ART pipeline 2025: exciting dual long-acting combinations and the challenge of generic dolutegravir

1 January 2025. Related: Conference reports, Pipeline report, Antiretrovirals, HIV 17 Glasgow 2024.

Simon Collins, HIV i-Base

The Glasgow 2024 conference included several important sessions on ART, including upcoming pipeline drugs and the issues of drug resistance with integrase inhibitors.

José Arribas, from La Paz Hospital, Madrid, presented an update on a wealth of drugs in development that have extended dosing options from oral weekly combinations to a range of compounds given by injection or infusion every 2, 3, 4 or 6 months. [1]

The great potency of many new compounds and stronger resistance profiles mean that many combinations only involve two drugs. Nine studies at Glasgow included new data on these compounds, see Table 1.

One caution is that these combinations are nucleoside-sparing and therefore without HBV coverage.

Table 1: HIV pipeline 2025 including new data presented at Glasgow 2024

* rHuPH20 enables the slow-release delivery.

Key: CI = capsid inhibitor. INSTI = integrase strand transfer inhibitor. NNRTI = non-nucleoside reverse transcriptase inhibitor. NRTTI = nucleoside reverse transcriptase translocation inhibitor, Ph = phase.

Novel once-daily oral combinations

Some of the extended release drugs are also being studied in new once-daily combinations.

Lenacapavir plus bictegravir

Two ongoing phase 2/3 studies – ARTISTRY-1 and -2 are looking at a new once-daily oral combination using a capsid inhibitor + integrase inhibitor combination.

Week 48 results from the ARTISTRY-1 switch study in people on complex combinations – taking a median of 3 (range: 2 to 9) tablets/day were previously reported at the IAS 2024 conference this year. This showed statistically similar virologic responses compared to continuing on existing combinations, but also reported more discontinuations, although all numbers were low. [2]

Two posters at Glasgow 2024 included metabolic results from this study with generally improved fasting lipids (TC, LDL, TG and Total:HDL) at week 48 in the lenacapavir vs complex regimen arms. [3]

Glasgow 2024 also included a poster from Priyanka Arora and colleagues reporting the pharmacokinetic data for the dose selection of this new single tablet regimen, which will be used in the roll-over phase 3 section of ARTISTRY-1. [4, 5]

A second phase 3 switch study called ARTISTRY-2 will compare lenacapavir/bictegravir to 3-drug Biktarvy. [6]

Daily oral lenacapavir/bictegravir is also being studied in children and adolescents in three different age bands including from as young as 2 years old. [7]

Doravirine + islatravir

Islatravir is being studied as a once-daily oral combination using a reduced 0.25 mg daily dose together with 100 mg doravirine.

Several studies using 100 mg/0.25 mg dose are ongoing as first-line ART and as switch studies, using B/F/TAF as a comparator.

Although not in time for Glasgow, MSD released a press release on 19 December 2024 announcing non-inferiority results from an open-label and randomised phase 3 studies. No further details were included though other than superiority was not met but results are likely to be a late-breaker at CROI 2025. [8]

Results from a phase 3 study using the higher 0.75 mg dose of islatravir were presented at IAS 2023 and were published earlier in Lancet HIV.

Once-weekly oral dosing

Six drugs (islatravir, lenacapavir, MK-8507/ulonivirine, GS-1720, GS-4182 and GS-5894) with the potential to be given every week are currently being studied in three different once-weekly combinations.

Some of these combinations are already in phase 3 studies and will likely be the next pipeline combinations to be approved.

One key concern about weekly dosing is to know whether the pharmacokinetics at day 14 are sufficiently robust to sustain viral suppression in the event of an inadvertently missed weekly dose.

Islatravir + lenacapavir

Islatravir (2 mg) is being studied with lenacapavir (300 mg) as an oral once-weekly combination.

Early results from a phase 2 switch study were presented at the Glasgow 2024 conference reporting comparable viral efficacy in a switch study compared to daily B/F/TAF at 48 weeks. [9]

A poster at the conference also presented the pharmacokinetic data supporting once-weekly dosing. [10]

This unfortunately doesn’t include information on PK at day 14 in the event of a missed weekly dose, which was one of the key questions asked after the oral presentation. This is a very strange current omission given that the first monotherapy studies in people who are HIV negative should have collected this data. [11]

Two phase 3 switch studies are already ongoing in the ISLEND-1 and ISLEND-2 studies with control arms using B/F/TAF and current ART, respectively. [12]

Islatravir + ulonivirine

Ulonivirine is an NNRTI similar to doravirine, also in development from MSD. A phase 2b dose-finding study for this dual combination is already ongoing. [13]

GS-1720 and GS-4182

Another two-drug once-weekly oral combination includes an integrase inhibitor (GS-1720) and capsid inhibitor (GS-4182), both in development from Gilead. Two phase2/3 studies are ongoing in naive participants and a switch study using B/F/TAF as a comparator. [14, 15]

GS-1720 is an integrase inhibitor similar to bictegravir, with a half-life of about 9 days.

