Sunlenca 464 mg solution for injection

Sunlenca injection, in combination with other antiretroviral(s), is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen (see sections 4.2 and 5.1).

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, 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

Initiation

On treatment Day 1 and Day 2, the recommended dose of Sunlenca is 600 mg per day taken orally. On treatment Day 8, the recommended dose is 300 mg taken orally. Then, on treatment Day 15, the recommended dose is 927 mg administered by subcutaneous injection.

Oral tablets can be taken with or without food (see Sunlenca tablet SmPC).

Maintenance

The recommended dose is 927 mg of Sunlenca administered by subcutaneous injection once every 6 months (26 weeks) from the date of the last injection (+/- 2 weeks).

Table 1: Recommended treatment regimen for Sunlenca: initiation and maintenance dosing schedule

^a Two injections, each at a separate site in the abdomen.

^b 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, the regimen should be restarted from Day 1 (see table 1).

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 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). Sunlenca injections must NOT be administered intradermally (see section 4.4). 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with strong inducers of CYP3A, P-gp, and UGT1A1, such as:

• antimycobacterials: rifampicin

• anticonvulsants: carbamazepine, phenytoin

• herbal products: St. John's wort (Hypericum perforatum)

(see section 4.5).

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 patients with HIV 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.

Injection Site Reactions

Injection Site Reactions with Improper Administration

Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer. Sunlenca injections must only be administered subcutaneously (see section 4.2).

Slow or non-resolving injection site nodules and indurations

Administration of Sunlenca may result in local injection site reactions (ISRs), including nodules and indurations. The healthcare professional should inform patients that nodules and indurations at the injection site may take longer to resolve than other ISRs or may not resolve. In CAPELLA (see section 5.1), nodules associated with the first injections of Sunlenca had not resolved in 10% of participants after a median follow-up of 554 days, whereas all indurations had resolved (see section 4.8). The mechanism driving the persistence of injection site nodules in some participants is not fully understood but may be related to the presence of the subcutaneous drug depot and an associated foreign body response at the injection site. Non-resolving ISRs should be subject to clinical monitoring.

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).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to say essentially 'sodium-free'.

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 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 2: 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

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

It is unknown whether lenacapavir is excreted in human milk. After administration to rats during pregnancy and lactation, lenacapavir was detected at low levels in the plasma of nursing rat pups, without effects on these nursing pups.

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 in heavily treatment-experienced adult participants with HIV were ISRs (76%) and nausea (6%).

Tabulated list of adverse reactions

A tabulated list of adverse reactions is presented in Table 3. 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 3: Tabulated list of adverse reactions

a Frequency based on all participants (Cohorts 1 and 2) in CAPELLA (see section 5.1).

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.

Description of selected adverse reactions

Immune Reconstitution Inflammatory Syndrome

In patients with HIV 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

Through Week 156 of treatment, most participants had mild (Grade 1, 54%) or moderate (Grade 2, 17%) ISRs. Six percent (4/72) of participants experienced a severe Grade 3 ISR with a median time to resolution of 15 (range: 1 to 71) days. No participants experienced a Grade 4 ISR. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days. The median time to resolution of nodules and indurations associated with the first injections of Sunlenca was 191 (Q1, Q3: 71, 366) and 113 (Q1, Q3: 29, 224) days, respectively. After a median follow-up of 554 days, nodules associated with the first injections of Sunlenca had not resolved in 10% (7/72) of the participants. All indurations associated with the first injections of Sunlenca had resolved.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

If overdose occurs the patient must be monitored 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 protein bound, 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 (CA) subunits. 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 CA subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

Antiviral activity and selectivity in vitro

The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes. The EC₅₀ and selectivity (CC₅₀/EC₅₀) values ranged from 30 to 190 pM and 140,000 to >1,670,000, respectively, for wild-type (WT) HIV-1 virus. The protein-adjusted EC₉₅ for lenacapavir was 4 nM (3.87 ng per mL) in the MT-4 T-cell line for WT HIV-1 virus.

