CROI 2023: Other lenacapavir studies – experienced and naive updates, the dosing window, HIV-2 and PrEP

10 March 2023. Related: Conference reports, Antiretrovirals, CROI 30 (Retrovirus) 2023.

Simon Collins, HIV i-Base

In addition to the results from the phase 1b study using lenacapavir with dual bNAbs as a six-monthly combination [1, 2], many other studies reported on different aspects of this long-acting new drug.

These other studies included longer follow-up in treatment-experienced and -naive studies, flexibility with the dosing window, more detail on the mechanism of action and potential activity against HIV-2,

Updated results in treatment-experienced CAPELLA study

A sub-group analysis of the phase 2/3 CAPELLA study in 72 heavily treatment-experienced participants showed that rates of viral suppression at week-52 were similar by baseline viral load, CD4 count, INSTI resistance and optimised background regimen (OBR) in both the open-label and randomised cohorts (n=36 in each). The randomised group included period of 14 days oral monotherapy added to the currently-failing ART before being changing to the OBR. [3]

Participants with lower baseline CD4 <200 vs >200  (72% vs 89%, p=0.07) and higher baseline viral load <100,000 vs >100,000 (81% vs 64%, p=0.11) had numerically lower rates of virological suppression, though in a larger study similar results might have become statistically significant.

This main study previously reported that 78% (56/72) of participants had undetectable viral load (<50 copies/mL) at week 52 with a median CD4 increase of 84 cells/mm³.

Updated results in treatment-naive CALIBRATE study

The ongoing phase 2 treatment-naive CALIBRATE study, was also updated with results from week-80. This study randomised 157 participants to one of three arms using subcutaneous or oral lenacapavir with a control arm of 25 participants using bictegravir/FTC/TAF. [4]

The first two groups used subcutaneous injections of lenacapavir with either tenofovir alafenamide (n=52) or bictegravir (n=53) and the third use emtricitabine/TAF in a triple combination (n=52).

At week 80, rates of viral load suppression to <50 copies/mL were 85%, 75% and 87% in groups 1, 2 and 3, respectively, This compared to 92% in the bictegravir/F/TAF control arm. Rates at the primary 54-week endpoint were 90%, 85% and 85% vs 92%, respectively. Differences between arms and timepoints were largely explained by missing data. By week 80, seven participants had detectable viral load >50 copies/mL, six in the lenacapavir arms and one in the control group.

Resistance to lenacapavir was detected in 3/157 participants (2%). One developed Q67H + K70R in capsid at week 80, another developed M184M/I in reverse transcriptase prior to Q67H + K70R in capsid at week 10, and one developed Q67H in capsid at week 54 with subsequent K70R (linked to low adherence).

Tolerability was generally good with few grade 3 and no grade 4 events, There were also low rates of generally mild injection site reactions.

Defining the window period for dosing

A modelling analysis based on population PK reported the flexibility for timing of subsequent injections and was supported by drug levels seen in the phase 2/3 studies. [5]

This was based maximum antiviral activity when the lower bound of the 90% confidence interval of mean trough concentration was above 15.5 ng/mL. This is four times higher than the inhibitory quotient (IQ4 ≥ 4-fold greater than the in vitro protein-adjusted 95% effective concentration).

This predicted a four-week window for the six-monthly injections, allowing for being two weeks early or two weeks late, before needing to use oral replacement ART.

When given two weeks early (at week 24), the Cmax is still similar to dosing at week 26. When given two weeks late (at week 28), lenacapavir Ctrough remained above the 4xPA IQ and with the lower bound of the 90%CI being 20.4 ng/mL [IQ 5.2] and 21.9 ng/mL [IQ 5.6], with original and simplified dosing, respectively. Simplified dosing only requires a single lead-in oral dose.

Activity against HIV-2 and mechanism of action

A macaque study reported potential benefits of lenacapavir as PrEP against rectal exposure of SHIV. [6]

In vitro activity against HIV-2 isolates was reported in a poster but was 11- to 16-fold less potent compared to HIV-1. This suggests that any potential role for treatment of multidrug HIV-2 resistance would need to be vary carefully approached.

Two other oral presentations at CROI reported on mechanisms of capsid activity, and how this compound is active at both early stage of the viral life cycle by distrupting the capsid before integration into the nucleus, but also, and perhaps more importantly, at the late stage by preventing maturation of new viral capsid. [7, 8]

Lenacapavir as PrEP

Finally, CROI included new data on the potential for lenacapavir as PrEP in a poster discussion. [9]

This included results from a macaque study showing protection against rectal exposure following a single high dose SHIV challenge, seven weeks after lenacapavir injection with various doses. Previous animal studies have reported protection against multiple vaginal and rectal challenges but have not been able to collect data in relation to timing of infection.

Importantly, lenacapavir in macaques is 4-fold less potent against SHIV than equivalent human exposure to HIV.

Out of 11 animals, 8/11 were protected and 3/11 became infected with SHIV, with infected animals having drug exposure that was significantly lower than target levels. None of the animals above target levels became SHIV positive.

These data support continued research into using lenacapavir for PrEP, and the two large phase 3 PURPOSE studies are already enroling. [10, 11]

comment

The early results are exciting both for HIV treatment and PrEP.

Further details will be needed from phase 3 and other studies to cover complexity of situations that are often exclusion criteria from the first studies.

Long-acting ART can also extend interpatient variability in pharmacokinetic parameters and have implications on the impact of viral rebound on developing drug resistance or compromising U=U compared to daily dosing.

References

Unless stated otherwise, references are to the Programme and Abstracts of the 30th Conference on Retroviruses and Opportunistic Infections, 19 – 22 February 2023, Seattle and hybrid.

Some 2023 abstracts are available via the online CROI abstract database, mainly for posters rather that oral abstracts.
www.croiconference.org/search-abstracts

Links to posters currently require a login to the conference platform.