This new antiretroviral with a unique mechanism of action may be lifesaving for those with treatment-resistant HIV infection.
Lenacapavir (LEN) is a new first-in-class capsid inhibitor for the treatment of HIV-1 infection. Capsid inhibition is a novel mechanism for drug therapy that hinders HIV-1 at multiple stages of the replication cycle, including nuclear transportation of proviral DNA and virion disassembly/ assembly.
Furthermore, the unique pharmacokinetic profile of LEN enables its use as a long-acting injectable antiretroviral agent. LEN is approved by the FDA for the treatment of multidrug-resistant HIV-1 in heavily treatment-experienced (HTE) adults as part of a full antiretroviral (ARV) regimen.1
This approval was supported by results of the CAPELLA study (NCT04150068); however, additional trial results for LEN form initial support for use in other populations.
LEN inhibits HIV-1 replication through a novel capsid inhibitory mechanism by binding to subunits of the capsid protein p24. This process interferes with 3 steps of HIV-1 replication: (1) inhibiting nuclear import proteins from binding to the capsid protein (thus blocking uptake of proviral DNA into the nucleus), (2) inhibiting proper functioning of Gag and Gag-Pol (reducing the virus’ ability to produce capsid protein), and (3) disrupting capsid core formation leading to production of the virus with dysfunctional capsid.1
The sole combined phase 2/3 study of LEN in HTE people living with HIV (PLWH) was CAPELLA. Eligible participants were 12 years and older and were on a failing ARV regimen (defined as a viral load [VL] of ≥ 400 copies/mL for at least 8 weeks) with known resistance to 3 of the 4 main ARV classes.
Eligible participants were enrolled in 1 of 2 cohorts based on change in VL between screening and cohort selection visits. Cohort 1 included the first 36 participants with less than a 0.5 log10 decrease in VL between screening and cohort selection visits (essentially nonresponsive to current ARV regimen). This cohort was randomly assigned to receive the failing regimen plus either an oral LEN loading dose (600 mg on days 1 and 2 with 300 mg on day 8) or matching placebo for the first 14 days of the study.
On day 15, participants in the LEN group were started on subcutaneous LEN 927 mg every 6 months; the placebo group received an oral LEN loading dose followed by subcutaneous LEN every 6 months. Both groups also received optimized background regimens starting on day 15.
Cohort 2 included participants who had at least a 0.5 log10 decrease in VL and/or a VL that fell below 400 copies/mL between the screening and cohort selection visits. In addition, participants enrolled who were deemed eligible for cohort 1 despite closure of that cohort’s enrollment were instead included in cohort 2. Given this enrollment, cohort 2 contained participants with significant ARV resistance and was more heterogeneous because it contained some participants who were responding to their current antiretroviral therapy and some who were not. Participants in cohort 2 received an open-label oral LEN loading dose followed by subcutaneous LEN combined with an optimized background regimen.
Primary and secondary end points were ascertained from cohort 1. The primary end point was the percentage of participants with at least a 0.5 log10 decrease in VL by day 15 (essentially the period of oral LEN vs placebo), and secondary end points included the percentage of participants at week 26 with a VL of less than 50 copies/mL and those with a VL of less than 200 copies/mL. The specified primary VL reduction occurred in 21 of 24 participants (88%) in the LEN group and in 2 of 12 (17%) in the placebo group.
At week 26 (when both arms of cohort 1 were receiving subcutaneous LEN plus optimized background therapy), 29 of 36 participants (81%) had a VL of less than 50 copies/mL, and 32 of 36 participants (89%) had a VL of less than 200 copies/mL. Nineteen participants across both cohorts met criteria for resistance analysis, with LEN resistance–associated mutations occurring in 8 of 19.2
There were no serious adverse events related to LEN. Injection-site reactions were common and included erythema (25%), swelling (31%), pain (31%), and nodule formation (24%); only 1 participant discontinued subcutaneous LEN due to an injection-site reaction. The most common non–injection-site reactions were nausea (13%), constipation (11%), and diarrhea (11%).
