Treatment of HIV-1

SUNLENCA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations.

HIV-1 Pre-Exposure Prophylaxis (PrEP)

SUNLENCA is indicated for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition.

Individuals must have a negative HIV-1 test prior to initiating SUNLENCA for HIV-1 PrEP.

Treatment of HIV-1

Therapy should be prescribed by a physician experienced in the management of HIV infection.

Each injection should be administered by a healthcare professional.

Prior to starting lenacapavir for HIV-1 treatment, the healthcare professional should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance associated with missed doses. In addition, the healthcare professional should counsel patients about the importance of adherence to an optimised background regimen (OBR) to further reduce the risk of viral rebound and potential development of resistance.

If SUNLENCA is discontinued, it is essential to adopt an alternative, fully suppressive antiretroviral regimen where possible, no later than 28 weeks after the final injection of SUNLENCA (see section 4.4).

Posology for Treatment of HIV-1

SUNLENCA for HIV-1 treatment can be initiated using one of the two recommended dosage regimens in Table 1 and Table 2 below. Continuation dosing is administered by subcutaneous injection every 6 months regardless of the initiation regimen. Healthcare professionals should determine the appropriate initiation regimen for the patient (see section 5.2). SUNLENCA oral tablets may be taken with or without food (see SUNLENCA tablet SmPC).

Table 1:      Treatment of HIV-1: Recommended Treatment Regimen for SUNLENCA Initiation and Continuation, Option 1

a       From the date of the last injection.

Table 2:      Treatment of HIV-1: Recommended Treatment Regimen for SUNLENCA Initiation and Continuation, Option 2

a         From the date of the last injection.

Anticipated Delayed Injections for Treatment of HIV-1

During continuation dosing, if the scheduled 6-month injection is anticipated to be delayed by more than 2 weeks, SUNLENCA tablets may be taken on an interim basis (for up to 6 months if needed) until injections resume. Refer to Table 3 below for the dosing schedule for delayed injections.

Table 3:      Dosing Schedule for Treatment of HIV-1 for Anticipated Delayed Injections: Weekly Oral Dosage

a     Use on an interim basis (for up to 6 months).

Missed Injections for Treatment of HIV-1

Patients being treated for HIV-1 who miss a scheduled injection visit should be clinically reassessed, including consideration of lenacapavir resistance testing, to ensure resumption of therapy remains appropriate. During continuation dosing, if more than 28 weeks have elapsed since the last injection and SUNLENCA tablets have not been taken, see Table 4 below for the dosing schedule after missed injections. Adherence to the injection dosing schedule is strongly recommended (see section 4.4 and section 5.1).

Table 4:           Treatment of HIV-1: Dosing Schedule after Missed Injections

HIV-1 PrEP

SUNLENCA should be prescribed by a healthcare professional experienced in the management of HIV prevention.

All individuals must be screened for HIV-1 infection prior to initiating SUNLENCA for HIV-1 PrEP, prior to each subsequent injection of SUNLENCA, and additionally as clinically appropriate, using a test approved by the local health authority for the diagnosis of acute or primary HIV-1 infection, in accordance with local guidelines. Individuals must have a negative HIV-1 test prior to initiating SUNLENCA (see sections 4.3, 4.4 and 5.1).

Prior to starting SUNLENCA for HIV-1 PrEP, healthcare professionals should select individuals who agree to the required testing and every 6-month injection dosing schedule, and counsel individuals about the importance of adherence to scheduled SUNLENCA dosing visits to help reduce the risk of acquiring HIV-1 infection and development of resistance (see sections 4.4 and 5.1).

Posology for HIV-1 PrEP

The SUNLENCA dosing schedule for HIV-1 PrEP in adults and adolescents weighing at least 35 kg consists of a required initiation dosing (subcutaneous injections and oral tablets) followed by once every 6-months continuation dosing (subcutaneous injections) (Table 5). SUNLENCA oral tablets may be taken with or without food (see SUNLENCA tablet SmPC).

Table 5:      HIV-1 PrEP: Dosing Schedule for SUNLENCA Initiation and Continuation in Adults and Adolescents Weighing at Least 35 kg
 

a     The complete initiation dosing schedule, consisting of subcutaneous injections and oral tablets, is required; the efficacy of SUNLENCA has only been established with this dosing schedule.

b    From the date of the last injection.

Anticipated Delayed Injections for HIV-1 PrEP

During continuation dosing, if the scheduled 6-month injection is anticipated to be delayed by more than 2 weeks, SUNLENCA tablets may be taken on an interim basis (for up to 6 months if needed) until injections resume. Refer to Table 6 below for the dosing schedule for delayed injections.

Table 6:      Dosing Schedule for HIV-1 PrEP for Anticipated Delayed Injections:                 Weekly Oral Dosage

a     Use on an interim basis (for up to 6 months).

Missed Injections for HIV-1 PrEP

Individuals receiving SUNLENCA for HIV-1 PrEP who miss a scheduled injection visit should be clinically reassessed to ensure resumption of SUNLENCA remains appropriate and that the individual remains HIV-1 negative. During continuation dosing, if more than 28 weeks have elapsed since the last injection and SUNLENCA tablets have not been taken, see Table 7 below for the dosing schedule after missed injections. Adherence to the injection dosing schedule is strongly recommended (see sections 4.2, 4.4 and 5.1).

Table 7:           HIV-1 PrEP: Dosing Schedule after Missed Injections

Treatment of HIV-1 (Regimen Option 1) and HIV-1 PrEP

Dosage Modifications for Co-administration with Strong or Moderate CYP3A Inducers in Individuals Receiving SUNLENCA for HIV-1 Treatment Using Regimen Option 1 or Receiving SUNLENCA for HIV-1 PrEP
 

Supplemental doses of SUNLENCA are recommended for individuals receiving SUNLENCA for HIV-1 treatment using regimen Option 1 (see Table 1) or receiving SUNLENCA for HIV-1 PrEP (see Table 5) and initiating therapy with either strong CYP3A inducers (see Table 8) or moderate CYP3A inducers (see Table 9) (see section 4.5).

Strong CYP3A inducers may be initiated starting at least 2 days after SUNLENCA is first initiated, while moderate CYP3A inducers may be started any time after SUNLENCA is first initiated.