In a study of lenacapavir in combination with representatives from the main classes of antiretroviral agents (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs], integrase strand-transfer inhibitors [INSTIs], and protease inhibitors [PIs]), synergistic antiviral effects were observed. No antagonism was observed for these combinations.

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, H.

Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.

Resistance

In cell culture

HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. In vitro resistance selections with lenacapavir identified 7 mutations in CA: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination. Phenotypic susceptibility to lenacapavir was reduced 4- to >3,226-fold, relative to WT virus. HIV-1 variants with >10-fold reduction in susceptibility to lenacapavir compared to WT virus displayed diminished replication capacity in primary human CD4+ T lymphocytes and macrophages (0.03 – 28% and 1.9 – 72% of WT virus, respectively).

In GS-US-200-4625 ('CAPELLA'), 39% (28/72) of heavily treatment-experienced participants met the criteria for resistance analyses through Week 156 (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 analysed for lenacapavir-associated mutation emergence. Lenacapavir-associated capsid mutations were found in 19.0% (n = 14) of participants. The M66I CA mutation was observed in 8.3% (n = 6) of participants, alone or in combination with other Sunlenca-associated capsid mutations including Q67Q/H/K/N, K70K/N/R/S, N74D/H, A105T and T107T/A/C. Four participants had emergence of Q67H + a K70R in CA with or without A105T and/or T107N. One participant had emergence of K70N + N74K + T107T/N, one participant had emergence of N74D alone, one participant had emergence of Q67Q/H alone, and one participant had emergence of Q67K + K70H. Eight participants with virologic failure had emergent resistance substitutions to components of the OBR.

Phenotypic analyses indicated that the M66I and Q67K + K70H mutation patterns were associated with a decrease in lenacapavir susceptibility of 234-fold (median) and 167-fold, respectively, in comparison to WT. The Q67H + K70R + A105T or T107N resistance pattern was associated with an average 195-fold decrease in lenacapavir susceptibility compared to WT, and Q67H + K70R alone was associated with a 15-fold decrease in lenacapavir susceptibility compared to WT. The presence of mutations K70N + N74K was associated with a 289-fold decrease in lenacapavir susceptibility compared to WT, and the Q67Q/H mutation was associated with a 5.9-fold decrease in lenacapavir susceptibility compared to WT.

Cross resistance

The in vitro antiviral activity of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the 4 main classes of antiretroviral agents (NRTIs, NNRTIs, INSTIs and PIs; n = 58), as well as to viruses resistant to maturation inhibitors (n = 24), and to viruses resistant to the entry inhibitors (EI) class (fostemsavir, ibalizumab, maraviroc, and 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.

Effects on electrocardiogram

In a parallel-design thorough QT/QTc study, lenacapavir had no clinically relevant effect on the QTcF interval. At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of Sunlenca), the predicted mean (upper 90% confidence interval) increase in QTcF interval was 2.6 (4.8) msec, and there was no association (p = 0.36) between observed lenacapavir plasma concentrations and change in QTcF.

Clinical data

The efficacy and safety of Sunlenca in heavily treatment-experienced participants with multidrug resistant HIV-1 is based on 156-week data from a partially randomised, placebo-controlled, double-blind, multicentre study, GS-US-200-4625 ('CAPELLA').

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 medicinal products from each of at least 3 of the 4 classes of antiretroviral medicinal products (NRTI, NNRTI, PI and INSTI), and no more than 2 fully active antiretroviral medicinal products from the 4 classes of antiretroviral medicinal products remaining at baseline due to resistance, intolerability, medicinal product access, contraindication, or other safety concerns.

The trial was composed of two cohorts. Participants were enrolled into the randomised 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-randomised 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. Participants were administered 600 mg, 600 mg, and 300 mg lenacapavir orally on Days 1, 2, and 8, respectively, followed by 927 mg subcutaneously on Day 15 and 927 mg subcutaneously every 6 months thereafter (see section 5.2).

