What is Lenacapavir?

Lenacapavir: A First-in-Class HIV Capsid Inhibitor

Lenacapavir is a novel, first-in-class, long-acting HIV-1 capsid inhibitor administered subcutaneously every 6 months for treating multidrug-resistant HIV infection and is being studied for HIV prevention. 1

Mechanism of Action

Lenacapavir works through a unique mechanism as a multistage, selective inhibitor of HIV-1 capsid function:

• Directly binds to the interface between capsid protein (p24) subunits in hexamers with high affinity (equilibrium binding constant of 1.4 nM) 2
• Inhibits multiple essential steps of the viral lifecycle:
  • Blocks nuclear import of HIV-1 proviral DNA
  • Interferes with virus assembly and release
  • Disrupts capsid core formation leading to malformed capsids 2

Current Approved Indications

Lenacapavir is currently approved for:

• Treatment of heavily treatment-experienced adults with multidrug-resistant HIV-1 infection for whom constructing a suppressive antiretroviral regimen is otherwise not possible 3
• Used in combination with an optimized background regimen of other antiretrovirals 3

Clinical Efficacy

In the pivotal Phase 2/3 trial for multidrug-resistant HIV:

• 83% of participants achieved HIV-1 RNA <50 copies/mL at week 52 4
• 62% maintained viral suppression at week 104 5
• Mean CD4 cell count increased by 122 cells/μL over 104 weeks 5
• The proportion of participants with CD4 count <200 cells/μL decreased from 64% at baseline to 29% at week 104 5

Administration

The approved dosing regimen consists of:

• Initial oral lead-in phase: 600 mg on days 1 and 2, followed by 300 mg on day 8 3
• Maintenance phase: 927 mg subcutaneous injection every 26 weeks (approximately 6 months) 3

Future Applications

Lenacapavir is being investigated for additional uses:

1. HIV Prevention (PrEP):

   • The PURPOSE-1 and PURPOSE-2 studies demonstrated high efficacy for HIV prevention when administered subcutaneously every 6 months 1
   • PURPOSE-2 showed 96% reduction in HIV incidence compared to background rates 1

2. Simplified Treatment Regimens:

   • Being studied in combination with islatravir as a once-weekly oral treatment 1
   • Being evaluated as a single daily pill (LEN/BIC) for people with multidrug-resistant virus 1
   • Being studied in combination with broadly neutralizing antibodies (bNAbs) as an every-6-months regimen 1

Safety Profile

The most common adverse effects include:

• Injection site reactions (63% of participants) 3
• Generally well-tolerated with no Grade 4 or serious treatment-related adverse events in long-term studies 5
• Only 1 participant discontinued due to injection site reaction in the 104-week study 5

Drug Interactions

Important drug interactions to consider:

• Should not be used with potent inducers of UGT1A1 2
• Rifampin significantly reduces lenacapavir exposure (84% reduction in AUC) 2
• Lenacapavir increases exposure to midazolam (3.59-fold increase in AUC) and other CYP3A substrates 2
• Modest increases in exposure to rosuvastatin (1.31-fold) and tenofovir (1.47-fold) 2

Special Populations

• No dosage adjustment needed for patients with mild to moderate hepatic impairment or severe renal impairment 6
• Lenacapavir exposures are approximately 1.5-fold higher in moderate hepatic impairment and 1.8-fold higher in severe renal impairment, but these increases are not considered clinically meaningful 6

Resistance Considerations

• Resistance to lenacapavir can develop through capsid mutations, particularly M66I which confers >3,226-fold reduced susceptibility 2
• In clinical trials, 41% of participants with virologic failure developed lenacapavir resistance-associated capsid substitutions 2
• Some patients (7 of 14) with emergent resistance were able to resuppress HIV-1 while maintaining lenacapavir use 5

Lenacapavir represents a significant advancement in HIV treatment, particularly for those with limited treatment options due to multidrug resistance, and shows promise for expanding the armamentarium of long-acting HIV prevention options.