Sunlenca® (lenacapavir)

Safety Overview

This document is in response to your request for information regarding the safety of Sunlenca® (lenacapavir [LEN]) in people with HIV-1 (PWH).

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

The primary safety assessment of LEN was based on data from HTE adult participants with HIV who received LEN in a phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks), as well as supportive data in TN adult participants with HIV who received LEN in a phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks).

The most common adverse reactions (all Grades) reported in ≥3% of participants in CAPELLA were nausea and ISRs.

Clinical Studies on Safety of LEN Use in PWH

In the phase 2/3 CAPELLA study in HTE PWH, no Grade ≥4 or serious TRAEs occurred during follow-up through a median (IQR) of 165 (146–178) weeks.2

In the phase 2 CALIBRATE study in TN PWH, most laboratory abnormalities observed in participants were Grade 1 or 2 in severity, and there were no treatment-related SAEs reported through the last study visit (up to Week 184).3

ISRs were reported in 63%, 46%, and 55% of participants in CAPELLA and 42%, 52%, and 43% of participants in CALIBRATE after the first, second, and third SUBQ LEN injections, respectively. The majority of these ISRs were Grade 1 or 2 in severity, and no Grade 4 ISRs were reported. Five participants discontinued SUBQ LEN due to ISRs.4

Product Labeling1

Warnings and Precautions

Immune reconstitution syndrome

Immune reconstitution syndrome has been reported in patients treated with combination ARV therapy. During the initial phase of combination ARV treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Long-acting properties and potential associated risks with LEN

Residual concentrations of LEN may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer after the last SUBQ dose). It is important to counsel patients that maintenance dosing by injection is required every 6 months, because missed doses or non-adherence to injections could lead to loss of virologic response and development of resistance.

LEN, a moderate CYP3A inhibitor, may increase the exposure to, and therefore potential risk of adverse reactions from, drugs primarily metabolized by CYP3A initiated within 9 months after the last SUBQ dose of LEN.

If LEN is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive ARV regimen where possible no later than 28 weeks after the final injection of LEN. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible.

ISRs

Administration of LEN may result in local ISRs. If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow-up.

Manifestations of ISRs may include swelling, pain, erythema, nodule, induration, pruritus, extravasation, or mass. Nodules and indurations at the injection site may take longer to resolve than other ISRs. In clinical studies, after a median follow-up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of LEN had not fully resolved. Measurements and qualitative assessments of ISRs were not routinely reported. Where described, the majority of the injection site nodules and indurations were palpable but not visible, and had a maximum size of approximately 1 to 4 cm.

The mechanism driving the persistence of injection site nodules and indurations in some patients is not fully understood, but based on available data, they may be related to the presence of the SUBQ drug depot. In some patients who had a skin biopsy performed of an injection site nodule or induration, dermatopathology revealed foreign body inflammation or granulomatous response.

Improper administration (intradermal injection) has been associated with serious ISRs, including necrosis and ulcer. Ensure LEN is only administered subcutaneously in the abdomen.

Adverse Reactions

The most common adverse reactions (all grades) reported in ≥3% of participants in CAPELLA were nausea and ISRs. The proportion of participants in CAPELLA who discontinued treatment with LEN due to AEs, regardless of severity, was 1% (Grade 1 injection site nodule in 1 participant).

The majority (96%) of all adverse reactions associated with LEN were mild or moderate in severity.

Laboratory abnormalities

The frequency of laboratory abnormalities (Grades 3–4) occurring in ≥2% of participants in CAPELLA are presented in Table 1.

Table 1. Selected Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Participants Receiving LEN in CAPELLA (Week 52 Analysis)1

Abbreviation: ULN=upper limit of normal.

aFrequencies are based on treatment-emergent laboratory abnormalities in all participants (Cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of participants with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except fasting hyperglycemia, n=57).

bGrade 3 only (no Grade 4 values reported).

