Sunlenca® (lenacapavir)

Use in Heavily Treatment-Experienced Individuals

This document is in response to your request for information regarding the use of Sunlenca® (lenacapavir [LEN]) in people with HIV-1 (PWH) who are heavily treatment-experienced (HTE), including those with baseline (BL) resistance.

Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.

The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.

Summary

Product Labeling1

LEN, in combination with other ARV(s), is indicated for the treatment of HIV-1 infection in HTE adults with multidrug resistant HIV-1 whose current ARV regimen is failing due to resistance, intolerance, or safety considerations.

Clinical Studies on LEN Use in HTE Individuals

In the ongoing phase 2/3 CAPELLA study that is evaluating LEN as an add-on therapy to a failing regimen in HTE PWH with multidrug resistance, significantly more participants in the LEN group than in the PBO group met the primary endpoint of a ≥0.5‑log10 reduction in HIV‑1 RNA at the end of the 14-day functional monotherapy phase (88% vs 17%, respectively; P<0.001).2

• At Week 156, 61.4% and 84.6% of participants achieved virologic suppression per FDA Snapshot and M=E analyses, respectively.3
• Subgroup analyses at Week 52 showed that LEN + OBR was associated with high rates of virologic suppression across various demographics and BL characteristics.3
• At Week 104, 27 participants met the criteria for resistance testing; 14 of these participants developed LEN resistance.4 There were no new cases of LEN resistance between Weeks 104 and 156.3
• From BL through a median (IQR) follow-up of 165 (146–178) weeks, Grade 3 TRAEs were reported in 6 participants (8.3%), and 2 participants discontinued due to Grade 1 injection site nodules.3
• Through Week 52, the mean CfB in SF-36, EQ-5D-5L, and NPRS scores did not reach the MIC thresholds, and most symptoms were reported as bothersome by fewer participants at Week 52 than at BL.5

Real-World Data on LEN Use in HTE Individuals

Real-world data on LEN use in HTE PWH is summarized in Table 7 below. Data may not be all inclusive.6-9

Clinical Studies on LEN Use in HTE Individuals

CAPELLA: LEN in HTE PWH

Study design and demographics

CAPELLA (NCT04150068) is an ongoing, phase 2/3, double-blinded, PBO‑controlled clinical study designed to evaluate LEN as add-on therapy to a failing regimen in HTE PWH with multidrug resistance. According to the change in the HIV-1 RNA level between the screening and cohort selection visits, participants were enrolled in either the randomized or non-randomized cohorts. Participants in the randomized cohort were assigned to receive oral LEN or PBO in a 2:1 ratio for 14 days, in addition to continuing their failing regimen. The non-randomized cohort started LEN (2-week oral initiation then SUBQ) with an OBR (Figure 1). Both cohorts are part of the maintenance phase evaluating the safety and efficacy of SUBQ LEN administered every 6 months in combination with an OBR.10,11

Figure 1. CAPELLA: Study Design2,10,12

Abbreviations: ATV/r=atazanavir/ritonavir; EFV=efavirenz; ETR=etravirine; NVP=nevirapine; TPV=tipranavir.

aParticipants with a <0.5 log10 decline in HIV-1 RNA and HIV-1 RNA ≥400 c/mL were enrolled in the randomized cohort; participants were enrolled in the non-randomized cohort if they had a ≥0.5 log10 decline in HIV-1 RNA and/or had HIV-1 RNA <400 c/mL or were enrolled after the randomized cohort was fully recruited.

bOral LEN dosing schedule: Day 1, 600 mg; Day 2, 600 mg; and Day 8, 300 mg.

cSUBQ LEN dosing schedule: 927 mg (2 × 1.5 mL) on Day 15 and then every 6 months.

Note: ATV, ATV/COBI, ATV/r, EFV, ETR, NVP, and TPV were not permitted for use in OBR.

The primary endpoint was the proportion of participants who achieved a ≥0.5‑log10 c/mL reduction in HIV‑1 RNA from BL to the end of the functional monotherapy phase in the randomized cohort. Secondary endpoints included the percentage of participants in the randomized cohort with HIV-1 RNA <50 c/mL or <200 c/mL and change in CD4 cell count at Weeks 26, 52, and 104.10 Twenty‑two percent of all participants (16/72) did not have changes in their OBR before they entered the open-label maintenance phase; the ARV classes and agents that comprised the failing regimen and OBR are shown in Table 2.13

Table 1. CAPELLA Study: BL Demographics and Disease Characteristics10,12

aPercentages may not equal 100 due to rounding.

bCollection of race or ethnicity data was prohibited by local regulators for 1 participant in the PBO group and was excluded from the denominator of the percentage calculation.

cTwo participants in the non-randomized cohort had HIV-1 RNA >400 c/mL at screening but <50 c/mL at enrollment.

