Examining the HIV Treatment Pipeline

Contagion, Contagion, August 2021 (Vol. 06, No. 04), Volume 6, Issue 4

A review of selected investigational long-active treatment options for HIV.

Since the start of the HIV epidemic 40 years ago, the FDA has approved over 40 medications and medication combinations to treat HIV.1 For years, people living with HIV (PLWH) and providers have been asking for long-acting therapy options with the hope that these would increase patient adherence, achieve a durable undetectable viral load, decrease HIV transmission, and improve quality of life.2 Earlier this year their request was answered with the US approval of long-acting cabotegravir/rilpivirine (CAB-LA/RPV-LA; Cabenuva). This regimen is a monthly set of dual injections for the treatment of HIV in PLWH who are virally suppressed.3 Although this is the first approved long-acting HIV treatment, there are numerous other long-acting HIV therapies under investigation by a wide array of pharmaceutical and biotechnology companies. Two of the treatments furthest along in development are islatravir and lenacapavir. Both options are also first-in-class medications and their approvals would bring 2 new classes of medications to the fight against HIV.

Islatravir

Islatravir (ISL, MK-8591) is the first nucleoside reverse transcriptase translocation inhibitor (NRTTI) and works with a dual mechanism of action. The agent rapidly undergoes phosphorylation intracellularly to its active form of islatravir triphosphate (ISL-TP).5,6 The active form then binds to reverse transcriptase and prevents the incorporation of nucleotides into the viral DNA, leading to immediate chain termination (Figure 119).5,6 If translation occurs, the active form also terminates the viral DNA chain by being added to the end of the viral DNA; this causes primer mismatch, leading to delayed chain termination (Figure 1).5,6 This secondary mechanism of action, delayed chain termination, is not seen in nucleoside reverse transcriptase inhibitors (NRTIs).7 ISL-TP is slowly metabolized back to islatravir intracellularly, can exit the cell in a usable form, be taken up by another cell, and undergo phosphorylation again to ISL-TP.6

Islatravir was designed to have a higher binding affinity for reverse transcriptase than current NRTIs. The higher affinity is the result of the addition of a 3’ hydroxyl group that is not found in other NRTIs but is found in natural nucleotides.5,8 A 2-fluoro group that is found in islatravir inhibits the metabolism of the drug and leads to a long half-life. The half-life of ISL-TP is estimated to be approximately 79 to 214 hours.7

Study findings have shown islatravir to have a high barrier to resistance and a potency 10 times greater than any therapy currently on the market.5,8 Islatravir has resistance to common NRTI mutations in vitro and “no single amino-acid substitution was shown to significantly decrease its potency.”8 Even though M184I and M184V did decrease the potency of islatravir, these mutations were still susceptible.8 Based on these properties, investigators are studying islatravir for a wide variety of clinical situations.

The Illuminate trials are currently investigating islatravir in combination with doravirine for the treatment of HIV. In these trials, patient are receiving oral islatravir 0.75 mg and oral doravirine (Pifeltro) 100 mg daily.9 Investigators are studying the combination as switch therapy in virally suppressed patients and as initial therapy in treatment-naive patients. In 1 of the treatment-naive trials, islatravir plus doravirine was compared with doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF; Delstrigo).9 At 48 weeks, 90% of patients in the 0.75-mg islatravir arm had achieved an HIV-1 RNA level of less than 50 copies/mL compared with 83.9% of patients in the DOR/3TC/TDF arm.10 The most common adverse events in the islatravir arm compared with the DOR/3TC/TDF arm were headache (11.1% vs 6.5%), nausea (8.9% vs 9.7%), and diarrhea (6.7% vs 16.1%).8 In this trial, 37.8% of participants in the islatravir arm had a weight gain greater than 5% (compared with 22.6% in the DOR/3TC/TDF arm),9 mostly seen in the first 24 weeks. The authors hypothesized that this may be the result of a “return-to health-effect” but more research is needed to determine the cause.9

The Illuminate series of trials is also evaluating the use of this combination in highly treatment-experienced patients and adolescents.8 Due to islatravir’s long half-life, investigators are examining extended dosing options. The combination of MK-8507 with islatravir is under investigation as a once-weekly oral HIV treatment option. MK-8507 is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that itself is also under development. It has a “similar resistance profile to doravirine” but extended dosing.11 Islatravir is not only being investigated for treatment, it is also being evaluated for pre-exposure prophylaxis (PrEP) in an array of formulations, including a once-monthly oral tablet and a yearly implant.10

