FDA approves lenacapavir (Sunleca®) in heavily pre-treated adults with multi-drug resistant HIV-1 infection

Oral antiretrovirals (ARTs) provide life-saving treatment for millions of people living with HIV. However, some heavily treatment-experienced (HTE) individuals have limited to no treatment options due to the emergence of multi-drug resistance (MDR). HIV-1 variants harbouring mutations associated with reduced antiretroviral drug susceptibility are common among ART-experienced patients.1–3 In Europe and the US, the emergence of triple-class drug-resistant viruses (i.e. resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI), one NNRTI, and one protease inhibitor (PI)) reportedly range from 3.5% to 10% across different cohorts of ART-experienced patients.4–6

These viral variants ultimately limit the success of subsequent lines of treatment and compromise clinical outcomes. Further, as individuals with MDR HIV grapple with limited treatment options, disease management becomes increasingly challenging. There are presently over 50 FDA-approved HIV drugs that fall into eight categories, classified by how the molecule interferes with the HIV life cycle.7 The categories include NNRTIs, NRTIs, PIs, fusion inhibitors, chemokine receptor antagonists, integrase strand transfer inhibitors (INSTIs), attachment and post-attachment inhibitors, as well as capsid function inhibitors. The latter represents the latest and most novel ART class to receive a US regulatory nod. 

Lenacapavir (Sunleca®), a first-in-class long-acting HIV-1 capsid function inhibitor, was approved by the FDA in December 2022 for HTE adults with MDR HIV who are not able to adequately manage the virus with their current treatment regimen.8 The FDA granted lenacapavir Priority Review, Fast Track and Breakthrough Therapy designations for this indication. Lenacapavir’s treatment protocol involves an initial phase involving both oral tablets and subcutaneous (SC) injection, followed by maintenance treatments administered every 6 months as an SC injection. Proper capsid formation and integrity are essential for virus infectivity.9 By interfering with capsid-mediated nuclear uptake of pre-integration complexes and impairing virion production, lenacapavir inhibits viral replication at both early and late stages of the life cycle. In vitro, lenacapavir has antiviral activity against viral mutations that are resistant to major ART classes of drug. 

FDA approval was based on data from the Phase 2/3 CAPELLA (NCT04150068)10 study, which was a double-blinded, placebo-controlled global multicenter trial designed to evaluate lenacapavir in HTE adults with MDR HIV infection. 

Population, intervention and comparators

• The study enrolled 72 patients on a randomized functional monotherapy cohort (Cohort 1; N=36) or a non-randomized cohort (Cohort 2: N=36)
• The median age of the study population was 52 years and 25% were female
• The ethnic breakdown was 41% White, 38% Black and 21% Asian patients
• The mean viral load was 4.17±1.03 log10 copies/mL
• 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI) and 17% did not have any fully active agents in the optimized background regimen

Efficacy outcomes

• Significantly more patients who received oral lenacapavir during the functional monotherapy period (15 days) had a reduction from baseline of at least 0.5 log10 copies/mL of HIV-1 RNA than those who received placebo (88% vs 17%; p < .001).
• At 26 weeks, SC lenacapavir was associated with a reduction in viral load (<50 copies/mL) in 81% of patients in the randomized cohort and 83% in the non-randomized cohort.
• At 26 weeks, SC lenacapavir was associated with a reduction in viral load (<200 copies/ml) in 89% of patients in the randomized cohort and 86% of patients in the non-randomized cohort. 
• The efficacy of lenacapavir was generally consistent regardless of the activity of the optimized background therapy, with similar results regardless of whether patients were receiving fully active agents or whether they had resistance to integrase inhibitors.
• At week 52, 83% of patients receiving lenacapavir in combination with a background ART regimen achieved an undetectable viral load. The subjects also had a mean rise in CD4 count of 82 cells/µL.

Safety findings

• In the combined analysis of both randomized and non-randomized cohorts, seven patients had serious side effects, none of which were related to lenacapavir. 
• The most common adverse effects included injection site reactions (63%), nausea (13%), constipation (11%) and diarrhoea (11%). These events were mostly grade 1.
• A total of 28% of patients experienced grade 3 or higher laboratory abnormalities. Low levels of creatinine clearance or estimated glomerular filtration rate or high creatinine levels were transient or unconfirmed abnormalities. Episodes of hyperglycaemia and glycosuria were transient, unconfirmed, or related to underlying diabetes.