Table 2. CAPELLA Study: Composition of Failing Regimens and OBR14

aOSSs were calculated with a proprietary algorithm (Monogram Biosciences Inc.), and investigators provided data for scoring from historical resistance reports. An OSS of 1 indicated full susceptibility; 0.5 indicated partial susceptibility; and 0 indicated no susceptibility. The OSS of the OBR was the sum of the individual scores.

BL resistance analyses15

The study enrolled participants who had resistance to ≥2 ARVs in ≥3 of the four main ARV classes (NRTIs, NNRTIs, PIs, and INSTIs; Table 3 and Table 4). BL resistance in these participants was assessed using genotypic and phenotypic assays (Monogram Biosciences, Inc.) at screening or historical data provided by the investigators. BL HIV‑1 capsid genotypic and phenotypic analyses were also performed. At BL, no RAMs associated with LEN resistance (eg, L56I, M66I, Q67H, K70N, K74D/S, and T107N) were found in the 62 participants for whom these data were available.

Table 3. CAPELLA Study: RAMs per ARV Class at BL15

Table 4. CAPELLA Study: BL Resistance to NRTI, NNRTI, PI, and INSTI Classes by Cohort and in the Overall Population15,16

aResistance to ≥2 ARVs in the class. To be eligible for the study, participants had to have resistance to ≥2 ARVs from ≥3 of the four classes noted above.

bFor this study, M184V/I alone was not sufficient to fulfill the NRTI resistance criteria.

cThis participant had three-class resistance in the presence of NRTI mutation M184V/I only, which was not sufficient to fulfill the NRTI resistance criteria in this study.

Efficacy results

Day 15: randomized cohort results2

From BL to Day 15 in this study, LEN showed potent antiviral activity when added to a failing regimen. Significantly more participants in the LEN group than in the PBO group met the primary endpoint of a ≥0.5-log10 reduction in HIV-1 RNA at the end of the 14-day functional monotherapy phase (88% [21/24] vs 17% [2/12], respectively; P<0.001) and had a greater mean change in HIV-1 RNA (-2.1 vs 0.07 log10 c/mL, respectively; P<0.001).

Week 26: subgroup analysis by BL HIV entry inhibitor resistance17

At Week 26 in both cohorts, treatment response to LEN + OBR was unaffected by BL entry inhibitor susceptibility, as no significant difference in susceptibility was observed between participants with viral suppression (HIV-1 RNA <50 c/mL) and those with treatment failure (HIV-1 RNA ≥50 c/mL or no virologic data; P>0.1).

Week 52: subgroup analysis by BL characteristics18

Among all participants (n=72), HIV-1 RNA <50 c/mL was achieved at a rate of 78%. Several prespecified, post hoc subgroup analyses of all participants (n=72) were conducted to determine the efficacy of LEN at Week 52 according to selected BL demographics (ie, age, sex at birth, and race) as well as BL CD4 and HIV‑1 RNA values, BL number of fully active agents in OBR and BL resistance to INSTI, and BL use of ARV agents (eg, DTG, DRV, IBA, or FTR). There were no statistically significant differences between the subgroups.

Week 104 results10,12

Twelve participants (17%) had no fully active ARVs in their OBR, with an OSS of 2 in the cohort randomized to LEN, 1.5 in the PBO cohort, and 2 in the nonrandomized LEN cohort. In an overall missing=failure analysis at Week 104, 44/71 participants (62%) had HIV-1 RNA <50 c/mL, and 45/71 (63%) had HIV-1 RNA <200 c/mL. At Week 104, 10 participants had HIV-1 RNA >50 c/mL while on study drug; 6 of these participants had achieved virologic suppression at ≥1 prior visit. The mean increase in CD4 cell count from BL to Week 104 in the 55 participants with available data was 122 cells/mcL.

