SUNLENCA 464mg injectible solution medication leaflet

Sunlenca 464 mg solution for injection

Each single-dose vial contains lenacapavir sodium equivalent to 463.5 mg of lenacapavir in 1.5 mL.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, yellow to brown solution.

Sunlenca injection, in combination with other antiretroviral(s), is indicated for the treatment of adultswith multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct asuppressive 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 tothe required injection schedule and counsel patients about the importance of adherence to scheduleddosing visits to help maintain viral suppression and reduce the risk of viral rebound and potentialdevelopment of resistance associated with missed doses. In addition, the healthcare professionalshould 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 antiretroviralregimen where possible, no later than 28 weeks after the final injection of Sunlenca (see section 4.4).

On treatment Day 1 and Day 2, the recommended dose of Sunlenca is 600 mg per day taken orally. Ontreatment Day 8, the recommended dose is 300 mg taken orally. Then, on treatment Day 15, therecommended 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 6months (26 weeks) from the date of the last injection (+/- 2 weeks).

Table 1: Recommended treatment regimen for Sunlenca: initiation and maintenance dosingschedule

Treatment time

Dose of Sunlenca: initiation

Day 1 600 mg orally (2 x 300 mg tablets)

Day 2 600 mg orally (2 x 300 mg tablets)

Day 8 300 mg orally (1 x 300 mg tablet)

Day 15 927 mg subcutaneous injection (2 x 1.5 mL injectionsa)

Dose of Sunlenca: maintenance

Every 6 Months 927 mg subcutaneous injection (2 x 1.5 mL injectionsa)(26 weeks)b+/- 2 weeksa Two injections, each at a separate site in the abdomen.b From the date of the last injection.

During the maintenance period, if more than 28 weeks have elapsed since the last injection and ifclinically appropriate to continue Sunlenca treatment, the regimen should be restarted from Day 1 (seetable 1).

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

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

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 thesepatients.

The safety and efficacy of Sunlenca in children under the age of 18 years old has not been established.

No data are available.

For subcutaneous use only.

Sunlenca injections must only be administered subcutaneously into the abdomen (two injections, eachat a separate site) by a healthcare professional (see section 6.6). Sunlenca injections must NOT beadministered 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 theinjection 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 adoptan alternative, fully suppressive antiretroviral regimen where possible, no later than 28 weeks after thefinal 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 systemiccirculation of patients for prolonged periods. These concentrations may affect the exposures of othermedicinal products (i.e. sensitive CYP3A substrates) that are initiated within 9 months after the lastsubcutaneous dose of Sunlenca (see section 4.5). These concentrations are not expected to affect theexposures of other antiretroviral agents that are initiated after discontinuation of Sunlenca.

In patients with HIV with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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 mycobacterialinfections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluatedand treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese 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 sitereactions, 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 andindurations. The healthcare professional should inform patients that nodules and indurations at theinjection site may take longer to resolve than other ISRs or may not resolve. In CAPELLA (see section5.1), nodules associated with the first injections of Sunlenca had not resolved in 10% of participantsafter a median follow-up of 554 days, whereas all indurations had resolved (see section 4.8). Themechanism driving the persistence of injection site nodules in some participants is not fullyunderstood but may be related to the presence of the subcutaneous drug depot and an associatedforeign body response at the injection site. Non-resolving ISRs should be subject to clinicalmonitoring.

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 physiciansexperienced in the treatment of patients with HIV associated diseases.

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 UGT1A1together (i.e. all 3 pathways), such as atazanavir/cobicistat is not recommended (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to sayessentially ‘sodium-free’.

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 lenacapavirresulting in loss of therapeutic effect and development of resistance, therefore co-administration iscontraindicated (see section 4.3). Moderate inducers of CYP3A and P-gp, such as efavirenz, may alsosignificantly decrease plasma concentrations of lenacapavir, therefore co-administration is notrecommended (see section 4.4).

Strong inhibitors of CYP3A, P-gp and UGT1A1 together (i.e., all 3 pathways), such asatazanavir/cobicistat, may significantly increase plasma concentrations of lenacapavir, thereforeco-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.

Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if Sunlenca isco-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

Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with Sunlenca

Cmax

ANTIMYCOBACTERIALS

Rifampicina,b,c (600 mg once daily) Lenacapavir: Co-administration is

AUC: ↓84% contraindicated (see section 4.3).

Cmax: ↓55%

Rifabutin Interaction not studied. Co-administration is notrecommended (see section 4.4).

Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with Sunlenca

Cmax

Co-administration of rifabutin maydecrease lenacapavir plasmaconcentrations, which may result inloss of therapeutic effect anddevelopment of resistance.

ANTICONVULSANTS

Carbamazepine Interaction not studied. Co-administration is

Phenytoin contraindicated (see section 4.3).

Oxcarbazepine Co-administration of Co-administration is not

Phenobarbital carbamazepine, oxcarbazepine, recommended (see section 4.4).

phenobarbital, or phenytoin withlenacapavir may decrease Alternative anticonvulsants shouldlenacapavir plasma concentrations, be considered.which may result in loss oftherapeutic effect and developmentof resistance.

HERBAL PRODUCTS

St. John’s wort (Hypericum Interaction not studied. Co-administration isperforatum) contraindicated (see section 4.3).

Co-administration of St.

John’s wort may decreaselenacapavir plasma concentrations,which may result in loss oftherapeutic effect and developmentof resistance.

ANTIRETROVIRAL AGENTS

Atazanavir/cobicistatb,d,e Lenacapavir: Co-administration is not(300 mg/150 mg once daily) AUC: ↑ 321% recommended (see section 4.4).

Cmax: ↑ 560%

Efavirenzb,d,f (600 mg once daily) Lenacapavir:

AUC:↓ 56%

Cmax:↓ 36%

Etravirine Interaction not studied.

Nevirapine

Tipranavir/ritonavir Co-administration of etravirine,nevirapine, or tipranavir/ritonavirmay decrease lenacapavir plasmaconcentrations, which may result inloss of therapeutic effect anddevelopment of resistance.

Cobicistatb,d,g (150 mg once daily) Lenacapavir: No dose adjustment of lenacapavir

AUC: ↑ 128% is required.

Cmax:↑ 110%

Darunavir/cobicistatb,d,h Lenacapavir:(800 mg/150 mg once daily) AUC:↑ 94%

Cmax:↑ 130%

Ritonavir Interaction not studied.

Co-administation of ritonavir mayincrease lenacapavir plasmaconcentrations.

Tenofovir alafenamided,i,j (25 mg) Tenofovir alafenamide: No dose adjustment of tenofovir

AUC:↑ 32% alafenamide is required.

Cmax:↑ 24%

Tenofovirk:

AUC:↑ 47%

Cmax:↑ 23%

Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with Sunlenca

Cmax

ERGOT DERIVATIVES

Dihydroergotamine Interaction not studied. Caution is warranted when

Ergotamine dihydroergotamine or ergotamine,

Plasma concentrations of these is co-administered with Sunlenca.

medicinal products may beincreased when co-administeredwith lenacapavir.

PHOSPHODIESTERASE-5 (PDE-5) INHIBITORS

Sildenafil Interaction not studied. Use of PDE-5 inhibitors for

Tadalafil pulmonary arterial hypertension:

Vardenafil Plasma concentration of PDE-5 Co-administration with tadalafil isinhibitors may be increased when not recommended.co-administered with lenacapavir.

Use of PDE-5 inhibitors for erectiledysfunction:

Sildenafil: A starting dose of 25 mgis recommended.

Vardenafil: No more than 5 mg in a24-hour period.

Tadalafil:

* For use as needed: no morethan 10 mg every 72 hours

* For once daily use: dose not toexceed 2.5 mg

CORTICOSTEROIDS (systemic)

Cortisone/hydrocortisone Interaction not studied. Co-administration of Sunlenca with

Dexamethasone corticosteroids whose exposures

Plasma concentrations of are significantly increased bycorticosteroids may be increased CYP3A inhibitors can increase thewhen co-administered with risk for Cushing's syndrome andlenacapavir. adrenal suppression. Initiate withthe lowest starting dose and titrate

Plasma concentrations of carefully while monitoring forlenacapavir may decrease when co- safety.administered with systemicdexamethasone, which may result Caution is warranted whenin loss of therapeutic effect and systemic dexamethasone isdevelopment of resistance. co-administered with Sunlenca,particularly for long-term use.

Alternative corticosteroids shouldbe considered.

HMG-CoA REDUCTASE INHIBITORS

Lovastatin Interaction not studied. Initiate lovastatin and simvastatin

Simvastatin with the lowest starting dose and

Plasma concentrations of these titrate carefully while monitoringmedicinal products may be for safety (e.g. myopathy).

Atorvastatin increased when co-administered No dose adjustment of atorvastatinwith lenacapavir. is required.