Table 8:      Dosing Recommendations for Individuals Receiving SUNLENCA for HIV-1 Treatment Using Regimen Option 1 or HIV-1 PrEP and Initiating Therapy with Strong CYP3A Inducers^a

a     Dosing recommendations are not available for the initiation of SUNLENCA in individuals already receiving strong CYP3A inducers, nor in individuals receiving the weekly oral dosage of SUNLENCA (see Table 3 and Table 6). This table does not apply to individuals receiving SUNLENCA for HIV-1 treatment using regimen Option 2 (see sections 4.3, 4.4 and 4.5).

b    26 weeks +/-2 weeks.

Table 9:      Dosing Recommendations for Individuals Receiving SUNLENCA for HIV-1 Treatment Using Regimen Option 1 or HIV-1 PrEP and Initiating Therapy with Moderate CYP3A Inducers^a

a     Dosing recommendations are not available for the initiation of SUNLENCA in individuals already receiving moderate CYP3A inducers, nor in individuals receiving the weekly oral dosage of SUNLENCA (see Table 3 and Table 6). This table does not apply to individuals receiving SUNLENCA for HIV-1 treatment using regimen Option 2 (see sections 4.4 and 4.5).

b    26 weeks +/-2 weeks.

Special populations (Treatment of HIV-1 and HIV-1 PrEP)

Elderly

No dose adjustment of SUNLENCA is required in elderly individuals (see section 5.2). There are limited data available on the use of lenacapavir in individuals aged 65 years and above (see section 5.2).

Renal impairment

No dose adjustment of SUNLENCA is required in individuals with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥ 15 mL/min). SUNLENCA has not been studied in individuals with end stage renal disease (CrCl < 15 mL/min or on renal replacement therapy) (see section 5.2), therefore SUNLENCA should be used with caution in these individuals.

Hepatic impairment

No dose adjustment of SUNLENCA is required in individuals with mild or moderate hepatic impairment (Child-Pugh Class A or B). SUNLENCA has not been studied in individuals with severe hepatic impairment (Child-Pugh Class C) (see section 5.2), therefore SUNLENCA should be used with caution in these individuals.

Paediatric population

The safety and efficacy of SUNLENCA for the treatment of HIV-1 in children under the age of 18 years old has not been established. No data are available.

The safety and efficacy of SUNLENCA for HIV-1 PrEP in children and adolescents weighing less than 35 kg have not been established. No data are available.

Method of administration (Treatment of HIV-1 and HIV-1 PrEP)

For subcutaneous use only.

SUNLENCA injections must only be administered subcutaneously into the abdomen (two injections, each at a separate site) by a healthcare professional (see section 6.6). The thigh can be used as an alternative injection site if preferred. SUNLENCA injections must NOT be administered intradermally (see section 4.4).

There are two available injection kits, which differ only in how SUNLENCA injection is prepared (components and associated method for withdrawal of the solution from the vials). For instructions on preparation and administration, see ‘Instructions for Use’ for the relevant injection kit in the package leaflet. ‘Instructions for Use’ are also available as a card in the injection kits.

Treatment of HIV-1

Risk of resistance following treatment discontinuation

If SUNLENCA is discontinued, to minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen where possible, no later than 28 weeks after the final injection of SUNLENCA.

If virologic failure is suspected, an alternative regimen should be adopted where possible.

Immune Reconstitution Inflammatory Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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

Opportunistic infections

Patients should be advised that SUNLENCA or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Co‑administration of other medicinal products

Co‑administration with medicinal products that are moderate inducers of CYP3A and P‑gp (e.g. efavirenz) is not recommended (see section 4.5) when using SUNLENCA treatment regimen Option 2 (see section 4.2, Table 2).

Co‑administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways), such as atazanavir/cobicistat is not recommended (see section 4.5).

HIV-1 PrEP

Comprehensive Management to Reduce the Risk of HIV-1 Infection and Other Sexually Acquired Infections when SUNLENCA is Used for HIV-1 PrEP

SUNLENCA should be used to reduce the risk of HIV-1 acquisition as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). SUNLENCA is not always effective in preventing HIV-1 acquisition (see section 5.1). The time from initiation of SUNLENCA for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Individuals should be counselled on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Individuals should be informed about and their efforts supported in reducing sexual behaviors associated with HIV-1 acquisition risk.

SUNLENCA should be used to reduce the risk of HIV-1 acquisition only in individuals confirmed to be HIV-1 negative (see section 4.3). Current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash) should be evaluated. HIV-1 negative status should be confirmed prior to initiating SUNLENCA, prior to each subsequent injection of SUNLENCA, and additionally as clinically appropriate (e.g., upon diagnosis of other sexually transmitted infections or if clinical symptoms consistent with acute HIV-1 infection are present) using a test approved by the local health authority for the diagnosis of acute or primary HIV-1 infection, in accordance with local guidelines (see section 4.2).

Individuals should be counselled and supported on adhering to the SUNLENCA administration schedule, on the use of other measures to reduce the risk of STIs, and on the importance of routine testing for HIV-1 and other STIs. Some individuals, such as adolescents, may benefit from additional counseling and appointment reminders to support adherence to the dosing and testing schedule.

Potential Risk of Resistance with SUNLENCA when Used for HIV-1 PrEP

There is a potential risk of developing resistance to SUNLENCA if an individual acquires HIV-1 either before or when receiving SUNLENCA, or following discontinuation of SUNLENCA. HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only SUNLENCA because SUNLENCA alone does not constitute a complete regimen for HIV-1 treatment (see section 5.1).

To minimize this risk, it is essential to test before each injection and additionally as clinically appropriate (e.g., upon diagnosis of other sexually transmitted infections or if clinical symptoms consistent with acute HIV-1 infection are present) to confirm HIV-1 negative status using a test approved by the local health authority for the diagnosis of acute or primary HIV-1 infection, in accordance with local guidelines. Individuals who are confirmed to have HIV-1 must immediately begin a complete HIV-1 treatment regimen to reduce the risk of developing resistance.

Co administration of other medicinal products

Co administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways) is not recommended (see section 4.5). 