There are numerous critical and pressing unmet needs for people living with HIV. These problems are particularly prominent for HTE individuals that account for over 2% of adults living with HIV globally.11,12 FDA’s approval of lenacapavir expands the MDR HIV treatment armamentarium, providing a new therapy option for patients challenged by increasingly limited treatment options. Further, as conventional ARTs typically involve the daily administration of a combination of drugs, lenacapavir provides patients with a potentially more convenient alternative that requires less frequent dosing (twice a year) and reduces pill burden.

At present, lenacapavir, alone or in combination, is approved by regulatory agencies in the US, United Kingdom, Canada and the European Union for use in HTE individuals with MDR HIV. At present, its use is also being investigated in other HIV settings and we await data from the following key studies within the manufacturer’s clinical trial pipeline:

• CALIBRATE (NCT04143594)13: evaluating the efficacy of lenacapavir-containing regimens in treatment-naïve people with HIV-1 infection. CALIBRATE includes men and women living with HIV-1 and is being conducted at research centres in North America, Puerto Rico and the Dominican Republic.
• PURPOSE 1 (NCT04994509)14 and PURPOSE 2 (NCT04925752)15: evaluating lenacapavir’s use in HIV prevention. 

References

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2. Lucas GM, Gallant JE, Moore RD. Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing. AIDS. 2004;18(11):1539-1548. doi:10.1097/01.aids.0000131339.68666.1a
3. Richman DD, Morton SC, Wrin T, et al. The prevalence of antiretroviral drug resistance in the United States. AIDS. 2004;18(10):1393-1401. doi:10.1097/01.aids.0000131310.52526.c7
4. Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe – PubMed. Accessed January 11, 2023. https://pubmed.ncbi.nlm.nih.gov/27625109/
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8. Commissioner O of the. FDA Approves New HIV Drug for Adults with Limited Treatment Options. FDA. Published December 23, 2022. Accessed January 11, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-drug-adults-limited-treatment-options
9. Cliver DO. Capsid and Infectivity in Virus Detection. Food Environ Virol. 2009;1(3):123-128. doi:10.1007/s12560-009-9020-y
10. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. New England Journal of Medicine. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542
11. Prevalence and Outcomes for Heavily Treatment-Experienced Individuals Living With Human Immunodeficiency Virus in a European Cohort – PubMed. Accessed January 11, 2023. https://pubmed.ncbi.nlm.nih.gov/33587506/
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13. Gilead Sciences. A Phase 2 Randomized, Open Label, Active Controlled Study Evaluating the Safety and Efficacy of Long-Acting Capsid Inhibitor GS-6207 in Combination With Other Antiretroviral Agents in People Living With HIV. clinicaltrials.gov; 2022. Accessed January 9, 2023. https://clinicaltrials.gov/ct2/show/NCT04143594
14. Gilead Sciences. A Phase 3, Double-Blinded, Multicenter, Randomized Study to Evaluate Safety and Efficacy of Twice Yearly Long-Acting Subcutaneous Lenacapavir, and Daily Oral Emtricitabine/Tenofovir Alafenamide for Pre-Exposure Prophylaxis in Adolescent Girls and Young Women at Risk of HIV Infection. clinicaltrials.gov; 2023. Accessed January 9, 2023. https://clinicaltrials.gov/ct2/show/NCT04994509
15. Gilead Sciences. A Phase 3, Double-Blind, Multicenter, Randomized Study to Evaluate the Efficacy and Safety of Subcutaneous Twice Yearly Long-Acting Lenacapavir for HIV Pre-Exposure Prophylaxis in Cisgender Men, Transgender Women, Transgender Men, and Gender Nonbinary People ≥ 16 Years of Age Who Have Sex With Male Partners and Are at Risk for HIV Infection. clinicaltrials.gov; 2022. Accessed January 9, 2023. https://clinicaltrials.gov/ct2/show/NCT04925752