IAS 2021: lenacapavir studies show impressive results in naive, extensive drug resistance and potential as PrEP
Simon Collins, HIV i-Base
Three studies at IAS 2021 included new data on the long-acting capsid inihibitor lenacapavir.
This included two late-breaking abstracts reporting clinical results from the phase 2 CALIBRATE induction/maintenance study in treatment naïve participants and the phase 3 CAPELLA study in treatment experienced participants. [1, 2]
Lenacapavir results in treatment naive
CALIBRATE randomised 182 participants (2:2:2:1) to one of three lenacapavir arms with F/TAF (two using injections with later reduction to two-drug ART at week 28, one using oral lenacavir plus F/TAF throughout) or to a control arm of bictegravir/F/TAF. 
Interim pre-specified 16-week results for achieving viral load <50 copies/mL included 92% (48/52), 94% (50/53), 94% (49/52), and 100% (25/25) in the three lenacapavir and control groups respectively.
Baseline characteristics included median age 29 years (range: 19 to 72), 7% women (yes, 7%), 52% black, 45% Hispanic/Latinx,
Median viral load and CD4 count at baseline were 4.3 log copies/mL (IQR: 3.8 to 4.7) with 15% >100,000 c/mL and 437 cells/mm3(IQR: 332 to 599), with only two participants <200 cells/mm3.
At week 16 by ITT analysis, viral load was <50 copies/mL in 94% (147/157) vs 100% (25/25) in the pooled lenacapavir vs control groups respectively. The two cases of virological failure included one participant who did not reach <50 copies/mL at week 28 and one who discontinued the study after two days. Early response rates at week 4 were similar in all groups. The primary endpoint is at week 54.
One participant who had an early viral response at week 2 that rebounded close to 100,000 copies/mL baseline by week 10, developed lenacapavir emergent mutations (capsid Q67H + K70R) associated with a 20-fold loss of sensitivity, together with M184V in RT. Lenacapavir drug levels were consistently within the target range and although viral load was dropping again, treatment was changed to AZT/3TC/TDF plus dolutegravir (an unusual choice) and then became undetectable.
Adverse events were similar across groups (including 11 cases of COVID-19 and 17 cases of syphilis overall) with no drug-related discontinuations or grade 4 side effects.
Injection site reactions (ISRs) were common (40/183) but mostly grade 1 (33/40), with only 1 grade 3 and no grade 4. However, the study reported some nodules lasting for several months that were “palpable but not visible” and these extended from 1 to 4 cms. Two participants discontinued due to grade 1 ISRs with local hardening of the skin.
Laboratory abnormalities included high creatine kinase (n=5 vs 0), mainly explained by recent exercise with no grade 3/4 results judged clinically relevant or leading to discontinuations.
These results support continuing to the dual therapy maintenance therapy switches with extended follow-up to week 80.
Lenacapavir with extensive drug resistance
Clinical results were also presented at IAS 2021 from the phase 2/3 CAPELLA study in 72 highly treatment experienced participants who had HIV multidrug resistance (MDR) to at least three drug classes. 
Half the participants were randomised to lenacapavir or placebo for 14 days (before optimising treatment) and half used open label lenacapavir.
The results at IAS 2021 were week 26 from the 36 participants in the randomised section of this study.
Median age was 52 years (range: 23 to 78), 25% were women, 38% were back and 28% Hispanic/Lantinx. Participants had been living with HIV for an estimated median or 24 years (range: 9 to 44 years).Extensive drug resistance to >2 drugsin each class was 99% (NRTIs), 97% (NNRTIs), 81% (PIs) and 69% (INSTIs) at baseline.
Virological results included 81% (n=29/36) of participants reaching an undetectable viral load (<50 copies/mL) and 89% (32/36) <200 copies/mL. There were no missing data, with 7 and 4 participants having viral load >50 and >200 copies/mL, respectively. Although numbers are small, 4/6 participants with no active background drugs also reached <50 copies/mL.
Themean CD4 count increased to 81 cells/mm3included increases to >50 cells/mm3in the 8/36 participants who had CD4 counts <50 cells/mm3at baseline.
Limited data were available for the 11 participants who met criteria for resistance testing. Of these, 4/11 developed emerging mutations associated with drug resistance to lenacapavir: M66I (4), Q67H (1), K70N/R/S (1) and N74D (1) although related phenotypic impact was not discussed. Of these, 3/4 later suppressed, one with OBR change and two without.One person without other sensitive drugs who did not become undetectable reported a –1.7 log reduction in viral load. Although no new resistant mutations were reported for other ART, this is likely related to the relatively short follow-up.
Tolerability was good with no study discontinuations and no serious drug-related side effects. Injection site reactions (ISRs) were common (56%; 40/72) but mainly grade 1 (28/40) that resolved in a few days. None were grade 4 and the two grade 3 reactions resolved by days 4 and 8.
All participants have since received a second 6-monthly injection.
Lenacapavir as PrEP
Finally, further results were presented on the potential of lenacapavir as PrEP. 
This was a study in 24 female macaques, randomised to one of two doses of a single lanacapavir injection or placebo followed by ten vaginal weekly challenges with SHIV.
The single administration of lenacapavirexceeded the protein adjusted EC95 value (30.2 nM) for at least 10 and 16 weeks (in the 150 mg/kg and 300 mg/kg groups, respectively).
All 8/8 control animals all became infected by week 8 (median of 4 weeks). In contrast, 6/8 animals became viraemic in the 150mg/kg at a median of 14 weeks (p<0.0001). However, there were no infections (100% protection) in the 8/8 animals in the 300 mg/kg group, (p<0.0001).
This showed similar efficacy to a rectal challenge macaque study reported at CROI 2021. 
These combined results show exciting potential of very long-acting drugs.
Phase 3 studies are already ongoing for both treatment and PrEP.
- Gupta S et al. Long-acting subcutaneous lenacapavir dosed every 6 months as part of a combination regimen in treatment-naïve people with HIV: interim 16-week results of a randomized, open-label, phase 2 induction-maintenance study (CALIBRATE). IAS 2021. Oral abstract OALB0302.
- Molina J-M et al. Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (Capella study). Oral abstract OALX01LB02.
- Bekerman E et al. Long-acting capsid inhibitor effective as PrEP against vaginal SHIV transmission in macaques. IAS 2021. Poster abstract PECLB24.
- CROI 2021: First results using capsid inhibitor lenacapavir against MDR HIV: potential for six-monthly ART and PrEP. HTB (1 April 2021).