Treatment of HIV-1 and HIV-1 PrEP

Long-Acting Properties and Potential Associated Risks with SUNLENCA

Healthcare professionals should take the long-acting properties of SUNLENCA into consideration when SUNLENCA is prescribed. Residual concentrations of lenacapavir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer after the last subcutaneous dose).

When SUNLENCA is used for the treatment of HIV-1, it is important to counsel patients that continuation dosing by injection is required every 6 months because non-adherence to these every-6-monthly injections or missed doses could lead to to loss of virologic response and development of resistance (see section 4.2). If SUNLENCA for HIV-1 treatment is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible (see section 4.2).

When SUNLENCA is used for HIV-1 PrEP, it is important to select individuals who agree to the required injection dosing schedule because non-adherence to every-6-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance. Alternative forms of PrEP should be considered following discontinuation of SUNLENCA for HIV-1 PrEP for those individuals with HIV-1 negative status who are at continuing risk of HIV-1 acquisition and initiated within 28 weeks of the last SUNLENCA injection.

Lenacapavir, 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 subcutaneous dose of SUNLENCA (see sections 4.5 and 5.2).

Injection Site Reactions with Improper Administration

Administration of SUNLENCA may result in local injection site reactions (ISRs). If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow-up.

See section 4.8 for detailed information on the manifestation of ISRs.

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 subcutaneous 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 injection site reactions, including necrosis and ulcer (see section 4.8). SUNLENCA injection must only be administered subcutaneously (see section 4.2).

Effect of other medicinal products on the pharmacokinetics of lenacapavir

Lenacapavir is a substrate of CYP3A, P‑gp and UGT1A1.

Strong or Moderate CYP3A Inducers

Strong or moderate inducers of CYP3A, P‑gp, and UGT1A1, such as rifampicin, may significantly decrease plasma concentrations of lenacapavir resulting in loss of therapeutic effect and development of resistance (when used for HIV-1 treatment) or reduced effectiveness of SUNLENCA (when used for HIV-1 PrEP).

Treatment of HIV-1 with SUNLENCA Option 2 Regimen:

Concomitant administration of SUNLENCA with strong CYP3A inducers is contraindicated when using the Option 2 regimen for treatment of HIV-1 (see sections 4.2, Table 2 and 4.3). Concomitant administration of SUNLENCA with moderate CYP3A inducers is not recommended when using the Option 2 regimen for treatment of HIV-1 (see section 4.2, Table 2).

Treatment of HIV-1 with SUNLENCA Option 1 Regimen or Use of SUNLENCA for HIV-1 PrEP:

Dosage modifications (supplemental doses) of SUNLENCA (see section 4.2) are recommended when initiating strong or moderate CYP3A inducers when SUNLENCA is used for treatment of HIV-1 with the Option 1 regimen (see section 4.2, Table 1) or SUNLENCA is used for HIV-1 PrEP (see section 4.2, Table 5).

Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors

Strong inhibitors of CYP3A, P‑gp and UGT1A1 together (i.e., all 3 pathways), such as atazanavir/cobicistat, may significantly increase plasma concentrations of lenacapavir, therefore co‑administration is not recommended (see section 4.4).

Medicinal Products without Clinically Significant Interactions with SUNLENCA

Strong CYP3A4 inhibitors alone (e.g. voriconazole) or strong inhibitors of CYP3A4 and P‑gp together (e.g. cobicistat) do not result in a clinically meaningful increase in lenacapavir exposures.

Effect of lenacapavir on the pharmacokinetics of other medicinal products

Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if SUNLENCA is co‑administered with a sensitive CYP3A and/or P-gp substrate with a narrow therapeutic index. Lenacapavir is not a clinically meaningful inhibitor of BCRP and does not inhibit OATP.

Table 10 provides a listing of clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with SUNLENCA or are drug interactions that may occur with SUNLENCA (see sections 4.3 and 5.2).

Table 10:         Interactions between SUNLENCA and other medicinal products

a       Fasted.

b       This study was conducted using lenacapavir 300 mg single dose administered orally.

c       Evaluated as a strong inducer of CYP3A, and an inducer of P-gp and UGT.

d       Fed.

e       Evaluated as a strong inhibitor of CYP3A, and an inhibitor of UGT1A1 and P-gp.

f        These antiretroviral medicinal products are probes for the referenced enzymes/transporters and are not to be co-administered with lenacapavir for PrEP.

g       Evaluated as a moderate inducer of CYP3A and an inducer of P-gp.

h       Evaluated as a strong inhibitor of CYP3A and an inhibitor of P-gp.

i        Evaluated as a strong inhibitor of CYP3A, and an inhibitor and inducer of P-gp.

j        This study was conducted using lenacapavir 600 mg single dose following a loading regimen of 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each co‑administered medicinal product.

k       Evaluated as a P-gp substrate.

l        Tenofovir alafenamide is converted to tenofovir in vivo.

m     Evaluated as an OATP substrate.

n       Evaluated as an BCRP and OATP substrate.

o       Evaluated as a CYP3A substrate.

p       Major active metabolite of midazolam.

q       Evaluated as a strong inhibitor of CYP3A.

r        This study was conducted using voriconazole 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily.

Women of childbearing potential

Individuals of childbearing potential should be counselled about the long-acting properties of lenacapavir injection.

If an individual plans a pregnancy, the benefits and the risks of initiating or continuing SUNLENCA during pregnancy should be discussed.

Pregnancy

Available data from a randomized, controlled trial (PURPOSE 1) with SUNLENCA used for HIV-1 PrEP during pregnancy have not identified a drug-associated risk for miscarriage, or adverse maternal or foetal outcomes when compared to the active control.

The rate of major birth defects in SUNLENCA-exposed pregnancies did not exceed the background prevalence rates. The risk estimates are imprecise due to small numbers of exposed pregnancies.

There is an increased risk of HIV-1 transmission from the mother to the child during acute HIV-1 infection. In women at risk of acquiring HIV-1, consideration should be given to methods to prevent acquisition of HIV-1, including continuing or initiating SUNLENCA for HIV-1 PrEP, during pregnancy.
 

In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥7 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA.

