Glasgow 2024: Once-weekly oral ART with islatravir plus lenacapavir sustains results to week 48

14 November 2024. Related: Conference reports, Antiretrovirals, HIV 17 Glasgow 2024.

Simon Collins, HIV i-Base

Glasgow 2024 included 48-week results from a randomised placebo-controlled phase 2 switch study comparing once-weekly islatravir plus lenacapavir (ISL+LEN) to a control group who continued on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). [1]

This extended data from a phase 2 study out to 48 weeks — as 24 week results were presented at CROI earlier this year. [2, 3]

This study randomised 104 participants (1:1) on stable ART to either change to islatravir (2 mg) plus lenacapavir (300 mg) or remain on daily bictegravir/F/TAF with appropriate placebo in each arm.

At 24 weeks, 49 (94.2%) vs 48 (92.3%) participants were undetectable in the ISL+LEN vs control groups. No data was available for 2 vs 4 pts respectively. One VL increase to 251 copies/mL) resuppressed without changing ART. No rebounds were seen with B/F/TAF.

New data at Glasgow were presented by Amy Colson from Community Research Initiative in Boston, who reported that high levels of efficacy continued between weeks 24 and 48. Secondary endpoint results were also presented.

Baseline characteristics included median age 40 (range: 26 to 76), just over 80% were cisgender men, with almost 20% cisgender women, one transgender woman and one non-binary participant, 50% were white, 35% Black and 30% were Latinx. Mean CD4 was 786 cells/mm³ (SD+/–250) with median BMI 27.1 (IQR: 24.5 to 29.4).

Viral response <50 copies/mL remained the same at week 48 with 49 (94.2%) vs 48 (92.3%) participants remaining undetectable. Three participants in each arm discontinued the study due to reasons unrelated to the study drugs and had done this when viral load was undetectable, with an additional participant in the BIC/F/TAF arm having missing data at week 48.

Adverse events were similar in each group with no serious grade 3/4 events linked to study drugs. The only lab abnormality reported as serious was an elevated ALT related to hepatitis B.

The lower dose of islatravir in this study didn’t lead to any significant differences between arms in mean change from baseline in CD4 (p=0.88) or lymphocyte counts (p=0.23) at week 48, or in any discontinuations. There were also no between-group differences in changes in weight or BMI between baseline and week 48.

At week 48, all participants were given the option to switch to ISL+LEN with extended follow-up visits every 3 months.

These results supported further development in two randomised, placebo-controlled phase 3 switch studies, using a similar design but with coformulated ISL/LEN. They are recruiting participants but currently only in US sites. [4, 5]

comment

If effective, once-weekly dosing has the potential to improve quality of life much more easily than injectable formulations, and without the need to reorganise clinic services.

The main concern related to adherence would be the risk of missing a complete dose, asked by Dr José Arribas during the questions.

Although the presenter suggested that PK data support a half-life that might cover being seven days late, the uncertainty over this was not helpful and the trough levels for both drugs at day 14 from phase 1 PK studies should have been included in the presentation.

Although the conference included a poster about drug levels in participants during the study, this related to steady-state with weekly adherence. [2]

Suboptimal drug levels at day 14 could be a significant caution.

References

1. Colson AE et al. Once-weekly islatravir plus lenacapavir in virologically suppressed PWH: week 48 safety, efficacy, and metabolic changes. HIV Glasgow, 10–13 November 2024. Oral abstract 21.
   https://onlinelibrary.wiley.com/doi/full/10.1002/jia2.26370
2. HTB. CROI 2024: Pipeline ART – new drugs and formulations. (19 March 2024).
   https://i-base.info/htb/47354
3. Colson A et al. Efficacy and safety of weekly islatravir plus lenacapavir in PWH at 24 weeks: a phase ii study. CROI 2024, Denver. Oral abstract 208.
   https://www.croiconference.org/abstract/efficacy-and-safety-of-weekly-islatravir-plus-lenacapavir-in-pwh-at-24-weeks-a-phase-ii-study (abstract)
   https://watch.croiwebcasts.org/croi2024/ap/52354 (webcast)
4. ClinicalTrials.gov. Study to Compare an Oral Weekly Islatravir/​Lenacapavir Regimen With Bictegravir/​Emtricitabine/​Tenofovir Alafenamide in Virologically Suppressed People With HIV-1 (ISLEND-1).
   https://clinicaltrials.gov/study/NCT06630286
5. 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
6. Longi D et al. Pharmacokinetics of oral islatravir plus lenacapavir given once weekly in an open-label, active-controlled, phase 2 study of virologically suppressed people living with HIV-1. HIV Glasgow, 10–13 November 2024. Poster abstract P224.