The safety and effectiveness of the long-acting agent is backed by data from trials of the drug among treatment-experienced individuals living with HIV-1 whose viral load is on the rise due to other regimens failing. Investigation continues among these patients, as well as treatment-naive patients.
Capsid inhibitors are showing potential as a possible eighth drug class of antiretroviral treatment (ART) agents in the ongoing fight against HIV. Gilead Sciences’ lenacapavir is leading the way as a first-in-class agent. The safety and effectiveness of the long-acting agent is backed by data from trials of the drug among treatment-experienced individuals living with HIV-1 whose viral load is on the rise due to other regimens failing.
This novel class works by interfering in the production cycle of the protein capsule (the capsid) that surrounds and protects the viral genome, facilitating its entry into a host cell. Capsid inhibitors accomplish this by blocking the capsid’s disassembly, which enables the virus to enter the nucleus and reprogram the RNA, and its formation around any new virus particles produced, essentially rendering them ineffective.1,2
“The lack of attention to the HIV capsid as a therapeutic target largely reflects the absence, until now, of an investigational agent in clinical trials from this mechanistic class,” noted David Alain Wohl, MD, professor at the University of North Carolina, site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina Aids Education & Training Center Program, and co-director of HIV services for the NC state prison system, in an email interview with The American Journal of Managed Care® (AJMC®). “Potential advantages of capsid inhibitors are multiple, including (1) a novel mechanism of action, as such it is anticipated to be effective against HIV that is resistant to other agents; (2) long-acting formulations; [and] (3) subcutaneous administration can allow for pill-free self-injection as a future option.”
The advancement of such a therapy with high barrier to resistance, and one that can be administered up to every 6 months, could be a major advance over daily oral therapy for patients who fit certain criteria, he added, including patients with acquired or transmitted HIV drug resistance.
Acquired resistance can occur through mutations that develop, typically as a result of inconsistent or suboptimal treatment adherence, Wohl said, whereas transmitted resistance stems from a drug-resistant virus transmitted between infected individuals. The former is seen in treatment-experienced HIV-positive individuals and the latter in treatment-naive persons.
Presently, there are 7 approved drug classes of ART agents to treat HIV infection: non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists, integrase strand transfer inhibitors, and postattachment inhibitors.3
Lenacapavir was initially known as GS-CA1 when Gilead first presented findings at 2017’s Conference on Retroviruses and Opportunistic Infections (CROI) showing the investigational agent’s activity against the viral replication cycle. At that time, GS-CA1 had “demonstrated similar potency against multiple HIV-1 clinical isolates from people with all major viral clades; maintained full activity against viral mutants resistant to all approved antiretroviral classes, [and] demonstrated less potent activity against HIV-2.” The agent was also shown to have a long half-life at that time.4
These positive findings were echoed in data presented at the 2019 Conference on Retroviruses and Opportunistic Infections. Now known as GS-6207, interim data from a phase 1 trial demonstrated a Tmax of 21 to 35 days and a median terminal T1/2 of 30 to 38 days for the capsid inhibitor. The agent was shown to be safe and well tolerated up to the maximum dose evaluated, 450 mg; doses of 30, 100, and 300 mg were also investigated.5
At present, there are no contraindications for lenacapavir. “It is too soon to determine that potential,” Martin Rhee, MD, executive director, Virology Clinical Research, Gilead Sciences, told AJMC®, when discussing results on the drug released late last year. “The safety, efficacy and dosing of lenacapavir are being evaluated in multiple ongoing clinical studies.” Two trials are currently underway.
The drug will not be a monotherapy. Although it is being evaluated as a twice-yearly treatment (subcutaneous [SC] administration treatment every 6 months), its development is as one component of a longer-acting ART regimen against HIV-16 that the investigators hope can increase treatment adherence and convenience.
The phase 2/3 CAPELLA trial is evaluating the capsid inhibitor in both oral and SC form in treatment-experienced patients. In the functional monotherapy period, patients receive oral lenacapavir plus their failing regimen, and in the maintenance period, SC lenacapavir plus an optimized background regimen.7 “We will follow all participants in both cohorts [treatment and placebo] for at least 1 year or until they discontinue lenacapavir,” Rhee stated when asked about the study design.
Updated data from CAPELLA were recently presented at the March 2021 virtual CROI.8 These phase 2/3 maintenance data add to the positive topline results from CAPELLA that Gilead announced in November 20206 and at 2020’s virtual CROI.9
At CROI this year, Gilead announced that high rates of virologic suppression, as indicated by an undetectable viral load (< 50 copies/mL), were maintained through 26 weeks in 73% of the participants who reached this treatment milestone after just 1 dose of SC lenacapavir.8 And in November’s results, there was at least a 0.5 log10 viral load decrease seen in 88% of trial participants by the end of a 2-week course of lenacapavir monotherapy.6 Only 17% of patients receiving placebo saw similar results, according to the November data,6 for an 80.7% difference in viral load improvement.
Meanwhile, the phase 2 CALIBRATE trial is examining the capsid inhibitor in treatment-naive patients. Induction has them receiving oral lenacapavir plus emtricitabine (F)/tenofovir alafenamide (TAF), with a 1-time dose of SC lenacapavir on day 15. In the maintenance phase, SC lenacapavir is initiated at week 28, as well as oral daily TAF following discontinuation of F/TAF. Participants will be followed for at least 1.5 years.10
Patients in both trials have the option to continue treatment beyond the study end date.