A poster at Glasgow reported on the results of a 10-day dose-ranging GS-1720 monotherapy study in 28 naive and experienced people who were not on ART. Mean viral load reductions on day 11 were 1.74, 2.18, 2.44 and 2.37 log copies/mL in the 30, 150, 450 and 900 mg groups, respectively. No drug resistance was reported. [16]

GS-4182 is a prodrug of the capsid inhibitor lenacapavir, with improved absorption, bioavailability and systemic exposure and a half-life of about 11 days. Absorption is primarily in the GI-tract and a poster at Glasgow 2024 reported there was no impact on lenacapavir levels from the acid-reducing drug esomeprazole in HIV negative participants. [17]

Two-monthly dosing

VH4011499 (VH-499) is a capsid inhibitor being developed by ViiV currently in a phase 2a study involving 10 days monotherapy in ART-naive participants. [18]

This compound is being developed to be used in 2-monthly ART with an integrase inhibitor as a self-administered injectable combination.

CABOTEGRAVIR-LA + lenacapavir

Although not covered in detail in the plenary talk, it is also appropriate to reference off-label use by independent investigators of cabotegravir-LA (every 4 or 8 weeks) plus 6-monthly lenacapavir injections as part of an individualised therapy.

CROI 2024 included a presentation by Monica Gandhi and colleagues of results in 34 participants, half with detectable viral load at baseline, with 32/34 then being able to suppress. The results were also published as a case series calling for a formal study. [19, 20]

And Glasgow 2024 included a poster on a French study using a similar approach in two hospitals in eight people on suppressed ART who were drug resistant to rilpivirine and who had significant psychological difficulties with adherence. This was a highly treatment-experienced group, with 4/8 having a CD4 nadir <10 cells/mm³.

All 8/8 participants (4 men, 4 women), including 4/8 with a current CD4 count <200 cells/mm³ maintained viral suppression <50 copies/mL during at least 6 to 12 months follow-up. [21]

Three-monthly dosing

GS-1614 is a prodrug of islatravir and GS-6212 is an integrase inhibitor, both in very early stage development with Gilead, and both were included in a phase 1b study in people living with HIV of novel compounds. Results have not yet been presented. [22]

Four-monthly dosing

Ultra long-acting (ULA) cabotegravir + rilpivirine

CAB-ULA has a flatter pharmacokinetic profile with the subcutaneous and intramuscular formulations having a 6-fold and 2-fold longer half-life respectively compared to the current 2-monthly IM formulation that supports >4-monthly dosing. [19, 23, 24]

Six-monthly dosing

Finally, eight compounds have the potential for 6-monthly dosing.

•  VH-184 (VH4524184) is a third-generation integrase inhibitor with similar potency to second-generation INSTIs but with a different drug resistance profile. In development with ViiV. Early results were reported in HTB from the IAS 2024 conference. [25]

• VH-310 is a cabotegravir prodrug but with a slower PK release allowing 6-monthly dosing. First in-human studies are planned for early 2025. In development with ViiV.

• N6LS (VH3810109) is a long-acting bNAb that is active against 98% of viral isolates and that uses recombinant human hyaluronidase PH20 (rHuPH20) to extend half-life to allow 6-monthly dosing. Phase 1 results from the BANNER study reported median antiviral activity of –1.7 log at day 11 monotherapy using the higher dose and were presented at CROI 2024. [19, 25]

A poster at Glasgow 2024 from the BANNER study, reported that baseline phenotypic sensitivity to N6LS, analysed retrospectively, positively correlated with the reduction in viral load and time of suppression. Overall, 81% of the cohort achieved minimum viral load response >0.5 log copies/mL. [26]

• Teropavimab (3BNC117/GS 5423) and zinlirvimab (10-1074/GS 2872) – shortened to TAB and ZAB – are two bNAbs developed at Rockefeller University and are now in development with Gilead. Approximately 90% of clade B viruses are susceptible to at least one of these bNAbs and 50% to both, although baseline sensitivity is difficult to predict and resistance can develop to bNAb monotherapy.