Largely, the CAPELLA trial has demonstrated that subcutaneous LEN can be used as part of an ARV regimen in HTE PLWH with significant resultant reductions in VL.2 The ongoing phase 2 clinical trial on LEN in treatment-naïve patients is CALIBRATE (NCT04143594). This open-label, active-controlled trial of the drug enrolled and randomly assigned 182 PLWH who were initiating antiretroviral therapy into 4 treatment arms. Inclusion criteria were an HIV-1 RNA level of 200 or more copies/mL and a CD4 cell count of 200 or more cells/µL.
Patients coinfected with either hepatitis B or hepatitis C were excluded. The first and second treatment arms received an oral LEN (30 mg daily) lead-in plus combined oral emtricitabine/tenofovir alafenamide (FTC/TAF) for 14 days. The groups then received 1 injection of subcutaneous LEN plus daily oral FTC/TAF for 28 weeks.
If participants in treatment arm 1 had a VL of 50 or less copies/mL at weeks 16 and 22, they were switched to subcutaneous LEN plus daily oral TAF. If participants in arm 2 met the same VL goals, they were switched to subcutaneous LEN plus daily oral bictegravir (BIC). The third treatment group received daily oral LEN plus daily oral FTC/ TAF. The fourth treatment group received daily oral BIC/FTC/TAF and served as the active control.
The primary end point of the CALIBRATE trial was the percentage of participants who remained virologically suppressed as defined by a VL of less than 50 copies/ mL.3 The 2023 Conference on Retroviruses and Opportunistic Infections (CROI 2023) contained a presentation of data from week 80 of treatment, during which groups 1, 2, 3, and 4 maintained viral suppression in 87%, 76%, 87%, and 92% of participants, respectively.
Discontinuation of the study drug mainly occurred due to reasons other than efficacy or safety, and comprised 11%, 17%, and 11% of discontinuations in groups 1, 2, and 3, respectively. Of note, the CALIBRATE trial was conducted during the COVID-19 pandemic, which may have influenced retention.4
Secondary end points included changes in CD4 count and adverse events. At week 80, mean CD4 counts increased by 272, 251, 245, and 260 cells/µL in groups 1, 2, 3, and 4, respectively. Injection-site reactions after the first subcutaneous LEN injection included erythema (27%), swelling (23%), and pain (19%). Only 4 participants (4% of those who received subcutaneous LEN) discontinued/ withdrew due to injection-site reactions. The most commonly reported non–injection-site reaction adverse events were headache (16%) and nausea (13%).
At week 80, LEN resistance had developed in 3 participants (2%), 1 in each LEN treatment group; each participant developed LEN resistance–associated mutations Q67H and K70R in the capsid protein.4
Overall, the CALIBRATE trial supports subcutaneous LEN along with BIC or TAF as a safe, well-tolerated, and effective treatment regimen for HIV-1 infection in a treatment-naïve population. Furthermore, this study supports oral LEN with FTC/TAF as a treatment for HIV-1 infection in that same population.4
In addition, LEN is being studied for HIV preexposure prophylaxis in the PURPOSE 1 and PURPOSE 2 trials. PURPOSE 1 (NCT04994509) is a phase 3 study of LEN for HIV preexposure prophylaxis in cisgender women living in South Africa and Uganda.5 PURPOSE 2 (NCT04925752) is a phase 3 study of LEN for HIV preexposure prophylaxis in cisgender men and transgender/ nonbinary individuals who have sex with partners assigned male sex at birth.6
LENACAPAVIR IN CLINICAL PRACTICE
As HIV continues to demonstrate resistance to antiretroviral therapy, new therapeutic targets are needed, and LEN meets this challenge. Through its novel inhibition of capsid protein, LEN interrupts multiple stages of the HIV replication cycle.
In the CAPELLA trial, LEN demonstrated its potential by significantly reducing the VL of a majority of HTE participants to less than 50 copies/mL and has earned FDA approval for the treatment of HIV-1 in this population.2 At the time of writing, LEN remains under development/study for use in treatment-naïve individuals. Subcutaneous LEN in combination with TAF or BIC resulted in an essentially undetectable VL for a large majority of the treatment-naïve participants at week 80 in the CALIBRATE trial; however, no other currently available long-acting injectable ARV can be dosed at a similar interval.4
Thus, even if subcutaneous LEN is approved for treatment-naïve PLWH, the initial clinical utility in this population will be low until other agents with similar pharmacokinetic profiles are developed. It is exciting, however, to envision a future where HIV-1 can be appropriately treated with long-acting injectables that exceed all other current options available.