HIV Meds Update: FDA Approves Lenacapavir, New Long-Acting Injectable ARV

The FDA recently granted approval to lenacapavir (LEN), a novel long-acting HIV antiretroviral (ARV) that is classified as a capsid inhibitor. Lenacapavir is marketed in the United States as Sunlenca.

Lenacapavir blocks HIV-1’s assembly of its protein capsid and interferes with other steps in HIV replication. It was approved for use in adults in whose HIV-1 infections “cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations.” It must be given with other antiretrovirals and is administered by subcutaneous (SC) injection every 6 months. 

LEN approval was based on the Phase 2/3 CAPELLA study of treatment-experienced persons whose virus had documented multi-class resistance (resistance to ≥2 ARVs from at least 3 of 4 major ARV classes [NRTI, NNRTI, INSTI, PI]), ≤2 fully active agents from these 4 classes, and ongoing virologic failure on their current stable regimen. The study enrolled 72 subjects and divided them into a randomized and a non-randomized cohort.  The first cohort was randomized 2:1 to continue their baseline (failing) antiretroviral therapy (ART) regimen and to add oral LEN for 14 days, then to receive an optimized background regimen (OBR) of oral ARVs + SC LEN; or to receive their baseline regimen + oral placebo for 14 days, then an OBR + LEN oral lead-in followed by SC injection. The nonrandomized cohort was immediately switched to the OBR + LEN protocol as described above.  

In the randomized cohort, the 14-day period of functional LEN monotherapy resulted in a mean HIV RNA decline of 2.1 log10 copies/mL (vs 0.07 log10 copies/mL in the placebo group). At weeks 26 and 52, HIV RNA was <50 copies/mL in 82% and 78%, respectively, of the combined cohorts.[1]  [2] In the randomized cohort, at week 52, viral suppression to <50 copies/mL was more frequent if there were at least 2 active ARVs in the OBR (94%) than with 1 (79%) or 0 fully active oral ARVs (67%).[3] Emergent LEN resistance mutations were identified in 9 subjects who experienced virologic failure on LEN; the resistance was attributed to subjects’ inadequate adherence to the oral OBR or to a lack of fully active ARVs in the OBR.  Adverse effects to LEN consisted primarily of injection site reactions, mostly mild-moderate, and particularly after the first injection (28% of subjects).

The LEN oral lead-in (OLI) protocol used in CAPELLA is somewhat complex and delays the first LEN injection until 14 days after the start of oral LEN. A recent PK study conducted by the manufacturer demonstrates that comparable plasma levels of LEN are achieved by use of a greatly simplified protocol consisting of oral LEN on days 1 and 2, with the first LEN injection given on day 1;[4] both OLI protocols are presented in the drug’s Prescribing Information.   

Clinical Bottom Line:

The approval of LEN is welcome – LEN provides a novel ARV for persons with limited treatment options, and a new long-acting injectable drug for persons who need non-oral ARVs. Of course, LEN must be combined with other active ARVs to create a complete ART regimen. To date, LEN has been used with optimized background regimens consisting of oral ARVs, and not with other long-acting injectable drugs. It is not known if LEN + long-acting cabotegravir (CAB) or LEN + long-acting rilpivirine (RPV) would be effective as a complete ART regimen; this is likely to be an area of active clinical exploration for patients for whom use of CAB or RPV is not appropriate.


  1. Stellbrink, et al.  Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med 2022; 386:1793-1803.
  2. . Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV: Week 52 Result., IDWeek 2022. October 19-26, 2022. Washington, DC. Abstract 1585.
  3. Castagna A, Blanco JL, Hung C-C, et al. Week 52 Subgroup Efficacy Analyses of Long-Acting Subcutaneous Lenacapavir in Phase 2/3 in Heavily Treatment-Experienced People with Multidrug-Resistant HIV (CAPELLA Study). HIV Glasgow 202223-26 October 2022. Abstract
  4. Jogiraju V, Graham H, West S, et al. Pharmacokinetics of a simplified subcutaneous lenacapavir regimen versus Phase 2/3 regimen. IAS 2022, July 29-Aug 1 Montreal 2022. Abstract PESUB22.





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