Results from a small switch study with lenacapavir were presented at CROI 2024 with 8/10 participants with susceptibility to only one bNAb maintaining viral suppression at 26 weeks. The two viral failures were very low-level rebounds (still <200 c/mL) in the low-dose ZAB arm. [19]

Glasgow 2024 also included an oral presentation of a switch study using these two bNAbs with lenacapavir in people who were sensitive to either one of both of the bNAbs. At week 26, 3/14 (21%) in the low dose (ZAB 10 mg) and 0/16 (0%) in the high dose (ZAB 30 mg) group had undetectable viral load <50 copies/mL. [27]

A larger phase 2 study using this combination is already ongoing. [28]

Challenge from approaching generic dolutegravir

One challenge against this exciting pipeline however, raised by Andrew Hill et al is that these pipeline combinations will be coming to market as dolutegravir will be steadily reaching the end of its patent in high and middle-income countries by 2029. [29]

This suggests that long-acting combinations might need to show superiority against current first-line ART and overcome other targets in order to enable premium pricing. Generic dolutegravir-based ART could potentially to drop US $50 per year in high-income settings.

José Arribas refuted this model in his talk however, believing that continuing to invest in an HIV pipeline for a post-generic dolutegravir world can achieve clinical superiority in some populations and with safer profiles for example, during pregnancy, ageing and with renal/hepatic impairment. Also that benefits to people living with HIV from reduced dosing could also provide population-based and provider-based benefits that would justify premium pricing.

Drug pricing is only one component of healthcare costs and significant reductions in other health costs could support higher drug pricing.

comment

Four years ago the i-Base 2020 pipeline report concluded that “Gilead GSK/ViiV and Merck/MSD all have long-acting molecules that cover both treatment and prevention […] and are also all running studies of dual-therapy ART”. [30]

By 2024 we are seeing these early compounds produce highly effective results.

With only a few exceptions, companies still seem focussed on developing their own exclusive combinations, rather than collaboratively looking at the best overall combinations.

References

Unless stated otherwise, references are to the Programme and Abstracts of HIV Glasgow, 10–13 November 2024.
https://onlinelibrary.wiley.com/toc/17582652/2024/27/S6 (abstract book)

Unfortunately, other webcast links are initially restricted to delegates.