Fourteen participants developed LEN resistance through Week 104, consisting of the following LEN RAMs: Q67H/K/N (n=8), K70H/N/R/S (n=7), M66I (n=6), T107A/C/N (n=6), N74D/H/K (n=5), and A105S/T (n=5). LEN RAMs were detected in combinations of 2 to 4 substitutions in 11 participants and occurred individually in 3 participants. All participants with LEN RAMs either had inadequate plasma concentrations of drugs in the OBR (n=10) or had no fully active drugs in their OBR (n=4). Of these 14 participants, 7 resuppressed on LEN following improved adherence (n=5) or following changes to their OBR (n=2).

Week 156: maintenance phase results3

At Week 156, 52/72 participants (72%) continued receiving LEN. Overall, 98% of the SUBQ doses were within ±14 days of the scheduled time. At Week 156, 61.4% and 84.6% of participants achieved virologic suppression per FDA Snapshot and M=E analyses, respectively (Figure 2).

Figure 2. CAPELLA Study: Virologic Outcomes Through Week 1563

aTwo participants who had missing HIV-1 RNA at Week 56 and had completed the study before reaching the upper limit of the analysis window for Week 156 were excluded.

bThe denominator was the number of participants with non-missing HIV-1 RNA values at each time point.

CD4 changes through Week 1563

Overall, CD4 count increased by a mean (95% CI) of 164 cells/mcL from BL to Week 156. At Week 156, the proportion of participants with CD4 counts <50 cells/mcL decreased from 24% of participants at BL to 2%, and the proportion of participants with CD4 counts <200 cells/mcL decreased from 64% to 22% (Figure 3).

Figure 3. CAPELLA Study: Changes in CD4 Counts at Week 1563

Abbreviation: D1=the first day SUBQ LEN was administered.

Post-BL resistance analyses through Week 156

Post-BL resistance analyses were conducted in participants with suboptimal virologic response (HIV-1 RNA ≥50 c/mL and <1‑log10 decrease in HIV RNA from LEN initiation; assessed at Week 4), virologic rebound (after suppression, HIV RNA ≥50 c/mL or >1‑log10 increase from nadir), or viremia at their last visit.18

Treatment-emergent resistance to LEN developed in 9 participants from BL to Week 52 and in an additional 5 participants from Week 52 to 104 (Table 5). All 14 participants were at high risk of developing resistance to LEN due to inadequate OBR adherence (n=10) or lack of fully active drugs in the OBR (n=4).10

Table 5. CAPELLA Study: Emergent LEN Resistance Through Week 1044

aOne participant developed a T107S polymorphism with no impact on LEN susceptibility (1.3-fold change vs wild type), and 1 participant developed a T107A polymorphism with no loss in LEN susceptibility (0.6-fold change vs wild type).

There were no new cases of LEN resistance between Weeks 104 and 156. Two participants who had previously detected resistance developed additional mutations: 1 participant had emergence of K70R+T107N with existing Q67H (reduction in LEN susceptibility from 4.5- to 85-fold of wild-type), and 1 participant had emergence of T107T/N with existing K70N+N74K (no LEN susceptibility data for triple mutant).3

Despite the emergence of LEN resistance, 5 participants were resuppressed while continuing LEN treatment (OBR was changed in 2 participants and unchanged in 3 participants). Six of the 9 participants who were not resuppressed continued study treatment (2 participants returned to their BL VL; mean log reduction for the 4 participants who did not return to BL VL: -1.64), and 3 participants discontinued the study (death, investigator’s discretion due to non‑compliance, and LTFU, n=1 each).3

Safety results3

The median (IQR) duration of follow-up on LEN was 165 (146–178) weeks. Safety results through Week 156 are reported in Table 6.

Table 6. CAPELLA Study: Safety Results Through Week 1563

Abbreviation: TEAE=treatment-emergent adverse event.

aISRs and COVID-19 were excluded. bISR, n=4; immune reconstitution inflammatory syndrome, n=1; abdominal abscess, n=1; rash, n=1. cGrade 1 injection site nodule, n=2. dMalignant neoplasm, n=1; acute respiratory failure, n=1; unknown, n=1.

Note: TEAEs occurring in ≥10% of participants: constipation (13.9%), headache (13.9%), pyrexia (13.9%), abdominal distention (11.1%), arthralgia (11.1%), back pain (11.1%).