In the 14-day functional monotherapy period, participants in Cohort 1 were randomised in a 2:1 ratio in a blinded fashion, to receive either Sunlenca or placebo, while continuing their failing regimen. 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.

The majority of participants in Cohort 1 were male (72%), White (46%) or Black (46%), and between 24 and 71 years of age (mean [SD]: 52 [11.2] years). At baseline, median viral load and CD4+ cell counts were 4.5 log₁₀ copies/mL (range 2.33 to 5.40) and 127 cells/mm³ (range 6 to 827), respectively. The majority (53%) of participants had no fully active agents within their initial failing regimen.

Participants in Cohort 2 initiated Sunlenca and an OBR on Day 1.

The majority of participants in Cohort 2 were male (78%), White (36%), Black (31%) or Asian (33%), and between 23 and 78 years of age (mean [SD]: 48 [13.7] years). At baseline, median viral load and CD4+ cell counts were 4.5 log₁₀ copies/mL (range 1.28 to 5.70) and 195 cells/mm³ (range 3 to 1296), 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.

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 demonstrated the superiority of Sunlenca compared with placebo, as shown in Table 4.

Table 4: Proportion of participants achieving a ≥ 0.5 log₁₀ decrease in viral load (Cohort 1)

The results at Weeks 26, 52 and 156 are provided in Table 5 and Table 6.

Table 5: Virologic outcomes (HIV-1 RNA < 50 copies/mL and < 200 copies/mL) at weeks 26^a, 52^b and 156^c with Sunlenca plus OBR in the CAPELLA trial (Cohort 1)

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

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

c Week 156 window was between Days 1052 and 1142 (inclusive).

d Two participants who completed the CAPELLA trial before Week 156 were excluded from the analysis.

e Based on missing = excluded analysis to impute missing values, 82% (23/28) of participants had HIV-1 RNA < 50 copies/mL at Week 156.

f Based on missing = excluded analysis to impute missing values, 86% (24/28) of participants had HIV-1 RNA < 200 copies/mL at Week 156.

g Includes participants who had ≥ 50 copies/mL or ≥ 200 copies/mL, respectively, in the Week 26, 52 or 156 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 or ≥ 200 copies/mL, respectively.

h 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.

i 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 6: Virologic outcomes (HIV-1 RNA < 50 copies/mL) by baseline covariates at weeks 26^a, 52^b and 156^c with Sunlenca plus OBR in the CAPELLA trial (Cohort 1)

ARV = antiretroviral; DRV = darunavir; DTG = dolutegravir; INSTI = integrase strand-transfer inhibitor; OBR = optimised background regimen

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

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

c Week 156 window was between Days 1052 and 1142 (inclusive).

In Cohort 1, at Weeks 26, 52 and 156, the mean change from baseline in CD4+ cell count was 81 cells/mm³ (range: -101 to 522), 82 cells/mm³ (range: -194 to 467), and 157 cells/mm³ (range: - 93 to 659), respectively.

In Cohort 2, at Weeks 26, 52 and 156, 81% (29/36), 72% (26/36), and 58% (21/36) of participants achieved HIV-1 RNA < 50 copies/mL, respectively, and the mean change from baseline in CD4+ cell count was 98 cells/mm³ (range: -103 to 459), 113 cells/mm³ (range: -124 to 405), and 173 cells/mm³ (range: -168 to 455), respectively.

Paediatric population

The Medicines and Healthcare products Regulatory Agency has deferred the obligation to submit the results of studies with Sunlenca in one or more subsets of the paediatric population in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

Lenacapavir exposures (AUC_tau, C_max and C_trough) were 29% to 84% higher in heavily treatment experienced participants with HIV-1 infection as compared to participants without HIV-1 infection based on population pharmacokinetics analysis.

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 84 days postdose.

Oral administration

Lenacapavir is absorbed following oral administration with peak plasma concentrations occurring approximately 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

Simulated steady state exposures of lenacapavir following recommended dosing regimen in heavily treatment experienced participants with HIV are provided in Table 7.