Breast-feeding

Lenacapavir is present in human milk. Lenacapavir was detected at very low levels in infants who were breastfed by individuals who became pregnant while receiving SUNLENCA for HIV-1 PrEP.

No adverse effects of lenacapavir in breastfed infants have been observed.

It is not known if SUNLENCA affects milk production.

In women without HIV-1 infection, the developmental and health benefits of breastfeeding and the mother’s clinical need for SUNLENCA for HIV-1 PrEP should be considered along with any potential adverse effects on the breastfed child from SUNLENCA and the risk of HIV-1 acquisition due to nonadherence and subsequent mother to child transmission.

Fertility

There are no data on the effects of lenacapavir on human male or female fertility. Animal studies indicate no effects on lenacapavir on male or female fertility (see section 5.3).

SUNLENCA is expected to have no or negligible influence on the ability to drive and use machines.

Treatment of HIV-1

Summary of the safety profile

The most common adverse reactions (all Grades) reported in at least 3% of participants in CAPELLA were nausea and injection site reactions.

Tabulated list of adverse reactions

Assessment of adverse reactions is based on data from heavily treatment-experienced adult participants with HIV who received SUNLENCA in a Phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks) (see section 5.1), as well as supportive data in treatment-naïve adult participants with HIV who received SUNLENCA in a Phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks).

A tabulated list of adverse reactions is presented in Table 11. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 11:         Tabulated list of adverse reactions

a     Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all participants (cohorts 1 and 2) in CAPELLA.

b    Includes injection site swelling, pain, nodule, erythema, induration, pruritus, extravasation, discomfort, mass, haematoma, oedema, and ulcer from CAPELLA; and necrosis identified from post-marketing surveillance.

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

Description of selected adverse reactions

Immune Reconstitution Inflammatory Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Local Injection Site Reactions (ISRs)

The most frequent adverse reactions were ISRs. Of the 72 participants in CAPELLA, 65% had experienced an ISR attributed to study drug through at least the Week 52 visit. Most participants had mild (Grade 1, 44%) or moderate (Grade 2, 17%) ISRs. Four percent of participants experienced a severe (Grade 3) ISR (erythema, pain, swelling) that resolved within 15 days. The ISRs reported in more than 1% of participants were swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%) and mass (3%). ISRs reported in 1% of participants included discomfort, hematoma, edema, and ulcer. Post marketing cases of injection site necrosis has been reported.

Nodules and indurations at the injection site took longer to resolve than other ISRs. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days (range: 1 to 183). The median time to resolution of nodules and indurations associated with the first injections of SUNLENCA was 148 (range: 41 to 727) and 70 (range: 3 to 252) days, respectively. 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 SUNLENCA had not fully resolved. Qualitative descriptions of injection site nodules and indurations were not routinely reported, but, where reported, the majority of injection site nodules and indurations were palpable but not visible. Measurements of injection site nodules and indurations were not routinely performed or standardized, but where measurements were reported, the maximum size for the majority of injection site nodules and indurations was approximately 1 to 4 cm.

HIV-1 PrEP

Summary of the safety profile

The most common adverse reaction in PURPOSE 1 and PURPOSE 2 was injection site reactions (71% and 85% respectively).

Tabulated list of adverse reactions

The primary safety assessment of SUNLENCA for HIV-1 PrEP is based on data from two randomized, double-blind, active-controlled trials, PURPOSE 1 and PURPOSE 2, in which a total of 8616 adult and adolescent participants received SUNLENCA (N=4323), DESCOVY (emtricitabine [FTC]/tenofovir alafenamide [TAF]; N=2135) once daily, or TRUVADA (FTC/tenofovir disoproxil fumarate [TDF]; N=2158) once daily for HIV-1 PrEP. In PURPOSE 1, the median duration of exposure to SUNLENCA, DESCOVY, and TRUVADA was 43, 42, and 41 weeks, respectively. In PURPOSE 2, the median duration of exposure to both SUNLENCA and TRUVADA was 39 weeks.

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 12: Tabulated list of adverse reactions

a     Frequency based on all adverse events in PURPOSE 1 and PURPOSE 2 (see section 5.1) attributed to lenacapavir (or to the procedure) by the investigator.

b    Includes injection site nodule, pain, induration, erythema, swelling, pruritus, bruising, warmth, discolouration, oedema, ulcer, haematoma, haemorrhage, and discomfort.

Description of injection-associated adverse reactions

Local injection site reactions (ISRs)

PURPOSE 1

In PURPOSE 1, 71% of participants receiving lenacapavir experienced ISRs, compared to 38% of participants receiving placebo injections (and emtricitabine/tenofovir alafenamide [FTC/TAF] or emtricitabine/tenofovir disoproxil fumarate [FTC/TDF]). Most participants who received lenacapavir had mild (Grade 1, 50%) or moderate (Grade 2, 21%) severity ISRs. Grade 3 ISRs were reported in 4 (0.2%) participants, and included ulcer and nodule. Lenacapavir was discontinued due to ISRs in 4 (0.2%) participants.

Nodules: Injection site nodule was reported in 66% of participants who received lenacapavir and resolved more slowly than other ISRs. The median duration of nodules was 274 (180, 407) days. Of the injection site nodule events associated with Day 1 lenacapavir injections, 70% had resolved within a median time of 276 days.

Other ISRs: The other ISRs reported in more than 2% of participants who received lenacapavir were pain (34%), swelling (5%), induration (4%), and pruritus (3%). The median duration of ISRs, excluding nodules and indurations, was 9 (4 to 30) days.

PURPOSE 2

In PURPOSE 2, 85% of participants receiving lenacapavir experienced ISRs, compared to 70% of participants receiving placebo injections (and FTC/TDF). Most participants had mild (Grade 1, 66%) or moderate (Grade 2, 18%) severity ISRs. Grade 3 ISRs were reported in 14 (0.6%) participants, and included ulcer, pain, erythema, oedema, and dermatitis. Lenacapavir was discontinued due to ISRs in 26 (1.2%) participants.

Nodules: Injection site nodule was reported in 65% of participants and resolved more slowly than other ISRs. The median duration of nodules was 239 (163, 362) days. Of the injection site nodule events associated with Day 1 lenacapavir injections, 70% had resolved within a median time of 269 days.