ISR results: Week 1563

Most ISRs (97.2%) reported through Week 156 were Grade 1 or 2, and the frequency reduced over time (Figure 4). Grade 1 ISRs of injection site nodules led to study discontinuation in 2 participants. The median (IQR) duration of swelling, erythema, pain, nodules, and induration was 8 (4–15), 5 (3–8), 3 (2–5), 288 (155–548), and 190 (67–410) days, respectively.

Figure 4. CAPELLA Study: ISRs Related to SUBQ LEN Through Week 1563

PROs5

At Week 52, PROs were evaluated to assess CfB in HIV symptoms (using the SF‑36 [scale: 0–100; higher scores are associated with better physical health, mental health, and function] and HIV-SI scales [scale: 0–4; higher scores indicate more bothersome HIV symptoms]), overall HRQoL (using the EQ-5D-5L [0- to 1-point index score and a 0- to 100‑point VAS score; higher numbers indicate better health and how a patient’s health condition may limit or worsen the patient’s daily activities]), and injection pain (using the NPRS scale [scale: 0–10; higher score indicates more intense pain]) during the most recently received injection.

At BL, the mean SF-36 physical and mental component scores were 48.5 and 48.4, respectively; normal SF-36 scores in the US are 50 for both components. Through 52 weeks, the SF-36 component summary scores remained stable (Week 52 mean CfB: physical component, 1; mental component, -0.9), and the score changes did not reach the MIC values (2 and 3, respectively).

At Week 52, the proportion of participants who reported symptoms as bothersome decreased in 15 of 20 symptom categories, with a decrease by ≥5% for 10 of 20 symptoms. The three symptoms with the greatest decrease on the HIV-SI were fatigue or loss of energy (-15%), feeling nervous or anxious (-‍14%), and muscle aches or joint pain (-‍10%). From BL to Week 52, reports of bothersome symptoms increased by 21% for pain, numbness, or tingling in hands or feet and increased by 5% increase for headache.

At BL, the mean EQ-5D-5L index and VAS scores were 0.87 and 81, respectively; normal EQ-5D-5L index and VAS scores in adults in the US are 0.851 and 80.4, respectively. Through 52 weeks, the EQ-5D-5L scores remained stable (Week 52 mean CfB: index, -‍0.06; VAS, 3), and the score changes did not reach the MIC values at any time (0.063 and 7, respectively).

The individual NPRS scores for all participants were highly variable over 52 weeks; however, the mean scores (range: 3.9–5.1) remained stable, and the mean CfB was less than the MIC threshold of 2.

Real-World Data on LEN Use in HTE Individuals

Table 7. Real-World Data on LEN Use in HTE Individuals6-9

Abbreviations: OPERA=Observational Pharmaco-Epidemiology Research & Analysis; VF=virologic failure.

References

1. SUNLENCA, Gilead Sciences Inc. SUNLENCA® (lenacapavir) tablets, for oral use. SUNLENCA® (lenacapavir) injection, for subcutaneous use. U. S. Prescribing Information. Foster City, CA.

2. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2022;386(19):1793-1803.

3. Ogbuagu O, McGowan JP, Stapleton A, et al. Long-Acting Subcutaneous Lenacapavir in People With Multi-Drug-Resistant HIV-1: 3-Year Results of the CAPELLA Study.[Presentation #155]. Paper presented at: IDWeek 2024; October 16-19, 2024; Los Angles, CA.

4. Margot NA, Jogiraju V, Pennetzdorfer N, et al. Resistance Analyses in Heavily Treatment-Experienced People with HIV Treated with the Novel HIV Capsid Inhibitor Lenacapavir After 2 years. J Infect Dis. 2025;231:1239–1245.

5. Ramgopal M, Mezzio DJ, Dunn K, et al. Participant-reported Outcomes from the CAPELLA Clinical Trial of Lenacapavir-based Regimens in Heavily Treatment-experienced Adults with HIV. AIDS Behav. 2025;29(5):1553-1561.

6. Mounzer K, Brunet L, Hsu R, et al. Lenacapavir Adherence and Effectiveness Over 2 Years of Use in the OPERA Cohort. [Presentation]. Paper presented at: IDWeek October 19-22, 2025; Atlanta, GA.

7. Charpentier C, Montrouge T, Wirden M, et al. French national real-world observatory of people initiating a lenacapavir-based treatment during the post-approval period [Presentation]. Paper presented at: 20th European AIDS Conference (EACS); October 15-18, 2025; Paris, France.