Table 7: Pharmacokinetic parameters of lenacapavir following oral and subcutaneous administration

CV = Coefficient of Variation; SC = subcutaneous

a Simulated exposures utilizing population PK analysis.

Distribution

Lenacapavir steady state volume of distribution was 976 litres in heavily treatment experienced participants with HIV-1 infection based on population pharmacokinetic analysis.

Lenacapavir is highly bound to plasma proteins (approximately 99.8%, based on in vivo data).

Biotransformation

Following a single intravenous dose of radiolabelled-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. Lenacapavir clearance was 3.62 L/h in heavily treatment experienced participants with HIV-1 infection based on population pharmacokinetic analysis.

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 population

Age, gender, and race

Population PK analyses using data from adult trials, including a limited number of elderly participants (n = 5; ≥ 65 to 78 years), did not identify any clinically relevant differences in the exposure of lenacapavir due to age, gender, race/ethnicity or weight.

Hepatic impairment

The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated Phase 1 trial in participants with moderate hepatic impairment (Child-Pugh Class B). Lenacapavir mean exposures (total and unbound) were 1.47- to 2.84-fold and 2.61- to 5.03-fold higher for AUC_inf and C_max, respectively in participants with moderate hepatic impairment (Child-Pugh B) compared to participants with normal hepatic function. However, this increase is not considered clinically relevant based on lenacapavir exposure-response. The pharmacokinetics of lenacapavir have not been studied in patients with severe hepatic impairment (Child-Pugh C) (see section 4.2).

Renal impairment

The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated study in participants with severe renal impairment (estimated creatinine clearance ≥ 15 and < 30 mL/minute). Lenacapavir exposures were increased (84% and 162% for AUC_inf and C_max, respectively) in participants with severe renal impairment compared with participants with normal renal function; however, the increase was not considered clinically relevant. The pharmacokinetics of lenacapavir have not been studied in patients with end-stage renal disease, including those on dialysis (see section 4.2). As lenacapavir is approximately 99.8% 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.

Lenacapavir was not mutagenic or clastogenic in conventional genotoxicity assays.

Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 300 mg/kg/dose once every 13 weeks, which resulted in exposures approximately 60 times the exposure in humans at the recommended human dose (RHD).

In a 2-year rat carcinogenicity study, there were lenacapavir-treatment induced subcutaneous primary sarcomas associated with fibrosis and inflammation present at the injection sites in animals administered 927 mg/kg/dose once every 13 weeks. 11/110 animals manifested sarcomas at the high dose where each animal had up to 16 injection sites – corresponding to an incidence of <1% total injection sites across animals at the high dose. Drug concentrations in the injection depot sites are difficult to determine but systemically, the 927 mg/kg dose corresponds to 44 times the exposure in humans at the RHD. At the no-observed-adverse-effect level (NOAEL), the 309 mg/kg/dose corresponds to 25 times the exposure in humans at the RHD. Rats are prone to sarcoma formation at the subcutaneous injection site, but a clinical relevance cannot be excluded considering the long duration of the drug depot in humans. There were no neoplasms associated with systemic exposure to lenacapavir at any dose.

In offspring from rat and rabbit dams treated with lenacapavir during pregnancy, there were no toxicologically significant effects on developmental endpoints.

In rats, male and female fertility was not affected at lenacapavir exposures up to 8 times the human exposure at the RHD. In rats and rabbits, embryofoetal development was not affected at exposures up to 21 and 172 times the human exposure, respectively, at the RHD. In rats, pre- and postnatal development was not affected at exposures up to 7 times the human exposure at the RHD.

Transfer of lenacapavir from maternal to neonatal rats was observed in a prenatal and postnatal development study, but it is not known whether the transport occurred via the placenta or the milk; therefore the potential for lenacapavir to pass into the placenta or be excreted into milk in humans is not known.

Macrogol (E1521)

Water for injections

Not applicable.

3 years

This medicinal product does not require any special temperature storage conditions. 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 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 the 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).