Postmarketing experience

In addition to adverse reactions reported from clinical trials, injection site necrosis was identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

For full safety information, please refer to the LEN US Prescribing Information Sections 5 and 6.

Clinical Studies on Safety of LEN Use in PWH

CAPELLA and CALIBRATE Studies

Study design and demographics

CAPELLA (NCT04150068) is an ongoing, randomized, placebo‑controlled, phase 2/3 clinical study of SUBQ LEN in combination with OBR in HTE PWH with multidrug resistance. Participants receiving SUBQ LEN started with an oral LEN initiation phase (Day 1, 600 mg; Day 2, 600 mg; Day 8, 300 mg), followed by SUBQ LEN 927 mg (2× 1.5 mL) administered in the maintenance phase on Day 15 and every 6 months thereafter with OBR.5,6

CALIBRATE (NCT04143594) was a randomized, open-label, active-controlled phase 2 study of LEN in combination with other ARVs vs BIC/FTC/TAF in TN PWH. Participants were randomized to one of four treatment groups: SUBQ LEN + FTC/TAFTAF (Group 1), SUBQ LEN + FTC/TAFBIC (Group 2), oral LEN + FTC/TAF (Group 3), or BIC/FTC/TAF alone (Group 4). Participants receiving SUBQ LEN started with an oral LEN initiation phase (Day 1, 600 mg; Day 2, 600 mg; Day 8, 300 mg), followed by SUBQ LEN 927 mg (2 ×1.5 mL) on Day 15 and every 26 weeks thereafter. The dosing schedule in the oral LEN group consisted of the following: Day 1, 600 mg; Day 2, 600 mg; Day 3 and thereafter, 50 mg daily.3,7

Table 2. CAPELLA and CALIBRATE: Baseline Demographics and Characteristics8,9

Abbreviations: CD4=clusters of differentiation-4; NR=not reported.

aPercentages may not equal 100 due to rounding.

bRace was reported by participants in CAPELLA. Collection of race or ethnicity data was prohibited by local regulators for 1 participant in the placebo group and was excluded from the denominator of the % calculation.

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

Safety: CAPELLA study

Abnormal laboratory results in CAPELLA through Week 104 are summarized in Table 3.6,9

Table 3. CAPELLA: Grade 3 or 4 Laboratory Abnormalities Through Week 1046,9

aLow CrCl or high creatinine were transient in duration.

bHyperglycemia and glycosuria were transient or related to pre‑existing diabetes.

Safety results through Week 156 are summarized in Table 4. No Grade ≥4 or serious TRAEs occurred. Median (IQR) duration of follow-up was 165 (IQR 146–‍178) weeks.2

Table 4. CAPELLA: Safety Results Through Week 1562

Abbreviation: TEAE=treatment-emergent adverse event.

aISRs and COVID-19 excluded.

bISR, n=4; immune reconstitution inflammatory syndrome, n=1; abdominal abscess, n=1; rash, n=1.

cMalignant neoplasm, n=1; acute respiratory failure, n=1; unknown cause, n=1.

Safety: CALIBRATE study

The safety analysis included data collected up to each participant’s last study visit (up to Week 184). Most laboratory abnormalities observed in participants were Grade 1 or 2 in severity. Grade 3 or 4 laboratory abnormalities observed through the last study visit are summarized in Table 5.3

Table 5. CALIBRATE: Grade 3 or 4 Laboratory Abnormalities Through Last Study Visit10

Through the last study visit, no treatment-related SAEs were reported. Rates of AEs, excluding ISRs, are shown in Table 6. No participants discontinued treatment with LEN due to AEs other than ISRs, except for one who discontinued due to a viral load increase. One participant in the SUBQ LEN + FTC/TAF→TAF group died due to non–small-cell lung cancer, and 1 participant in the oral LEN + FTC/TAF group died of unknown causes; both deaths were considered non–‍drug-related SAEs.3  

Table 6. CALIBRATE: Safety Results Through Last Study Visit (Excluding ISRs)3

Abbreviation: URTI=upper respiratory tract infection.