Lenacapavir

Lenacapavir (LEN, GS-6207) is the first capsid inhibitor. It works by “interfering with capsid-protein-mediated interactions between proteins that are essential” for capsid stability and transport.12 Specifically, lenacapavir inhibits “HIV replication as it interferes with the disassembly of the HIV capsid core, inhibits the role of capsid proteins during viral RNA/DNA translocation to the nucleus, and disrupts assembly of the capsid core(Figure 220)."13

Both oral and subcutaneous formulations of lenacapavir are currently in development.14 Oral lenacapavir has a half-life of approximately 12 days and accumulates significantly with multiple doses.16 This allows for extended dosing intervals, with the oral formulation being dosed once weekly and the subcutaneous formulation being dosed every 6 months.15 Lenacapavir has been shown in vitro to be fully active against major resistance mutations including K65R, M184V, K103N, Q148R, and N155H.16 Based on data from ongoing trials the most common adverse events with lenacapavir, not including injection site reactions, are headache (11.1%), nausea (11.1%), and diarrhea (9.7%).15 Injection site reactions (swelling, erythema, nodule, and pain) were common with lenacapavir (46%) but were mostly grade 1 (82%) and resolved within a few days.15 Injection site reactions did not cause any patient to discontinue participating in the CAPELLA trial.15

The CAPELLA trial (NCT04150068) is currently investigating lenacapavir for use in highly treatment-experienced patients, in combination with an optimized background regimen.15 The CALIBRATE trial (NCT04143594) is investigating the combinations of lenacapavir with bictegravir (BIC), lenacapavir with FTC/TDF, and lenacapavir with TDF compared with the standard of care (BIC/F/TAF).17 In both trials, patients will start on a loading dose of oral lenacapavir at 600 mg on day 1, 600 mg on day 2, and 300 mg on day 8. On day 15, patients will receive their first subcutaneous dose of lenacapavir 927 mg, then a subcutaneous dose of lenacapavir 927 mg every 6 months.17 The oral loading dose of lenacapavir is required to optimize therapeutic concentrations, unlike the oral load used with CAB-LA/RPV-LA, which is for safety only. Lenacapavir is also being investigated as a twice-yearly subcutaneous injection for PrEP.16

Combination

Earlier this year, the companies developing islatravir and lenacapavir announced a codevelopment partnership. They plan to study the combination of these medications as a complete 2-drug regimen for the treatment of HIV.18 Under the partnership, the companies will develop both an oral and an injectable formulation of the combination.18 The first trials for the oral formulation are slated to begin later this year.18 Neither company has confirmed the extended dosing strategy that will be investigated in these trials.

Conclusions

Islatravir and lenacapavir are both promising HIV treatments currently in development. The array of formulations and extended dosing options of these treatments will enable providers to better tailor a patient’s treatment to their needs. The addition of 2 new classes of medications for HIV treatment provides new treatment options for those patients who have been living with HIV for decades and who are highly treatment experienced. These patients usually have few treatment options and are on multiple, partially active medications. Although long-acting therapy alone will not solve adherence issues, it will be interesting to see the impact these therapies have on patients. As with any new medications, cost, insurance coverage, and implementation barriers will all be considerations for these treatments if they are approved by the FDA.

