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 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.

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, 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

SUNLENCA can be initiated using one of two recommended dosage regimens, see Table 1 and Table 2 below. 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       Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 1

a       From the date of the last injection.

Table 2       Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 2

a         From the date of the last injection.

Missed dose

During the maintenance period, if more than 28 weeks have elapsed since the last injection and if clinically appropriate to continue SUNLENCA treatment, restart the initiation dosage regimen from Day 1, using either Option 1 or Option 2.

Special populations

Elderly

No dose adjustment of SUNLENCA is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustment of SUNLENCA is required in patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥ 15 mL/min). SUNLENCA has not been studied in patients 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 patients.

Hepatic impairment

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

Paediatric population

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

Method of administration

For subcutaneous use.

SUNLENCA injections should be administered into the abdomen (two injections, each at a separate site) by a healthcare professional (see section 6.6). For instructions on preparation and administration, see ‘Instructions for Use’ in the package leaflet. ‘Instructions for Use’ are also available as a card in the injection kit.

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.

Use of other medicinal products after discontinuation of lenacapavir

If SUNLENCA is discontinued, residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods. These concentrations may affect the exposures of other medicinal products (i.e. sensitive CYP3A substrates) that are initiated within 9 months after the last subcutaneous dose of SUNLENCA (see section 4.5). These concentrations are not expected to affect the exposures of other antiretroviral agents that are initiated after discontinuation of SUNLENCA.

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).

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).

Effect of other medicinal products on the pharmacokinetics of lenacapavir

Lenacapavir is a substrate of CYP3A, P‑gp and UGT1A1. Strong 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, therefore co‑administration is contraindicated (see section 4.3). Moderate inducers of CYP3A and P‑gp, such as efavirenz, may also significantly decrease plasma concentrations of lenacapavir, therefore co‑administration is not recommended (see section 4.4).

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).

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

Table 3: 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 UGT1A1 and P-gp.

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

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

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

i        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.

j        Evaluated as a P-gp substrate.

k       Tenofovir alafenamide is converted to tenofovir in vivo.

l        Evaluated as an OATP substrate.

m     Evaluated as an BCRP substrate.

n       Evaluated as a CYP3A substrate.

o       Major active metabolite of midazolam.

p       Evaluated as a strong inhibitor of CYP3A.

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

Pregnancy

There are no or limited amount of data from the use of lenacapavir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of SUNLENCA during pregnancy unless the clinical condition of the women requires treatment with SUNLENCA.

Breast-feeding

It is unknown whether lenacapavir is excreted in human milk, affects human milk production, or has effects on the breastfed infant. After administration to pregnant rats, lenacapavir was detected in the plasma of nursing rat pups, without effects on these nursing pups.

Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving SUNLENCA.

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.

Summary of the safety profile

The most common adverse reactions (all Grades) reported in at least 3% of subjects 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 subjects 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 subjects 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 4. 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 4: 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 subjects (cohorts 1 and 2) in CAPELLA.

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

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 subjects, 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.

To reports any side effect(s):

Saudi Arabia:

No data are available on overdose of SUNLENCA in patients. If overdose occurs, monitor the patient 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 patient. 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

In CAPELLA, 31% (22/72) of heavily treatment-experienced subjects 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 subjects with confirmed virologic failure who had post-baseline capsid genotypic resistance data (n=22). The M66I CA substitution was observed in 27% (6/22) of subjects, 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 subjects 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 subjects 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 subjects with virologic failure had emergent resistance substitutions to components of the optimized background regimen (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/cobistat, and rilpivirine in OBR; and emergent NRTI substitution K65K/R with tenofovir disoproxil fumarate plus darunavir/cobistat, dolutegravir, and emtricitabine in OBR.

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.

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 subjects with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of subjects 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-fold higher than the therapeutic exposures of SUNLENCA), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent.

Clinical data

The efficacy and safety of SUNLENCA in HIV-1 infected, heavily treatment-experienced subjects with multidrug resistance 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 subjects with multiclass resistant HIV-1. Subjects 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. Subjects 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. Subjects 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, subjects 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, subjects who had received SUNLENCA continued on SUNLENCA along with an optimized background regimen (OBR); subjects who had received placebo during this period initiated SUNLENCA along with an OBR.

Subjects 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 subjects 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 subjects 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 subjects had CD4⁺ cell counts below 200 cells/mm³. The mean number of years since subjects 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 subjects 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 subjects 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 subjects were who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial.

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

Subjects 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 subjects 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 subjects 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 subjects had CD4⁺ cell counts below 200 cells/mm³. The mean number of years since subjects 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 subjects 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 subjects 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 subjects who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial.

The primary efficacy endpoint was the proportion of subjects 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 Table 5.

Table 5      Proportion of Subjects 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 6 and Table 7.

Table 6       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 subjects who had ≥ 50 copies/mL in the Week 26 or 52 window; subjects who discontinued early due to lack or loss of efficacy; subjects 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 subjects 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 subjects 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 7       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 Week 26 and 52, 81% (29/36) and 72% (26/36) of patients 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.

Absorption

Subcutaneous Administration

Lenacapavir is completely absorbed following subcutaneous administration. Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex 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 6% to 10%). 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 are provided in Table 8.

Table 8       Lenacapavir Exposures Following Oral and Subcutaneous Administration of SUNLENCA in Heavily Treatment Experienced Subjects with HIV

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

a.      Predicted exposures.

b.      Post hoc exposures from CAPELLA (N=62).

The estimated exposures of lenacapavir were 43% to 100% higher in subjects with HIV-1 infection compared to subjects without HIV-1 infection.

Distribution

The apparent volume of distribution was 19240 litres after oral administration, and ranged from 9500 to 11700 litres after subcutaneous administration.

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

Biotransformation

Following a single intravenous dose of radiolabeled-lenacapavir to healthy subjects, 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. Mean apparent clearance was 55 L/h following oral administration and 4.2 L/h following subcutaneous administration.

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 (18 to 78 years), sex, ethnicity, race (white, black, asian or other), body weight (41.4 to 164 kg), 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.

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 2-year rat carcinogenicity study is ongoing.
 

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 times the exposure to humans at the recommended human dose of SUNLENCA.

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 packaged in a dosing kit containing:

·                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, 12.7 mm).

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.

The injection kit components are for single use only. Use of a vial access device is required. 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).