1. Arribas J et al. New treatments and future combinations. Plenary talk. Glasgow 2024. Monday 11 November 2024.
   https://virtual.hivglasgow.org/programme/antiretroviral-treatment-strategies (webcast)
2. Collins S. Switching to daily oral bictegravir and lenacapavir dual therapy to simplify ART in ARTISTRY-1 study. HTB (10 August 2024).
   https://i-base.info/htb/48337
3. Prelutsky D et al. Metabolic changes at 48 weeks in virologically suppressed people with HIV switching from complex antiretroviral regimens to bictegravir plus lenacapavir: ARTISTRY-1 trial. Glasgow 2024. Poster abstract P050.
4. Arora P et al. Pharmacokinetic (PK) analysis of oral once-daily bictegravir (BIC) plus lenacapavir (LEN) administered separately (BIC 75 mg + LEN 25 mg; BIC 75 mg + LEN 50 mg) and as BIC/LEN 75/50 mg single-tablet regimen to support phase III dose selection. Glasgow 2024. Poster abstract 049.
5. Study to compare bictegravir/​lenacapavir versus current therapy in people with HIV-1 who are successfully treated with a complicated regimen (ARTISTRY-1).
   https://clinicaltrials.gov/study/NCT05502341
6. Study to compare bictegravir/​lenacapavir versus current therapy in people with HIV-1 who are successfully treated with Biktarvy (ARTISTRY-2).
   https://clinicaltrials.gov/study/NCT06333808
7. Study of bictegravir/​lenacapavir in children and adolescents with HIV-1.
   https://clinicaltrials.gov/study/NCT06532656
8. Merck/MSD press release. Merck announces results from Phase 3 trials evaluating investigational regimen of doravirine/islatravir. (19 December 2024).
   https://www.merck.com/news/merck-announces-topline-results-from-pivotal-phase-3-trials-evaluating-investigational-once-daily-oral-two-drug-single-tablet-regimen-of-doravirine-islatravir-dor-isl-for-the-treatment-of-adults/
9. Colson AE et al. Once-weekly islatravir plus lenacapavir in virologically suppressed PWH: Week 48 safety, efficacy, and metabolic changes. Glasgow 2024. Oral abstract O21.
10. Longo D et al. Pharmacokinetics of oral islatravir (ISL) plus lenacapavir (LEN) given once weekly in an open-label, active-controlled, phase II study of virologically suppressed people with HIV-1. Glasgow 2024/ Poster abstract P224.
11. Collins S et al. Once-weekly oral ART with islatravir plus lenacapavir sustains results to week 48. HTB (28 November 2024).
    https://i-base.info/htb/49326
12. ClinicalTrials.gov. Study to compare an oral weekly islatravir/​lenacapavir regimen with standard of care in virologically suppressed people with HIV-1 (ISLEND-2).
    https://clinicaltrials.gov/study/NCT06630299
13. ClinicalTrials.gov. Dose ranging switch study of islatravir (ISL) and ulonivirine (MK-8507) once-weekly in virologically-suppressed adults with HIV-1 [MK-8591-013].
    https://clinicaltrials.gov/study/NCT04564547
14. ClinicalTrials.gov. Study of oral weekly GS-1720 and GS-4182 compared with Biktarvy in people with HIV-1 who have not been treated.
    https://clinicaltrials.gov/study/NCT06613685
15. ClinicalTrials.gov. Study of oral weekly GS-1720 and GS-4182 vs Biktarvy in people with HIV-1 who are virologically suppressed.
    https://clinicaltrials.gov/study/NCT06544733
16. ClinicalTrials.gov. Proof of concept treatment study of orally administered VH4004280 or VH4011499 in HIV-1 infected adults (CINNAMON).
    https://clinicaltrials.gov/study/NCT06039579
17. Falkard B et al. Pharmacokinetic/pharmacodynamic and resistance analyses of GS-1720, a once-weekly oral integrase strand transfer inhibitor. Glasgow 2024. Poster abstract P035.
18. Shaik N et al. Effect of acid-reducing agents on the pharmacokinetics of oral GS-4182. Glasgow 2024. Poster abstract P036.
19. CROI 2024: Pipeline ART – new drugs and formulations
    https://i-base.info/htb/47354
20. Gandhi M et al. Case series of people with HIV on the long-acting combination of lenacapavir and cabotegravir: call for a trial. Open Forum Infectious Diseases, 11(4), ofae125, doi: 10.1093/ofid/ofae125. April 2024.
    https://academic.oup.com/ofid/article/11/4/ofae125/7646382
21. Palich R et al. Long-acting cabotegravir plus lenacapavir as a fully injectable maintenance antiretroviral regimen in people with HIV with adherence issues. Glasgow 2024. Poster abstract P058.
22. ClinicalTrials.gov. An umbrella phase 1b, open-label, multi-cohort study to evaluate safety, pharmacokinetics, and antiviral activity of novel antiretrovirals in participants with HIV-1.
    https://clinicaltrials.gov/study/NCT05585307
23. Han K et al. Phase I study of cabotegravir long-acting injectable formulations supports ≥4-monthly dose interval. CROI 2024, Denver. Oral abstract 130.
    https://www.croiconference.org/abstract/phase-i-study-of-cabotegravir-long-acting-injectable-formulations-supports-%e2%89%a54-monthly-dose-interval/
    
24. Collins S. First data on third-generation integrase inhibitor from ViiV. HTB (10 August 2024).
    https://i-base.info/htb/48342
25. ClinicalTrials.gov. A study to evaluate the antiviral effect, safety and tolerability of GSK3810109A in viremic HIV-1 adults  https://clinicaltrials.gov/study/NCT04871113?tab=results
26. Correlation of baseline phenotypic sensitivity with virological response to VH3810109 (N6LS) in BANNER Margaret Gartland M et al. Correlation of baseline phenotypic sensitivity with virological response to VH3810109 (N6LS) in BANNER. Glasgow 2024. Poster abstract P037.
27. Cook PP et al. Efficacy and safety analysis of lenacapavir with broadly neutralising antibodies, teropavimab and zinlirvimab, in people with HIV-1 highly sensitive to one or both broadly neutralising antibodies. Glasgow 2024. Oral abstract O23.
28. ClinicalTrials.gov. Study to evaluate the safety and efficacy of teropavimab and zinlirvimab in combination with lenacapavir (GS-6207) in virologically suppressed adults with HIV-1.
    https://clinicaltrials.gov/study/NCT04811040
29. Fairhead C, Levi J, Hill A. Challenges for novel antiretroviral development in an era of widespread TLD availability. Clin Infect Dis. 2024 Jul 11:ciae361. doi: 10.1093/cid/ciae361.
    https://doi.org/10.1093/cid/ciae361
30. ARV pipeline report 2020.
    https://i-base.info/htb/37221