Other ISRs: The other ISRs reported in more than 2% of participants who received lenacapavir were pain (58%), erythema (18%), induration (16%), swelling (7%), pruritus (4%), bruising (3%), and warmth (2%). The median duration of ISRs, excluding nodules and indurations, was 4 (2 to 8) days.

Paediatric population

The safety of lenacapavir was evaluated in 59 adolescents aged 16 to <18 years and weighing ≥35 kg in PURPOSE 1 and PURPOSE 2. The adverse reactions in adolescents were consistent with those in adults.

To reports any side effect(s):

Saudi Arabia:

No data are available on overdose of SUNLENCA. If overdose occurs, monitor the individual for signs or symptoms of adverse reactions (see section 4.8). Treatment of overdose with SUNLENCA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual. As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis.

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX31

Mechanism of action

Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

Antiviral Activity in Cell Culture

Lenacapavir has antiviral activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2). The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4⁺ T lymphocytes with EC₅₀ values ranging from 30 to 190 pM. Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G with EC₅₀ values ranging from 20 and 160 pM. The median EC₅₀ value for subtype B isolates (n=8) was 40 pM. Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.

In a study of lenacapavir in combination with representatives from the major classes of anti-retroviral agents (INSTIs, NNRTIs, NRTIs, and PIs), no antagonism of antiviral activity was observed.

Resistance

In cell culture

HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. Resistance selections with lenacapavir identified 7 substitutions in capsid: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination that conferred 4- to >3,226-fold reduced phenotypic susceptibility to lenacapavir relative to wild-type (WT) virus. The M66I substitution alone or in combination conferred >3,226-fold decreased susceptibility to lenacapavir in a single-cycle infectivity assay; substitutions Q67H and T107N, conferred 4- to 6.3-fold decreased susceptibility; K70N, N74D and Q67H/N74S conferred 22- to 32-fold decreased susceptibility; and L56I conferred 239-fold decreased susceptibility. 

In Clinical Trials
 

Treatment of HIV-1

In CAPELLA, 31% (22/72) of heavily treatment-experienced participants met the criteria for resistance analyses through Week 52 (HIV-1 RNA ≥ 50 copies/mL at confirmed virologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit]) and were analyzed for lenacapavir resistance-associated substitution emergence. Lenacapavir resistance-associated capsid substitutions were found in 41% (n=9) of participants with confirmed virologic failure who had post-baseline capsid genotypic resistance data (n=22). The M66I capsid substitution was observed in 27% (6/22) of participants, alone or in combination with other lenacapavir resistance-associated capsid substitutions including Q67Q/H, Q67Q/H/K/N, K70K/R, K70N/S, N74D, N74N/H, A105T, and T107A. The other 3 participants with virologic failure had emergent lenacapavir resistance-associated capsid substitutions Q67K+K70H, Q67H+K70R+T107S, and Q67Q/H. 

Phenotypic analyses of the confirmed virologic failure isolates with emergent lenacapavir resistance-associated substitutions showed 6- to >1428-fold decreases in lenacapavir susceptibility when compared to WT.

Among the 9 participants with virologic failure who developed lenacapavir resistance-associated substitutions in capsid, 4 received SUNLENCA in combination with a background regimen with no fully active antiretrovirals based on the baseline genotypic and/or phenotypic resistance. Therefore, given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to SUNLENCA in the treatment regimen.

Four participants with virologic failure had emergent resistance substitutions to components of the OBR: emergent NRTI substitution M184I/V and NNRTI substitution K103N/Y with emtricitabine and doravirine plus atazanavir, bictegravir, and tenofovir alafenamide in OBR; emergent NNRTI substitution V106M from a mixture at baseline (in addition to lenacapavir resistance-associated substitutions M66I + T107A) with doravirine plus emtricitabine and ibalizumab in OBR; emergent NRTI substitutions K65R and S68N from mixtures at baseline (in addition to lenacapavir resistance-associated substitution M66I) with tenofovir alafenamide, plus emtricitabine, dolutegravir, darunavir/cobicistat, and rilpivirine in OBR; and emergent NRTI substitution K65K/R with tenofovir disoproxil fumarate plus darunavir/cobicistat, dolutegravir, and emtricitabine in OBR.

Weekly Oral Continuation Dosing for Delayed Injections in Participants Receiving SUNLENCA for Treatment of HIV-1

Of the 57 participants with HIV-1 who received the weekly oral continuation dosing in CAPELLA, 9 participants (5 participants in Cohort 1 and 4 participants in Cohort 2) met the criteria for resistance analysis. Six of these 9 participants had emergent lenacapavir resistance substitutions in capsid (Q67H [n=4], K70R or N [n=2], N74D or K [n=2], T107N [n=1]) with 4.5- to 393-fold decreased lenacapavir susceptibility. In addition, 2 participants had emergent resistance substitutions to darunavir in their OBR.

Lenacapavir Resistance with Suboptimal Adherence to Other Antiretroviral Drugs in the Regimen in Participants Receiving SUNLENCA for Treatment of HIV-1

The development of lenacapavir-associated capsid resistance substitutions in 6 participants during the oral continuation dosing period in CAPELLA was likely due to suboptimal adherence to the optimized background oral regimens that included dolutegravir and/or darunavir. After developing lenacapavir resistance, 5 of the 6 participants achieved HIV-1 RNA resuppression (HIV-1 RNA < 50 copies/mL) while maintaining SUNLENCA treatment. With the emergence of lenacapavir resistance substitutions and decreased susceptibility to lenacapavir, it is unclear how much antiviral activity lenacapavir is contributing to the resuppression of HIV-1 RNA in these 5 participants.

Thus, adherence to other antiretroviral drugs in the regimen should be optimized while the patient is receiving SUNLENCA for HIV-1 Treatment. During SUNLENCA treatment, if suboptimal adherence to the oral antiretroviral regimen occurs with concurrent HIV-1 RNA viral load increases (i.e., virologic failure), lenacapavir resistance should be assessed, and if detected, consideration should be given to discontinuing SUNLENCA treatment (see section 4.2 and section 4.4).