Lenacapavir received a breakthrough therapy designation from the FDA in May 20196 based on preliminary clinical evidence, Rhee told AJMC®.
“Therapeutic options that address the complex needs of people living with HIV who are heavily treatment-experienced remain a significant unmet need,” Rhee concluded. “Without effective new options, those who are heavily treatment-experienced and are not able to maintain viral suppression with currently available medication due to resistance, tolerability, or safety considerations are at great risk of progressing to AIDS.”
“There are people living with HIV with severely limited treatment options due to resistance to multiple antiretroviral therapy classes. They rely on complex treatment regimens, sometimes involving infused medication, in combination with multiple pills taken more than once a day. This type of complexity further increases the chance of suboptimal adherence and treatment failure,” Wohl said, in echoing Rhee’s sentiments. “This underscores the need for continuing to strive to develop new agents that are active against resistant variants of HIV and target novel mechanisms of action, in order to provide simpler and more efficacious treatment options to all people living with HIV, irrespective of their prior treatment history.”
Lenacapavir is also being investigated in injectable form for use as twice-yearly preexposure prophylaxis (PrEP) through the Women’s HIV Prevention Study. Gilead is partnering with the FDA in this trial to evaluate Descovy (F 200 mg/TAF 25 mg) and Truvada (F 200 mg/tenofovir disoproxil fumarate 300 mg) as PrEP among cisgender adolescent girls and young women in sub-Saharan Africa (SSA).11 Seventy-one percent of new HIV infections are seen in these groups in SSA.12
Gilead is also planning to initiate a safety and efficacy study later this year of lenacapavir as PrEP among men who have sex with men and transgender individuals.
1. Highleyman L. HIV capsid inhibitor may offer long-term viral suppression. NAM aidsmap. March 11, 2019. Accessed March 2, 2021. https://www.aidsmap.com/news/mar-2019/hiv-capsid-inhibitor-may-offer-long-term-viral-suppression
2. Boskey E. How a retrovirus or RNA virus works. Verywell Health. July 24, 2020. Accessed March 2, 2021. https://www.verywellhealth.com/hiv-is-a-retrovirus-what-does-that-mean-3132822#:~:text=Retroviruses%20use%20reverse%20transcriptase%20to,genome%20of%20the%20infected%20cells
3. HIV treatment. National Institutes of Health. Accessed March 2, 2021. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/what-start-choosing-hiv-regimen
4. Highleyman L. New HIV capsid inhibitors show high potency and prolonged activity in early studies. NAM aidsmap. March 3, 2017. Accessed March 4, 2021. https://www.aidsmap.com/news/mar-2017/new-hiv-capsid-inhibitors-show-high-potency-and-prolonged-activity-early-studies
5. Sager JE, Begley R, Rhee M, et al. Safety and PK of subcutaneous GS-6207, a novel HIV-1 capsid inhibitor. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA. Accessed March 4, 2021. https://www.croiconference.org/abstract/safety-and-pk-subcutaneous-gs-6207-novel-hiv-1-capsid-inhibitor/
6. Gilead announces investigational long-acting HIV-1 capsid inhibitor, lenacapavir, achieves primary endpoint in phase 2/3 study in heavily treatment-experienced people living with HIV. News release. Gilead; November 18, 2020. Accessed March 4, 2021. https://www.gilead.com/news-and-press/press-room/press-releases/2020/11/gilead-announces-investigational-longacting-hiv1-capsid-inhibitor-lenacapavir-achieves-primary-endpoint-in-phase-23-study-in-heavily-treatmentex
7. Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (CAPELLA). ClinicalTrials.gov. Updated February 8, 2021. Accessed March 8, 2021. https://clinicaltrials.gov/ct2/show/NCT04150068
8. Gilead’s investigational lenacapavir demonstrates sustained long-acting efficacy through week 26 in data presented at CROI. News release. Businesswire; March 9, 2021. Accessed March 15, 2021. https://www.businesswire.com/news/home/20210309005909/en/Gilead%E2%80%99s-Investigational-Lenacapavir-Demonstrates-Sustained-Long-Acting-Efficacy-Through-Week-26-in-Data-Presented-at-CROI
9. Volney-Anne A. Long-acting capsid inhibitor GS-6207 confirms safety and antiviral activity. NAM aidsmap. March 12, 2020. Accessed March 15, 2021. https://www.aidsmap.com/news/mar-2020/long-acting-capsid-inhibitor-gs-6207-confirms-safety-and-antiviral-activity
10. Study to evaluate the safety and efficacy of lenacapavir in combination with other antiretroviral agents in people living with HIV (CALIBRATE). ClinicalTrials.gov. Updated October 22, 2020. Accessed March 12, 2021. https://clinicaltrials.gov/ct2/show/NCT04143594
11. Gilead announces new arm of HIV Women’s Prevention Study to evaluate the investigational long-acting HIV-1 capsid inhibitor lenacapavir in addition to Descovy for PrEP. News release. Gilead; December 21, 2020. Accessed March 12, 2021. https://www.gilead.com/news-and-press/company-statements/gilead-announces-new-arm-of-hiv-womens-prevention-study
12. HIV/AIDS. Gilead. Accessed March 15, 2021. https://www.gilead.com/purpose/medication-access/global-access/hiv-aids