Lenacapavir: First Approval

Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) being developed by Gilead Sciences Inc. It is available as an oral tablet and injectable solution, with the latter being a slow-release formulation to allow bi-annual subcutaneous administration. In August 2022, lenacapavir received its first approval in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen. This article summarizes the milestones in the development of lenacapavir leading to this first approval for the treatment of HIV-1 infection. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-022-01786-0.


Introduction
Infection with human immunodeficiency virus type 1 (HIV-1) can typically be managed with antiretroviral treatments, including combination antiretroviral therapy, which may increase the life expectancy of patients with HIV-1 to levels comparable to that of the general population [1]. However, treatment success relies on proper treatment adherence, the lack of which contributes to the development of viral resistance [2]. Barriers to adherence in the context of HIV-1 treatments include tolerability issues and social factors such as stigma and lack of support, in addition to factors relating to convenience (e.g. forgetting treatment, change in routine) [3]. As such, durable and convenient treatments requiring less frequent administration that can facilitate high adherence are crucial to successfully manage the disease, particularly in those with multi-drug resistant HIV.
Lenacapavir (Sunlenca ® ) is a long-acting HIV capsid inhibitor being developed by Gilead Sciences Inc. for the treatment of HIV-1 infection, formulated as an oral tablet and an injectable solution [4]. Lenacapavir inhibits viral replication at both the early and late stages of the HIV life cycle, and its injectable formulation is designed to slowly release the drug from the injection site to allow bi-annual subcutaneous administration. On 22 August 2022 [5], lenacapavir was approved in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen [4].
When initiating treatment, oral lenacapavir 600 mg/day is recommended for days 1 and 2, and lenacapavir 300 mg on day 8; on day 15, lenacapavir 927 mg should be administered via subcutaneous (SC) injection. For maintenance treatment, SC lenacapavir 927 mg should be administered once every 6 months from the date of the last injection. No dose adjustments of lenacapavir is required in patients with mild or moderate hepatic impairment, nor in those with mild, moderate, or severe kidney impairment. Lenacapavir use has not been studied in patients with end-stage kidney

Lenacapavir (Sunlenca®): Key Points
A long-acting HIV capsid inhibitor allowing bi-annual SC administration is being developed by Gilead Sciences Inc. for the treatment of HIV-1 infection Received its first approval on 22 August 2022 in the EU Approved in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen disease [creatinine clearance (CrCl) < 15 mL/min]; caution is needed if lenacapavir is used in these patients. Its use is contraindicated in patients also receiving strong inducers of CYP3A, P-glycoprotein, and UDP-glucuronosyltransferase 1A1 [4].

Company Agreements
In March 2021, Gilead Sciences Inc. and Merck Sharp & Dohme entered into an agreement to jointly co-develop and co-commercialize lenacapavir and islatravir (a nucleoside reverse transcriptase translocation inhibitor) for the treatment of patients with HIV [6]. The initial focus of this collaboration is on long-acting oral and long-acting injectable formulations of these combination products, with other formulations potentially added to the collaboration as mutually agreed. Beyond the potential combinations of lenacapavir and islatravir, Gilead Sciences Inc. will also have the option to license certain investigational oral integrase inhibitors from Merck Sharp & Dohme to develop in combination with lenacapavir [6].