HIV-1 PrEP

There were 2 incident infections (infections that occurred after starting SUNLENCA for HIV-1 PrEP) and 4 prevalent infections (acute infection at baseline identified after starting SUNLENCA for HIV-1 PrEP) among participants in the SUNLENCA arm of the PURPOSE 1 trial. Both incident infections occurred after the time of the primary analysis. One of the incident infections occurred in a participant after lenacapavir exposures fell below the target concentration following discontinuation of SUNLENCA, and virus from this participant had no lenacapavir resistance-associated capsid substitutions detected. The second participant with an incident infection had viral loads that were too low for genotyping. Viruses with lenacapavir resistance-associated capsid substitutions were detected in 3 of the 4 participants with prevalent infections, 2 with N74D and 1 with T107A.

There were 3 incident and 4 prevalent infections among participants in the SUNLENCA arm of the PURPOSE 2 trial. One of the incident infections occurred after the time of the primary analysis. Lenacapavir resistance-associated substitutions were detected in viruses from the 3 participants with incident infections, 2 with N74D, and 1 with Q67H/K70R. Genotypic data were available for 3 of the 4 participants with prevalent infections. Viruses with lenacapavir resistance-associated capsid substitutions were detected in 2 of these 3 participants, both with N74D.

Cross-Resistance

The antiviral activity in cell culture of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the four main classes of anti-retroviral agents (INSTI, NNRTI, NRTI, and PI; n=58), as well as to viruses resistant to the gp120-directed attachment inhibitor fostemsavir, the CD4⁺-directed post-attachment inhibitor ibalizumab, the CCR5 co-receptor antagonist maraviroc, and the gp41 fusion inhibitor enfuvirtide (n=42). These data indicated that lenacapavir remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms and substitutions at protease cleavage sites.

Treatment of HIV-1: Exposure-Response

In CAPELLA, oral loading doses (600 mg on Day 1 and Day 2, 300 mg on Day 8) followed by subcutaneous doses (927 mg every 6 months starting on Day 15) of SUNLENCA in heavily treatment-experienced participants with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of participants with HIV-1 RNA less than 50 copies/mL at Week 26) were similar across the range of observed lenacapavir exposures.

Cardiac Electrophysiology

At supratherapeutic exposures of lenacapavir (9 and 16-fold higher than the therapeutic exposures of SUNLENCA for HIV-1 treatment and HIV-1 PrEP, respectively), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent.

Clinical data

Treatment of HIV-1

The efficacy and safety of SUNLENCA in heavily treatment-experienced participants with multidrug resistant HIV-1 is based on 52-week data from CAPELLA, a randomized, placebo-controlled, double-blind, multicenter trial (NCT 04150068).

CAPELLA was conducted in 72 heavily treatment-experienced participants with multiclass resistant HIV-1. Participants were required to have a viral load ≥ 400 copies/mL, documented resistance to at least two antiretroviral medications from each of at least 3 of the 4 classes of antiretroviral medications (NRTI, NNRTI, PI and INSTI), and ≤ 2 fully active antiretroviral medications from the 4 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, drug access, contraindication, or other safety concerns.

The trial was composed of two cohorts. Participants were enrolled into the randomized cohort (cohort 1, N=36) if they had a < 0.5 log₁₀ HIV-1 RNA decline compared to the screening visit. Participants were enrolled into the non-randomized cohort (cohort 2, N=36) if they had a ≥ 0.5 log₁₀ HIV-1 RNA decline compared to the screening visit or after cohort 1 reached its planned sample size.

In the 14-day functional monotherapy period, participants in cohort 1 were randomized in a 2:1 ratio in a blinded fashion to receive either SUNLENCA or placebo, while continuing their failing regimen. This period was to establish the virologic activity of SUNLENCA. After the functional monotherapy period, participants who had received SUNLENCA continued on SUNLENCA along with an OBR; participants who had received placebo during this period initiated SUNLENCA along with an OBR.

Participants in cohort 1 had a mean age of 52 years (range: 24 to 71), 72% were male, 46% were White, 46% were Black, and 9% were Asian. 29% percent of participants identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.3 log₁₀ copies/mL (range: 2.3 to 5.4). 19% of participants had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4⁺ cell count was 161 cells/mm³ (range: 6 to 827). 75% of participants had CD4⁺ cell counts below 200 cells/mm³. The mean number of years since participants first started HIV treatment was 24 years (range: 7 to 33); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 1 to 7). The percentage of participants in the randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 97%, 94%, 78% and 75%, respectively. In cohort 1, 53% of participants had no fully active agents, 31% had 1 fully active agent, and 17% had 2 or more fully active agents within their initial failing regimen, including 6% of participants were who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial.

Participants in cohort 2 initiated SUNLENCA and an OBR on Day 1.

Participants in cohort 2 had a mean age of 48 years (range: 23 to 78), 78% were male, 36% were White, 31% were Black, 33% were Asian, and 14% of participants identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.1 log₁₀ copies/mL (range: 1.3 to 5.7). 19% of participants had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4⁺ cell count was 258 cells/mm³ (range: 3 to 1296). 53% of participants had CD4⁺ cell counts below 200 cells/mm³. The mean number of years since participants first started HIV treatment was 19 years (range: 3 to 35); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 2 to 7). The percentage of participants in the non-randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 100%, 100%, 83% and 64%, respectively. In cohort 2, 31% of participants had no fully active agents, 42% had 1 fully active agent, and 28% had 2 or more fully active agents within their initial failing regimen, including 6% of participants who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial.

The primary efficacy endpoint was the proportion of participants in cohort 1 achieving ≥ 0.5 log₁₀ copies/mL reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period. The results of the primary endpoint analysis are shown in Table13.

Table 13:   Proportion of Participants Achieving a ≥ 0.5 log₁₀ Decrease in Viral Load at the End of the Functional Monotherapy Period in the CAPELLA Trial (Cohort 1)

   a.     p < 0.0001
 

The results at Weeks 26 and 52 are provided in Table 14 and Table 15.