References

  1. FDA-approved HIV medicines. National Institutes of Health. Updated February 8, 2021. Accessed May 12, 2021. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/fda-approved-hiv-medicines
  2. Panel on Antiretrovial Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Updated June 3, 2021. Accessed June 11, 2021. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.
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  3. ViiV Healthcare announces FDA approval of Cabenuva (cabotegravir, rilpivirine), the first and only complete long-acting regimen for HIV treatment. Press release. ViiV Healthcare. January 21, 2021. Accessed May 12, 2021. https://viivhealthcare.com/en-gb/media/press-releases/2021/january/viiv-healthcare-announces-fda-approval-of-cabenuva/
  4. HIV pipeline 2020: new drugs in development – March 2020. HIV i-Base. March 12, 2020. Accessed May 10, 2021. https://i-base.info/htb/37221
  5. Moina JM, Yazdanpanah Y, Afani Saud A, et al. Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial. Lancet HIV. 2021;8(6):e324-e333. doi:10.1016/S2352-3018(21)00021-7
  6. Rudd DJ, Cao Y, Vaddady P, et al. Modeling-supported islatravir dose selection for phase III. Poster presented at: 2020 Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston, MA. Abstract 462. Accessed June 2, 2021. https://user-degqumh.cld.bz/CROI-2020-Abstract-eBook/164
  7. Molina JM, Yazdanpanah Y, Afani Saud A, et al. Islatravir efficacy and safety for selected demographic and baseline subgroups from a phase 2 trial in treatment-naïve adults with HIV-1 infection. Presented at: 17th European AIDS Conference; November 6-9, 2019; Basel, Switzerland. Accessed June 21, 2021. https://www.natap.org/2019/EACS/EACS_81.htm
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  10. Merck announces new analyses showing additional safety and efficacy data for investigational islatravir in combination with doravirine in adults with HIV-1 infection. News release. Merck. July 6, 2020. Accessed June 1, 2021. https://www.merck.com/news/merck-announces-new-analyses-showing-additional-safety-and-efficacy-data-for-investigational-islatravir-in-combination-with-doravirine-in-adults-with-hiv-1-infection/
  11. Diamond TL, Lai MT, Feng M, et al. Abstract presented at: 2021 Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021; Virtual. Accessed June 5, 2021. https://www.natap.org/2021/CROI/croi_47.htm
  12. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020;584(7822):614-618. doi:10/1030/s41586-020-2443-1
  13. Gilead’s investigational lenacapavir demonstrates sustained long-acting efficacy through week 26 in data presented at CROI. Press release. Gilead. March 09, 2021. Accessed May 8, 2021. https://www.gilead.com/news-and-press/press-room/press-releases/2021/3/gileads-investigational-lenacapavir-demonstrates-sustained-long-acting-efficacy-through-week-26-in-data-presented-at-croi
  14. Gilead presents data on investigational HIV-1 capsid inhibitor GS-6207 as a potential component of long-acting HIV therapy. Press release. Gilead. November 8, 2019. Accessed May 9, 2021. https://www.gilead.com/news-and-press/press-room/press-releases/2019/11/gilead-presents-data-on-investigational-hiv-1-capsid-inhibitor-gs-6207-as-a-potential-component-of-long-acting-hiv-therapy
  15. Segal-Maurer S, Castagna A, Berhe M, et al. Potent antiviral activity of lenacapavir in phase 2/3 in heavily ART-experienced PWH. Abstract presented at: 2021 Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021; Virtual. Accessed June 5, 2021. https://www.natap.org/2021/CROI/croi_47.htm
  16. Rhee M. Lenacapavir (GS-6207): a first-in-class long acting HIV capsid inhibitor. Abstract presented at: HIV DART 2020; December 10, 2020; Virtual. Accessed May 31, 2021. https://vimeo.com/489119224/cbfc8d128a
  17. Study to evaluate the safety and efficacy of lenacapavir in combination with other antiretroviral agents in people with HIV (CALIBRATE). Clinicaltrials.gov. Updated April 28, 2021. Accessed May 9, 2021. https://clinicaltrials.gov/ct2/show/NCT04143594
  18. Gilead and Merck announce agreement to jointly develop and commercialize long-acting, investigational treatment combinations of lenacapavir and islatravir in HIV. Press release. Gilead. March 15, 2021. Accessed May 10, 2021. https://www.gilead.com/news-and-press/press-room/press-releases/2021/3/gilead-and-merck-announce-agreement-to-jointly-develop-and-commercialize-longacting-investigational-treatment-combinations-of-lenacapavir-and-islatr
  19. Rudd DJ, Cao Y, Vaddady P, et al. Modeling-supported islatravir dose selection for phase III. Poster presented at: 2020 Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston, MA. Abstract 462. Accessed July 8, 2021.
  20. VanderVeen L. Activity and resistance characterization of the HIV capsid inhibitor lenacapavir. Oral abstract presented at: 2021 Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021; Virtual. Accessed June 5, 2021. https://www.askgileadmedical.com/downloads/pdfs/conference-materials/hiv/croi%202021/VanderVeen_LEN%20activity%20&%20resistance_CROI%202021_O128.pdf