Pharmacodynamics
Lenacapavir selectively inhibits HIV-1 capsid function and therefore HIV-1 replication by binding directly to the interface between capsid protein subunits [4]. This inhibition occurs at multiple stages of the HIV replication lifecycle, including viral nuclear import (via inhibition of capsid-binding import co-factors), virion assembly (by compromising the stability of Gag and/or Gag-Pol polyproteins, which are crucial for virion assembly and within which capsid proteins are expressed), and capsid core assembly (by impairing its proper assembly) [7,8]. In vitro data in HIV-1-infected cells showed lenacapavir to have half maximal effective concentrations (EC 50 ) of 105 pmol/L in MT-4 cells, 32 pmol/L in primary human CD4 + cells, and 56 pmol/L in macrophages [8]. Lenacapavir also demonstrated antiviral activity against all major HIV-1 subtypes (including A, A1, AE, AG, B, BF, C, D, E, F, G and H) [8,9]. HIV-1 variants with the capsid mutations L56I, M66I, Q67H, K70N, Q67H+N74S and Q67H+T107N each showed reduced susceptibility to lenacapavir in vitro (6 to > 3200-fold resistance vs wild type) [8].
In the ongoing, multinational phase II/III CAPELLA clinical trial, 8 of 19 patients receiving lenacapavir plus optimized background therapy (OBT) and assessed for resistance developed lenacapavir-associated capsid substitutions after 26 weeks of treatment, including M66I (6 patients; 1 with M66I+N74D), Q67H+K70H (1 patient), and K70H (1 patient) [10]. Relative to wild type, susceptibility to lenacapavir was reduced by 15-fold, 234-fold and 265-fold in patients with Q67H+K70R, M66I, and K70H mutations, respectively. All 8 cases of resistance to lenacapavir developed in patients on functional lenacapavir monotherapy, either due to poor adherence to OBT (n = 4) or no other fully active agents in the OBR (n = 4) [10]. In the ongoing phase II CALIBRATE trial assessing lenacapavir in treatment-naïve patients, 2 (of 157) patients had emergent resistant mutations occurring in the setting of likely or confirmed non-adherence to oral antiretroviral therapy, including Q67H+K70R and M184M/I in one patient (at week 10) and Q67H in the other (at week 54) [11].
The antiviral activity of lenacapavir was not affected in HIV-1 isolates with resistance mutations to protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), maturation inhibitors [12] and entry inhibitors [13]. Further in vitro data suggest that lenacapavir in combination with islatravir, rilpivirine or cabotegravir may have an additive antiviral effect, particularly at higher doses [14].
Lenacapavir had no clinically relevant effect on the QTcF interval, with no association seen between plasma concentrations of lenacapavir and changes in QTcF [4].

Pharmacokinetics
The single-dose pharmacokinetics of oral lenacapavir are non-linear and less than dose-proportional over a dose range of 50-1800 mg, and those of SC lenacapavir are dose proportional over a dose range of 309-927 mg [4]. Peak plasma concentrations occur ≈ 4 h post-dose with oral lenacapavir and (due to slow release from the injection site) 84 days post-dose with SC lenacapavir; absolute bioavailability after administering oral lenacapavir is ≈ 6-10%. The pharmacokinetics of oral lenacapavir are unaffected by food [4].
In a population pharmacokinetic analysis, exposure to lenacapavir with respect to area under the concentrationtime curve over a dosing interval (AUC tau ), maximum plasma concentration (C max ) and trough concentration (C trough ) were 29-84% higher in heavily treatment-experienced patients infected with HIV-1 relative to individuals without HIV-1 [4].
Lenacapavir is not extensively metabolized; none of its circulating metabolites individually accounted for > 10% of total plasma exposure [4]. It is primarily metabolized via CYP3A4 and UGT1A1. After a single intravenous dose of radiolabelled lenacapavir in healthy individuals, 76% of the total radioactivity was found in faeces and < 1% from urine. The median half-life of lenacapavir was 10-12 days and 8-12 weeks with oral and SC administration, respectively [4].
Although lenacapavir exposure was found to be higher in patients with severe kidney impairment (estimated CrCl 15-29 mL/min) and moderate hepatic impairment compared with that in healthy individuals, these increases were not considered to be clinically meaningful [15,16]. Dialysis is not expected to affect the exposure of lenacapavir as lenacapavir is ≈ 99.8% protein bound [4].
Because lenacapavir is a substrate of CYP3A, UGT1A1 and P-glycoprotein (P-gp), co-administration with strong inducers of these enzymes is contraindicated as they may reduce plasma lenacapavir concentrations, potentially impacting the therapeutic effect of lenacapavir and leading to the development of viral resistance [4]. Co-administration with strong inhibitors of all three enzymatic pathways (e.g. atazanavir/cobicistat) is not recommended as this may significantly increase plasma lenacapavir levels [4].