8. Palich R, Ghosn J, Valantin M-A, et al. Real world use of lenacapavir in France: a national, observational study.[Poster #eP101]. Paper presented at: 20th European AIDS Conference (EACS); October 15-18, 2025; Paris, France.

9. Delaugerre C, Mafi S, Zenuni A, et al. Capsid Inhibition with Lenacapavir in HIV-1 Infection: Real-life Results from the French Compassionate Use Program. [Poster #EP0195]. Paper presented at: 13th International AIDS Society (IAS) Conference on HIV Science; July 13–17, 2025; Kigali, Rwanda.

10. Ogbuagu O, Molina JM, Chetchotisakd P, et al. Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multidrug-Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial. Clin Infect Dis. 2025;80(3):566-574.

11. Ogbuagu O, DeJesus E, Berhe M, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in heavily treatment experienced people with multi drug resistant HIV: Week 104 results [Poster 1596]. Paper presented at: ID Week 2023; October 11-15, 2023; Boston, MA.

12. Ogbuagu O, Molina JM, Chetchotisakd P, et al. Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multidrug-Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial [Supplementary Appendix]. Clin Infect Dis. 2025;80(3):566-574.

13. Castagna A, Blanco JL, Hung C, et al. Week 52 Subgroup Efficacy Analyses of Long-Acting Subcutaneous Lenacapavir in Phase 2/3 in Heavily Treatment-Experienced People With Multidrug-Resistant HIV (CAPELLA Study) [Poster P026]. Paper presented at: HIV Glasgow 23-26 October, 2022; Glasgow, UK.

14. Stellbrink H, DeJesus E, Segal-Maurer S, et al. Subgroup Efficacy Analyses of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People With HIV in the Phase 2/3 CAPELLA Study [Poster]. Paper presented at: 18th European AIDS Conference (EACS); October 27-30, 2021; London, UK.

15. Margot NA, Naik V, et al. USE ENDNOTE 75466 Resistance analyses in Highly Treatment-Experienced People with HIV Treated with the Novel Capsid HIV Inhibitor Lenacapavir. J Infect Dis. 2022:1-7.

16. Margot N, VanderVeen L, Naik V, et al. Resistance Analysis of Long-Acting Lenacapavir in Highly Treatment-Experienced People with HIV after 26 Weeks of Treatment [Presentation]. Paper presented at: 18th European AIDS Conference (EACS); October 27-30 2021; London, UK.

17. Margot N, Naik V, Rhee MS, Callebaut C. Absence of Cross-Resistance to Lenacapavir in HIV Entry Inhibitor-Resistant Isolates [Poster 508]. Paper presented at: Virtual Conference on Retroviruses and Opportunistic Infections (CROI) 2022; 12-16 February, 2022.

18. Ogbuagu O, Segal-Maurer S, Ratanasuwan W, et al. Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial. Lancet HIV. 2023;10(8):e497-e505.

Abbreviations

ANRS=Agence Nationale de Recherche sur le Sida et les Hepatites
ARV=antiretroviral ATV=atazanavir
BL=baseline
c/mL=copies/mL
CAB=cabotegravir
CAI=capsid protein inhibitor
CD4=cluster of differentiation 4
CfB=change from baseline
COBI=cobicistat
DRV=darunavir
DRV/r=darunavir/ritonavir
DTG=dolutegravir
FTR=fostemsavir
HIV-SI=HIV symptom index
HRQoL=health-related quality of life
HTE=heavily treatment‑experienced
IBA=ibalizumab
INSTI=integrase strand transfer inhibitor
ISR=injection site reaction
LEN=lenacapavir
LTFU=lost to follow-up
M=E=missing equals excluded
MIC=minimal important change
MVC=maraviroc
NNRTI=non-nucleos(t)ide reverse transcriptase inhibitor
NPRS=numeric pain rating scale
NRTI=nucleos(t)ide reverse transcriptase inhibitor

OBR=optimized background regimen
OSS=overall susceptibility score
PBO=placebo
PI=protease inhibitor
PRO=patient-reported outcomes
PWH=people with HIV
RAM=resistance-associated mutation
SF-36=36-item Short Form Survey
SUBQ=subcutaneous
T20=enfuvirtide
TRAE=treatment-related adverse event
VAS=visual analogue scale
VL=viral load
 

Product Label

For the full indication, important safety information, and boxed warning(s), please refer to the Sunlenca US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.

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