIV-1 infections (incidence rate per 100 person-years) | 0 (0.00) | 16 (1.69) | Lenacapavir / FTC/TDF: 0.000 (0.000, 0.101) p < 0.0001 |
CI = confidence interval
This study was conducted in sexually active cisgender men, transgender women, transgender men, and gender nonbinary individuals. Participants were randomised to receive lenacapavir per the recommended dosing schedule (see Table 1, section 4.2; n=2179) or once daily FTC/TDF (n=1086) in a 2:1 ratio.
The median age of participants was 29 years (range, 17-74); 33% were White; 27% were Black, 13% were Asian; 63% were Hispanic/Latine; 22% identified as gender-diverse (transgender women, transgender men, and gender nonbinary people); and 1% were over 65 years. Baseline characteristics in the randomised participants were similar to the screened population.
The efficacy of lenacapavir was established by comparing the HIV-1 incidence in the lenacapavir group to the HIV-1 incidence in the FTC/TDF group. Incident HIV-1 infections were observed in 2 (0.1%) participants in the lenacapavir group compared to 9 (0.8%) participants in the FTC/TDF group. Lenacapavir demonstrated superiority with an 89% reduction over FTC/TDF (Table 4). HIV-1 infections in the two participants receiving lenacapavir were diagnosed using standard serologic HIV testing.
Table 4. Overall HIV-1 Infection Outcomes in PURPOSE 2:
| Lenacapavir n=2179 | FTC/TDF n=1086 | Rate Ratio (95% CI) | |
|---|---|---|---|
| Person-years | 1938 | 967 | - |
| HIV-1 infections (incidence rate per 100 person-years) | 2 (0.1) | 9 (0.93) | Lenacapavir / FTC/TDF: 0.111 (0.024, 0.513) p = 0.00245 |
CI = confidence interva
The European Medicines Agency has deferred the obligation to submit the results of studies with lenacapavir in one or more subsets of the paediatric population in prevention of HIV-1 (see section 4.2 for information on paediatric use).
Absolute bioavailability of lenacapavir following subcutaneous administration was 91% based on population pharmacokinetic analysis. Subcutaneously administered lenacapavir forms a drug depot whereby lenacapavir is slowly released from the site of administration, with peak plasma concentrations occurring 84 days post dose.
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 based on population pharmacokinetic analysis (approximately 4 to 7%). 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.
The population pharmacokinetic parameter estimates of lenacapavir after oral and subcutaneous administration to adult and adolescent (weighing at least 35 kg) participants are provided in Table 5. Similar exposures are achieved when lenacapavir is administered subcutaneously in the abdomen or thigh.
Table 5. Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration to adult and adolescent participants receiving Yeytuo:
| Parameter Mean (%CV)a,b | Day 1 to end of Week 26 | Steady State |
|---|---|---|
| AUCtau (h•ng/mL) | 188112 (41.0) | 257332 (38.7) |
| Cmax (ng/mL) | 73.8 (55.6) | 82.5 (48.4) |
| Ctrough (ng/mL) | 27.0 (58.3) | 37.0 (60.7) |
CV = Coefficient of Variation
a Simulated exposures utilising population PK analysis.
b Mean lenacapavir plasma concentrations reached inhibitory quotient 4 (IQ4; 4-fold greater than the in vitro protein adjusted 95% effective concentration) associated with significant antiviral activity by Day 2 of the required initiation dosing and were maintained above IQ4 through the dosing interval of 26 weeks.
Lenacapavir steady state volume of distribution was 1657 litres based on population pharmacokinetic analysis. Lenacapavir is highly bound to plasma proteins (99.8%).
Following a single intravenous dose of radiolabelled-lenacapavir to healthy subjects, 76% of the total radioactivity was recovered from faeces and <1% from urine. Unchanged lenacapavir was the predominant moiety in plasma (69%) and faeces (33%). Metabolism played a lesser role in lenacapavir elimination. Lenacapavir was metabolised via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A 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. Systemic clearance of lenacapavir was 3.4 L/h 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 pharmacokinetic analysis using data from trials in adults, including a limited number of elderly participants (n=19; ≥65 to 78 years), and adolescents weighing at least 35 kg did not identify any clinically relevant differences in the exposure of lenacapavir due to age, sex assigned at birth, gender identity, race, ethnicity, or weight.
The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated Phase 1 trial in participants with moderate hepatic impairment (Child-Pugh Class B). Lenacapavir mean 16 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 individuals with moderate hepatic impairment (Child-Pugh B) compared to participants 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 individuals with severe hepatic impairment (Child-Pugh C) (see section 4.2).
The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated study in participants 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 participants with severe renal impairment compared with participants with normal renal function; however, the increase was not considered clinically relevant. The pharmacokinetics of lenacapavir have not been studied in individuals with end-stage renal disease, including those on dialysis (see section 4.2). As lenacapavir is approximately 99.8% protein bound, dialysis is not expected to alter exposures of lenacapavir.
No clinically relevant changes in lenacapavir exposure during pregnancy and postpartum were observed compared to lenacapavir exposures in non-pregnant participants.
The median (Q1, Q3) lenacapavir concentration in human breast milk to maternal plasma ratio in participants (n=102 matched pairs) who received Yeytuo was 0.52 (0.38, 0.77). The median (Q1, Q3) infant plasma concentration (n=98) was 1.63 ng/mL (0.87, 2.85) as compared to the median (Q1, Q3) matched maternal plasma concentration (n=96) of 65.65 ng/ml (46.00, 91.10). The median (Q1, Q3) infant-to-mother plasma ratio for lenacapavir in infants (n=98 matched pairs) who were breastfed by participants receiving Yeytuo was 0.02 (0.01, 0.05).
Non-clinical data revealed 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 88 times the exposure in humans at the recommended human dose (RHD).
In a 2-year rat carcinogenicity study, there were lenacapavir-treatment induced subcutaneous primary sarcomas associated with fibrosis and inflammation present at the injection sites in animals administered 927 mg/kg/dose once every 13 weeks. 11/110 animals manifested sarcomas at the high dose where each animal had up to 16 injection sites – corresponding to an incidence of <1% total injection sites across animals at the high dose. Drug concentrations in the injection depot sites are difficult to determine but systemically, the 927 mg/kg dose corresponds to 44 times the exposure in humans at the RHD. At the no-observed-adverse-effect level (NOAEL), the 309 mg/kg/dose corresponds to 25 times the exposure in humans at the RHD. Rats are prone to sarcoma formation at the subcutaneous injection site, but a clinical relevance cannot be excluded considering the long duration of the drug depot in humans. There were no neoplasms associated with systemic exposure to lenacapavir at any dose.
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 9 (male) and 6 (female) times the human exposure at the RHD. In rats and rabbits, embryofoetal development was not affected at exposures up to 20 and 159 times the human exposure, respectively, at the RHD. In rats, 17 pre- and postnatal development was not affected at exposures up to 6 times the human exposure at the RHD.
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