Therapeutic Trials
Lenacapavir reduced HIV-1 viral load in patients with multidrug-resistant infection in the CAPELLA trial (NCT04150068; n = 72) [10]. After 15 days (i.e. at the end of the functional monotherapy period), 88% and 17% of lenacapavir and placebo recipients on failing antiretroviral therapy (i.e. cohort 1) had a decrease in plasma HIV-1 RNA of ≥ 0.5 log 10 copies/mL from baseline [10].
Patients eligible for CAPELLA (age ≥ 12 years) had resistance to ≥ 2 retroviral medications from ≥ 3 of the 4 main drug classes (i.e. protease inhibitors, NRTIs, NNR-TIs, INSTIs) and no more than 2 fully active antiretroviral drugs that could be combined from the 4 drug classes [10]. The first 36 enrolled patients with no response to previous antiviral therapy, as indicated by stable viremia (i.e. HIV-1 RNA levels reduced by < 0.5 log 10 copies/mL) between screening and cohort allocation were placed in cohort 1 and randomized 2:1 to receive oral lenacapavir at the recommended dosage or placebo in addition to their failing antiviral therapy over a 15-day functional monotherapy period. During maintenance therapy (starting on day 15), lenacapavir recipients received SC lenacapavir at the recommended dosage plus OBT, while initial placebo recipients received oral lenacapavir at dosages of 600 mg/day on days 15 and 16 and 300 mg on day 22 before receiving SC lenacapavir plus OBT. All 36 patients in cohort 2 received lenacapavir plus OBT throughout the study and included those with HIV-1 RNA level reductions of ≥ 0.5 log 10 copies/mL between screening and cohort allocation, as well as those eligible for (but enrolled after the filling of) cohort 1 [10].
After 26 days in cohorts 1 and 2, a viral load of < 50 copies/mL was seen in 81% and 83% of patients and < 200 copies/mL in 89% and 86% of patients, with mean changes in viral load of −2.58 ± 1.04 log 10 copies/mL and −2.49 ± 1.34 log 10 copies/mL from baseline [10]. Least-squares mean increases of 75 cells/mm 3 and 104 cells/mm 3 in CD4+ count were seen in the two cohorts [10]. More recent findings indicate that lenacapavir maintained its efficacy over long term treatment; after 52 weeks, 83% of patients in cohort 1 had a viral load of < 50 copies/mL (most patients in cohort 2 had not reached 52 weeks of treatment at the time of analysis) [17]. Lenacapavir therapy appeared to be similarly efficacious in patients considered more difficult to treat, including those with low CD4+ count, resistance to INSTI, no fully active agents, or no dolutegravir or darunavir in their OBT [18].
In the open-label phase II CALIBRATE study (n = 182), lenacapavir in combination with tenofovir alafenamide (TAF), bictegravir, or emtricitabine/TAF resulted in high viral suppression rates in treatment-naïve patients [11]. After 54 weeks, the majority of patients receiving lenacapavir combination therapy (85-90% across three treatment groups) and 92% of patients receiving bictegravir/emtricitabine/TAF had HIV-1 RNA levels of < 50 copies/mL [11]. Eligible patients, who had HIV-1 RNA counts of ≥ 200 copies/mL and CD4+ cell counts of ≥ 200 cells/µL, were randomized 2:2:2:1 to treatment groups 1-4; groups 1 and 2 received SC lenacapavir (at the recommended dosage) plus oral daily emtricitabine/TAF for 28 weeks, with group 1 receiving SC lenacapavir plus oral daily TAF as maintenance therapy beyond week 28 and group 2 receiving SC lenacapavir plus oral daily bictegravir as maintenance therapy beyond week 28, and group 3 received oral daily lenacapavir plus emtricitabine/TAF and group 4 received oral daily bictegravir/emtricitabine/TAF throughout the study [11]. Reductions in viral load were also seen with lenacapavir in combination with these antiretrovirals after 16 weeks and 28 weeks [11,19].
Lenacapavir plus any of the assessed combination treatments in CALIBRATE was also generally well tolerated [11]. After 54 weeks in those who received SC lenacapavir, injection site reactions were mostly mild or moderate in severity and included erythema (27%), swelling (23%) and pain (19%). The most common non-injection site-related AEs were headache and nausea (13% each). No SAEs related to lenacapavir were reported [11].

Ongoing Clinical Trials
The CAPELLA and CALIBRATE trials are ongoing. Two multinational phase III trials, PURPOSE 1 (NCT04994509) and PURPOSE 2 (NCT04925752), are currently recruiting; both will assess lenacapavir as a single agent for pre-exposure prophylaxis in individuals at risk of HIV-1 infection, with PURPOSE 1 focusing on adolescent girls and young women and PURPOSE 2 focusing on individuals assigned male at birth. Recruitment is also underway for a phase II/ III trial, NCT05502341, which will assess the efficacy of oral bictegravir/lenacapavir in virologically suppressed, treatment-experienced individuals living with HIV on complex regimens switching from stable antiretroviral therapy versus continuing stable antiretroviral therapy.

Current Status
Lenacapavir received its first approval on 22 August 2022 for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen in the EU [5].