Incidence and severity of most common SUBQ LEN-related ISRs4

An analysis of ISRs was conducted in 175 participants who received ≥1 dose of SUBQ LEN in CAPELLA (N=72) and CALIBRATE (n=103). Participants in CAPELLA received a median (IQR) of 10 (8–10) injections with a median (IQR) duration of exposure of 125 (111–‍140) weeks, and participants in CALIBRATE had a median (IQR) of 6 (6–‍8) injections with a median (IQR) duration of exposure of 88 (83–107) weeks. In both studies, SUBQ LEN 927 mg (2 ×1.5 mL) was administered into the abdomen every 6 months.

ISRs were reported in 63%, 46%, and 55% of participants in CAPELLA and 42%, 52%, and 43% of participants in CALIBRATE after the first, second, and third SUBQ LEN injections, respectively. Figure 1 shows the frequency and severity of the most common ISRs related to SUBQ LEN in CAPELLA and CALIBRATE. The majority of ISRs were Grade 1 or 2 in severity, and no Grade 4 ISRs were reported. Five participants discontinued SUBQ LEN due to ISRs.

Figure 1. CAPELLA and CALIBRATE: ISRs After the First Three Injections4a

aPercentages are based on participants who received an injection at the respective visit; percentages may not total 100% because of rounding.

The durations of the most common ISRs in each study are presented in Table 7.

Table 7. CAPELLA and CALIBRATE: Durations of ISRs Related to SUBQ LEN4

One participant in CAPELLA and 4 participants in CALIBRATE discontinued SUBQ LEN due to ISRs (Grade 1 induration, n=3; Grade 1 nodule, n=1; Grade 1 erythema and swelling, n=1), and only 1 discontinuation occurred after the first year of follow-up.

SUBQ LEN-related ISR data: Week 156 CAPELLA results2

Most ISRs (97.2%) reported through Week 156 were Grade 1 or 2, and the frequency reduced over time (Figure 2). 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 2. CAPELLA: ISRs Related to SUBQ LEN Through Week 1562

References

1. Enclosed, Gilead Sciences Inc. SUNLENCA® (lenacapavir) tablets, for oral use. SUNLENCA® (lenacapavir) injection, for subcutaneous use. U.S. Prescribing Information. Foster City, CA.
2. 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.
3. Hagins D, Berhe M, Crofoot GE, et al. Final efficacy and safety of twice-yearly subcutaneous lenacapavir in treatment-naive people with HIV: randomized study. AIDS. 2025.
4. Castagna A, Arevalo JLB, Jean-Michel M, et al. Follow-Up of Injection Site Reactions in Clinical Studies of People Using Lenacapavir Every 6 Months for HIV Treatment.[Poster: eP.A.104]. Paper presented at: The 19th European AIDS Conference; October,18–21, 2023; Warsaw, Poland.
5. 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.
6. 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.
7. Gupta SK, Berhe M, Crofoot G, et al. Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial. Lancet HIV. 2023;10(1):e15-e23.
8. Hagins D, Koenig E, Safran R, et al. Long-Acting Lenacapavir in a Combination Regimen for Treatment Naïve PWH: Week 80 [Poster 522]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 19-22 February, 2023; Seattle, WA.
9. 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.
10. Hagins D, Berhe M, Crofoot GE, et al. Final efficacy and safety of twice-yearly subcutaneous lenacapavir in treatment-naive people with HIV: randomized study [Supplementary Materials]. AIDS. 2025.

AE=adverse event
ARV=antiretroviral
BIC=bictegravir
c/mL=copies per mL
FTC=emtricitabine

HTE=heavily treatment‑experienced
ISR=injection site reaction
LEN=lenacapavir
OBR=optimized background regimen
PWH=people with HIV
SAE=serious adverse event
SUBQ=subcutaneous
TAF=tenofovir alafenamide
TN=treatment naïve
TRAE=treatment-related adverse event
 

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.

Follow-Up

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