Table 14:    Virologic Outcomes (HIV-1 RNA < 50 copies/mL) at Weeks 26 ^a and
52 ^b with SUNLENCA plus OBR in the CAPELLA Trial (Cohort 1)

OBR = optimized background regimen

a.     Week 26 window was between Days 184 and 232 (inclusive).

b.     Week 52 window was between Days 324 and 414 (inclusive).

c.     Includes participants who had ≥ 50 copies/mL in the Week 26 or 52 window; participants who discontinued early due to lack or loss of efficacy; participants who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

d.     Includes participants who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

e.     Includes participants who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.

Table 15:    Virologic Outcomes (HIV-1 RNA < 50 copies/mL) by Baseline Covariates at Weeks 26 ^a and 52^b with SUNLENCA plus OBR in the CAPELLA trial (Cohort 1)

ARV = antiretroviral; DRV=darunavir; DTG=dolutegravir; INSTI = integrase strand-transfer inhibitor; OBR = optimized background regimen;
a.     Week 26 window was between Days 184 and 232 (inclusive).
b.     Week 52 window was between Days 324 and 414 (inclusive).

In cohort 1, at Weeks 26 and 52, the mean change from baseline in CD4⁺ cell count was 81 cells/mm³ (range: ‑101 to 522) and 82 cells/mm³ (range: -194 to 467), respectively.

In cohort 2, at Weeks 26 and 52, 81% (29/36) and 72% (26/36) of participants achieved HIV-1 RNA < 50 copies/mL, respectively, and the mean change from baseline in CD4⁺ cell count was 97 cells/mm³ (range: -103 to 459) and 113 cells/mm³ (range: -124 to 405), respectively.

Oral bridging

In CAPELLA across cohorts 1 and 2, 79% of participants (57/72) received SUNLENCA 300 mg once every 7 days as oral bridging. A total of 13, 29, and 15 participants started oral bridging following Weeks 26, 52, and 78 injections, respectively. The median (Q1, Q3) duration of oral bridging was 19 weeks (11, 22), and 12% (7/57) received oral bridging for at least 28 weeks.

In a post-hoc analysis, rates of virologic suppression and change from baseline in CD4⁺ cell counts in the subset of patients who received oral bridging were consistent before and during the oral bridging period.

HIV-1 PrEP

The efficacy and safety of SUNLENCA in reducing the risk of HIV-1 acquisition were evaluated in two randomized, double-blind, active-controlled, multinational trials (PURPOSE 1 and PURPOSE 2).

PURPOSE 1 was in cisgender adolescent girls and young women between 16 and 25 years of age in South Africa and Uganda who had unknown HIV-1 status at screening and who were at risk of acquiring HIV-1 based on sexual activity with male partners. Participants who tested negative for HIV-1 at screening and baseline were randomized to receive SUNLENCA (N=2134), once daily DESCOVY (N=2136), or once daily TRUVADA (N=1068) in a 2:2:1 ratio.

PURPOSE 2 was in cisgender men, transgender women, transgender men, and gender nonbinary individuals 16 years of age and older who had unknown HIV-1 status at screening and who were at risk of acquiring HIV-1 based on sexual activity with male partners. PURPOSE 2 enrolled participants in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States. Participants who tested negative for HIV-1 at screening and baseline were randomized to receive SUNLENCA (N=2179) or once daily TRUVADA (N=1086) in a 2:1 ratio.

PURPOSE 1

In PURPOSE 1, the median age of participants was 21 years (range, 16-26); and 99.9% were Black. Baseline characteristics in the randomized participants were similar to the screened population. Over 99% of SUNLENCA injections were administered into the abdomen and each dose was administered in two locations. A total of 32 pregnant participants received SUNLENCA injections into the thigh and each dose was administered bilaterally (i.e., one injection in the right thigh and one injection in the left thigh).

The efficacy endpoint was the rate of incident HIV-1 infections per 100 person-years in participants randomized to SUNLENCA compared with the rate of incident HIV-1 infections per 100 person-years in participants randomized to TRUVADA. SUNLENCA demonstrated superiority with a 100% reduction in the risk of incident HIV-1 infection over TRUVADA (Table 16).

Table 16:         Overall HIV-1 Infection Outcomes in PURPOSE 1^a

CI = confidence interval

a     The determination of efficacy was based on planned interim analyses (which became the final analyses) following sequential testing of HIV-1 incidence for SUNLENCA compared to background followed by SUNLENCA compared to TRUVADA, all at alpha level of 0.0026 when 50% of randomized participants completed at least 52 weeks of follow-up or prematurely discontinued from the study. SUNLENCA also demonstrated superiority in the risk of incident HIV-1 infection over background HIV‑1 incidence.

PURPOSE 2

In PURPOSE 2, the median age of participants was 29 years (range, 17-74); 67% were non White; 63% were Hispanic/Latine; and 22% identified as gender-diverse (transgender women, transgender men, and gender nonbinary people). Baseline characteristics in the randomized participants were similar to the screened population. SUNLENCA injections were administered into the abdomen and each dose was administered in two locations.

The efficacy endpoint was the rate of incident HIV-1 infections per 100 person-years in participants randomized to SUNLENCA compared with the rate of incident HIV-1 infections per 100 person-years in participants randomized to TRUVADA. SUNLENCA demonstrated superiority with an 89% reduction in the risk of incident HIV-1 infection over TRUVADA (Table 17).

Table 17:         Overall HIV-1 Infection Outcomes in PURPOSE 2^a

CI = confidence interval

a     The determination of efficacy was based on planned interim analyses (which became the final analyses) following sequential testing of HIV-1 incidence for SUNLENCA compared to background followed by SUNLENCA compared to TRUVADA, all at alpha level of 0.0026 when 50% of randomized participants completed at least 52 weeks of follow-up or prematurely discontinued from the study. SUNLENCA also demonstrated superiority in the risk of incident HIV-1 infection over background HIV‑1 incidence.

Absorption

Subcutaneous Administration

Absolute bioavailability of lenacapavir following subcutaneous administration was 91%. Subcutaneously administered lenacapavir forms a drug depot whereby lenacapavir is slowly released from the site of administration, with peak plasma concentrations occurring 77 to 84 days postdose.

Oral Administration

Lenacapavir is absorbed following oral administration with peak plasma concentrations occurring 4 hours after administration of SUNLENCA. Absolute bioavailability following oral administration of lenacapavir is low (approximately 4% to 7%). Lenacapavir is a substrate of P-gp.

