LENACAPAVIR 464 mg SOLUTION FOR INJECTION GILEAD

Indications

• HIV-1 infection
• HIV treatment-naive patients
• Patients with limited treatment options due to resistance

Mechanism of action

Lenacapavir inhibits HIV-1 replication by interfering with critical steps in the virus's lifecycle. It binds to the HIV-1 capsid protein, specifically to the phenylalanine-glycine binding pocket between the N-terminal and C-terminal domains of the capsid proteins. This binding disrupts the interaction of the capsid with essential host factors, such as CPSF6 and Nup153, which are necessary for the viral capsid's entry into the nucleus and subsequent integration of the viral genome into the host DNA. By preventing these interactions, lenacapavir effectively blocks viral uptake, assembly, and release, leading to reduced viral load in infected individuals.

Pharmacodynamics

Lenacapavir exhibits an extended pharmacokinetic profile that allows for prolonged antiviral activity. It has shown that single subcutaneous doses of 100 mg or more result in plasma concentrations that exceed the 95% effective concentration (EC95) for over 12 weeks, and doses of 300 mg or more maintain these levels for over 24 weeks. In treatment-naive HIV-1-infected patients, a single dose ranging from 20 mg to 450 mg has demonstrated significant reductions in plasma HIV-1 RNA levels by the ninth day post-injection, indicating robust antiviral efficacy.

Pharmacokinetics

Lenacapavir is administered subcutaneously, leading to systemic absorption with a long half-life that supports its extended dosing intervals. The pharmacokinetics are characterized by a prolonged duration of action, with significant plasma concentrations sustained for weeks after administration. Further details on its metabolism and excretion are not specified but are critical to understanding individual patient variability and potential drug interactions.

Pregnancy

There is insufficient data on the use of lenacapavir in pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown whether lenacapavir is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a refrigerator (2°C to 8°C). Do not freeze. Protect from light.

Formulations

• Subcutaneous injection

Mechanism of action

HIV-1 co-opts various host factors during its replicative cycle, including during host cell entry, nuclear integration, replication, and virion assembly. Following the initial fusion with the host cell membrane, the viral capsid is released into the host cell cytoplasm. The capsid comprises approximately 250 hexamers and exactly 12 pentamers, each composed of monomeric capsid proteins (CA). Each CA monomer has an N-terminal and C-terminal domain (NTD/CTD) and offers an interaction surface for host cell machinery. Several important protein-protein interaction interfaces occur between CA monomers in the assembled multimers; the binding constants of these proteins are substantially lower for assembled multimers than individual capsid monomers. To facilitate HIV-1 genomic integration, the capsid must cross the nuclear envelope, for which it utilizes the nuclear pore complex (NPC). Two host proteins shown to be essential for capsid nuclear entry that directly bind to the capsid are cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and nucleoporin 153 (Nup153, an NPC protein present on the nucleoplasmic face of the complex). Both proteins bind the same phenylalanine-glycine binding pocket between the NTD and CTD of neighbouring CA monomers in multimeric CA assemblies. Lenacapavir contains a difluorobenzyl ring that occupies the same binding pocket as CPSF6/Nup153, overlapping with the benzyl group of F321 in CPSF6 and F1417 in Nup153 in the overlayed structures. Crystal structures of lenacapavir bound to CA hexamers reveal that six lenacapavir molecules bind to each hexamer, establishing extensive hydrophobic interactions, two cation-π interactions, and seven hydrogen bonds, contacting ~2,000 Ų of buried protein surface area. Strong binding of lenacapavir, therefore competitively interrupts capsid interactions with CPSF6 and Nup153. _In vitro_ HIV-1 replication inhibition experiments in a variety of cell lines show EC₅₀ values of ~12-314 pM, with greater efficacy against early steps over later steps. At very low concentrations (0.5 nM), lenacapavir inhibits viral nuclear entry, while at higher concentrations (5-50 nM), it additionally inhibits viral DNA synthesis and reverse transcription. As CPSF6 and Nup153 are essential for nuclear entry, it is likely that lenacapavir binding inhibits these interactions and blocks capsid nuclear entry. Lenacapavir may have additional effects beyond blocking interactions with host cell factors. Lenacapavir increases the rate and extent of CA assembly, dramatically extends the lifetime of assembled CA structures, even at high salt concentrations, and alters assembled capsid morphology. The stabilizing concentration is ~1:1, closely mimicking the observed binding stoichiometry to isolated CA hexamers. Further analysis suggests that lenacapavir binding alters intra- and inter-hexamer interactions, altering the structure and stability of the resulting assemblies. Serial passage of HIV-1 in increasing concentrations of lenacapavir resulted in the appearance of major resistance mutations Q67H and N74D, which remain sensitive to other antiretroviral drugs. Extended passage resulted in the additional mutations L56I, M66I, K70N, N74S, and T107N. All identified resistance mutations map to the lenacapavir binding site, and all but the Q67H variant show reduced replication capacity _in vitro_. Additional studies have shown no lenacapavir resistance in variants associated with resistance to other antiretrovirals or naturally occurring polymorphisms, suggesting a very low potential for cross-resistance in combination therapy.

Pharmacodynamics

Lenacapavir is an antiviral drug with an extended pharmacokinetic profile. Lenacapavir works against the HIV-1 virus by inhibiting viral replication: it interferes with a number of essential steps of the viral lifecycle, including viral uptake, assembly, and release. Single subcutaneous doses ≥100 mg in healthy volunteers resulted in plasma concentrations exceeding the 95% effective concentration (EC₉₅) for ≥12 weeks while doses ≥300 mg exceeded the EC₉₅ for ≥24 weeks. In treatment-naive HIV-1-infected patients, a single subcutaneous dose of 20-450 mg resulted in a mean maximum log₁₀-transformed reduction in plasma HIV-1 RNA of 1.35-2.20 by the ninth-day post-injection.