Lenacapavir AUC, C_max and T_max were comparable following administration of a low fat (~400 kcal, 25% fat) or high fat (~1000 kcal, 50% fat) meal relative to fasted conditions. Oral lenacapavir can be administered without regard to food.

Pharmacokinetic Parameters

The population pharmacokinetic parameter estimates of SUNLENCA after oral and subcutaneous administration to adults for HIV-1 treatment and HIV-1 PrEP are provided in Table 18 and Table 19, respectively. Similar exposures are achieved when SUNLENCA is administered subcutaneously in the abdomen or thigh.

Table 18:    Lenacapavir Exposures Following Oral and Subcutaneous Administration of SUNLENCA in Heavily Treatment Experienced Participants with HIV

CV = coefficient of variation; NA = not applicable; SC = subcutaneous

a.      Predicted exposures utilizing population PK analysis.

Lenacapavir exposures after subcutaneous administration were similar between heavily treatment experienced participants with HIV-1 and participants without HIV-1 based on population pharmacokinetics analysis. Lenacapavir exposures (AUC_tau, C_max and C_trough) after oral administration were 28% to 43% higher in participants with HIV-1 who were heavily treatment experienced, compared to participants without HIV-1 based on population PK analysis. These differences were not considered clinically relevant.

Table 19:    Pharmacokinetic Parameters of Lenacapavir Following Oral and Subcutaneous Administration to Adult Participants Receiving SUNLENCA for HIV-1 PrEP

CV = coefficient of variation

Paediatrics

The population PK parameter estimates of SUNLENCA after oral and subcutaneous administration to adolescents (weighing at least 35 kg) for HIV-1 PrEP are provided in Table 20.

Table 20:       Pharmacokinetic Parameters of Lenacapavir Following Oral and Subcutaneous Administration to Adolescent Participants Receiving SUNLENCA for HIV-1 PrEP

CV = coefficient of variation
 

Distribution

The apparent volume of distribution was 1657 litres.

Lenacapavir is highly bound to plasma proteins (> 98.5%).

Biotransformation

Following a single intravenous dose of radiolabeled-lenacapavir to healthy participants, 76% of the total radioactivity was recovered from feces and < 1% from urine. Unchanged lenacapavir was the predominant moiety in plasma (69%) and feces (33%). Metabolism played a lesser role in lenacapavir elimination. Lenacapavir was metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A and UGT1A1. No single circulating metabolite accounted for > 10% of plasma drug-related exposure.

Elimination

The median half-life following oral and subcutaneous administration ranged from 10 to 12 days, and 8 to 12 weeks, respectively. Systemic clearance of lenacapavir was 3.4 L/h.

Linearity/Non-linearity

The single dose pharmacokinetics of lenacapavir after oral administration are non-linear and less than dose proportional over the dose range of 50 to 1800 mg.

The single dose pharmacokinetics of lenacapavir after subcutaneous injection (309 mg/mL) are dose proportional over the dose range of 309 to 927 mg.

Other special populations

There were no clinically significant differences in the pharmacokinetics of lenacapavir based on age, sex assigned at birth, gender identity, ethnicity, race, body weight, severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir.

Pregnancy

Changes in lenacapavir exposures during pregnancy and postpartum in participants who received SUNLENCA for HIV-1 PrEP were not considered clinically relevant compared to lenacapavir exposures observed in non-pregnant participants.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.

Carcinogenesis

Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study in males or females at doses of up to 300 mg/kg/dose once every 13 weeks.
 

A 104-week carcinogenicity study was conducted in male and female rats at lenacapavir doses of 0, 102, 309, or 927 mg/kg by subcutaneous injection once every 13-weeks. A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg). This dose in rats resulted in an exposure approximately 34 and 44-times the human exposure at the RHD for HIV-1 treatment and HIV-1 PrEP, respectively, based on AUC. These tumors are considered to be a secondary response to chronic tissue irritation and granulomatous inflammation, due to the depot effect of lenacapavir following subcutaneous injection. The clinical relevance of these findings is unknown.

Mutagenesis

Lenacapavir was not mutagenic in a battery of in vitro and in vivo genotoxicity assays, including microbial mutagenesis, chromosome aberration in human peripheral blood lymphocytes, and in in vivo rat micronucleus assays.

Impairment of Fertility

There were no effects on fertility, mating performance or early embryonic development when lenacapavir was administered to rats at systemic exposures (AUC) 5 and 8-times the exposure to humans at the recommended human dose of SUNLENCA for HIV-1 treatment and HIV-1 PrEP, respectively.

Polyethylene glycol 300

Water for injection

Not applicable.

Store below 30°C.

Store in the original outer carton in order to protect from light. Once the solution has been drawn into the syringes, the injections should be used immediately, from a microbiological point of view. Chemical and physical in-use stability has been demonstrated for 4 hours at 25 °C outside of the package.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

SUNLENCA injection is available as two different injection kits, each containing the following:

Vial access device injection kit:

·                2 clear glass vials, each containing 1.5 mL solution for injection. Vials are sealed with an elastomeric butyl rubber closure and aluminum overseal with flip off cap;

·                2 vial access devices, 2 disposable syringes, and 2 injection safety needles for subcutaneous injection (22-gauge, 13 mm).

Withdrawal needle injection kit:

·                2 clear glass vials, each containing 1.5 mL solution for injection. Vials are sealed with an elastomeric butyl rubber closure and aluminum overseal with flip off cap;

·                2 withdrawal needles (18-gauge, 40 mm), 2 disposable syringes, and 2 injection safety needles for subcutaneous injection (22-gauge, 13 mm).

Not all injection kits may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. SUNLENCA injection is a yellow to brown solution. Do not use SUNLENCA injection if the solution is discoloured or if it contains particulate matter. Once the solution is withdrawn from the vials, the subcutaneous injections should be administered as soon as possible.

There are two available injection kits, which differ only in how SUNLENCA injection is prepared (the components and associated method for withdrawal of the solution from the vials).

The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose.

Full instructions for use and handling of SUNLENCA injection are provided in the package leaflet (see Instructions for Use for the relevant injection kit).