Pitavastatind,i,l (2 mg single dose; Pitavastatin: No dose adjustment of pitavastatinsimultaneous or 3 days after AUC:↔ and rosuvastatin is required.lenacapavir) Cmax:↔

Rosuvastatind,i,m (5 mg single dose) Rosuvastatin:

AUC:↑ 31%

Cmax:↑ 57%

ANTIARRHYTHMICS

Digoxin Interaction not studied. Caution is warranted andtherapeutic concentration

Plasma concentration of digoxin monitoring of digoxin ismay be increased when recommended.

Medicinal product by Effects on concentrations. Recommendation concerningtherapeutic areas Mean percent change in AUC, co-administration with Sunlenca

Cmaxco-administered with lenacapavir.

SEDATIVES/HYPNOTICS

Midazolamd,i,n (2.5 mg single dose; Midazolam: Caution is warranted whenoral; simultaneous administration) AUC: ↑ 259% midazolam or triazolam, is

Cmax: ↑ 94% co-administered with Sunlenca.

1-hydroxymidazolamo:

AUC: ↓ 24%

Cmax: ↓ 46%

Midazolamd,i,n (2.5 mg single dose; Midazolam:oral;1 day after lenacapavir) AUC: ↑ 308%

Cmax: ↑ 116%1-hydroxymidazolamo:

AUC: ↓ 16%

Cmax: ↓ 48%

Triazolam Interaction not studied.

Plasma concentration of triazolammay be increased whenco-administered with lenacapavir.

ANTICOAGULANTS

Direct Oral Anticoagulants Interaction not studied. Due to potential bleeding risk, dose(DOACs) adjustment of DOAC may be

Rivaroxaban Plasma concentration of DOAC required. Consult the Summary of

Dabigatran may be increased when Product Characteristics of the

Edoxaban co-administered with lenacapavir. DOAC for further information onuse in combination with moderate

CYP3A inhibitors and/or P-gpinhibitors.

ANTIFUNGALS

Voriconazolea,b,p,q (400 mg twice Lenacapavir: No dose adjustment of lenacapavirdaily/200 mg twice daily) AUC:↑ 41% is required.

Cmax:↔

Itraconazole Interaction not studied.

Ketoconazole

Plasma concentration oflenacapavir may be increased whenco-administered with itraconazoleor ketoconazole.

H2-RECEPTOR ANTAGONISTS

Famotidinea,b (40 mg once daily, 2 Famotidine: No dose adjustment of famotidinehours before lenacapavir) AUC:↑ 28% is required.

Cmax:↔

ORAL CONTRACEPTIVES

Ethinylestradiol Interaction not studied. No dose adjustment of

Progestins ethinylestradiol and progestins is

Plasma concentrations of required.ethinylestradiol and progestins maybe increased when co-administeredwith lenacapavir.

GENDER AFFIRMING HORMONES17β-estradiol Interaction not studied. No dose adjustment of these gender

Anti-androgens affirming hormones is required.

Progestogen Plasma concentrations of these

Testosterone medicinal products may beincreased when co-administeredwith lenacapavir.

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 2days, 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 mgmaintenance dose twice daily.

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, foetaldevelopment, parturition or postnatal development (see section 5.3).

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

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

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

There are no data on the effects of lenacapavir on human male or female fertility. Animal studiesindicate 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.

The most common adverse reactions in heavily treatment-experienced adult participants with HIVwere ISRs (76%) and nausea (6%).

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

Frequencya Adverse reaction

Not known immune reconstitution inflammatory syndrome

Common nausea

Very common injection site reactionsba 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.

In patients with HIV with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (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 toresolution of 15 (range: 1 to 71) days. No participants experienced a Grade 4 ISR. The median time toresolution of all ISRs, excluding nodules and indurations, was 5 days. The median time to resolutionof 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, nodulesassociated with the first injections of Sunlenca had not resolved in 10% (7/72) of the participants. Allindurations associated with the first injections of Sunlenca had resolved.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If overdose occurs the patient must be monitored for signs or symptoms of adverse reactions (seesection 4.8). Treatment of overdose with Sunlenca consists of general supportive measures includingmonitoring of vital signs as well as observation of the clinical status of the patient. As lenacapavir ishighly protein bound, it is unlikely to be significantly removed by dialysis.

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

Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to theinterface between capsid protein (CA) subunits. Lenacapavir inhibits HIV-1 replication by interferingwith multiple, essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (byinterfering with Gag/Gag-Pol functioning, reducing production of CA subunits), and capsid coreformation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid 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 antiretroviralagents (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptaseinhibitors [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), includingsubtypes 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.

HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. In vitroresistance 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 wasreduced 4- to >3,226-fold, relative to WT virus. HIV-1 variants with >10-fold reduction insusceptibility to lenacapavir compared to WT virus displayed diminished replication capacity inprimary 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 metthe criteria for resistance analyses through Week 156 (HIV-1 RNA ≥50 copies/mL at confirmedvirologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit])and were analysed for lenacapavir-associated mutation emergence. Lenacapavir-associated capsidmutations 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 mutationsincluding Q67Q/H/K/N, K70K/N/R/S, N74D/H, A105T and T107T/A/C. Four participants hademergence of Q67H + K70R in CA with or without A105T and/or T107N. One participant hademergence of K70N + N74K + T107T/N, one participant had emergence of N74D alone, oneparticipant 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 associatedwith a decrease in lenacapavir susceptibility of 234-fold (median) and 167-fold, respectively, incomparison to WT. The Q67H + K70R + A105T or T107N resistance pattern was associated with anaverage 195-fold decrease in lenacapavir susceptibility compared to WT, and Q67H + K70R alonewas associated with a 15-fold decrease in lenacapavir susceptibility compared to WT. The presence ofmutations K70N + N74K was associated with a 289-fold decrease in lenacapavir susceptibilitycompared to WT, and the Q67Q/H mutation was associated with a 5.9-fold decrease in lenacapavirsusceptibility compared to WT.

The in vitro antiviral activity of lenacapavir was determined against a broad spectrum of HIV-1site-directed mutants and patient-derived HIV-1 isolates with resistance to the 4 main classes ofantiretroviral agents (NRTIs, NNRTIs, INSTIs and PIs; n = 58), as well as to viruses resistant tomaturation 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 fullyactive against all variants tested, thereby demonstrating a non-overlapping resistance profile. Inaddition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence ofnaturally occurring Gag polymorphisms.

In a parallel-design thorough QT/QTc study, lenacapavir had no clinically relevant effect on the QTcFinterval. 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 was2.6 (4.8) msec, and there was no association (p = 0.36) between observed lenacapavir plasmaconcentrations and change in QTcF.

The efficacy and safety of Sunlenca in heavily treatment-experienced participants with multidrugresistant 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 atleast two antiretroviral medicinal products from each of at least 3 of the 4 classes of antiretroviralmedicinal products (NRTI, NNRTI, PI and INSTI), and no more than 2 fully active antiretroviralmedicinal products from the 4 classes of antiretroviral medicinal products remaining at baseline due toresistance, 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 every6 months thereafter (see section 5.2).

In the 14-day functional monotherapy period, participants in Cohort 1 were randomised in a 2:1 ratioin 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 between24 and 71 years of age (mean [SD]: 52 [11.2] years). At baseline, median viral load and CD4+ cellcounts 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 1achieving ≥ 0.5 log10 copies/mL reduction from baseline in HIV-1 RNA at the end of the functionalmonotherapy 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)

Sunlenca Placebo(n = 24) (n = 12)

Proportion of participants achievinga ≥ 0.5 log decrease in viral load 87.5% 16.7%

Treatment difference (95% CI); p-value 70.8% (34.9% to 90.0%); p < 0.0001

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 26a, 52band 156c with Sunlenca plus OBR in the CAPELLA trial (Cohort 1)

Sunlenca plus OBR

Week 26 Week 52 Week 156n = 36 n = 36 n = 34d

HIV-1 RNA < 50 copies/mL 81% 83% 65%e

HIV-1 RNA < 200 copies/mL 89% 86% 68%f

HIV-1 RNA ≥ 50 copies/mLg 19% 14% 18%

HIV-1 RNA ≥ 200 copies/mLg 11% 11% 15%

No virologic data in week 26, 52 or 156 Window 0 3% 18%

Discontinued study drug due to AE or death h 0 0 3%

Discontinued study drug due to other reasons i and last available

HIV-1 RNA < 50 copies/mL or < 200 copies/mL 0 3% 9%

Missing data during window but on study drug 0 0 6%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 < 50copies/mL at Week 156.f Based on missing = excluded analysis to impute missing values, 86% (24/28) of participants had HIV-1 RNA < 200copies/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 thanan adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50copies/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 thisresulted 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., withdrewconsent, loss to follow-up, etc.

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

Sunlenca plus OBR

Week 26 Week 52 Week 156n = 36 n = 36 n = 34

Baseline plasma viral load (copies/mL)≤ 100,000 86% (25/29) 86% (25/29) 67% (18/27)> 100,000 57% (4/7) 71% (5/7) 57% (4/7)

Sunlenca plus OBR

Week 26 Week 52 Week 156n = 36 n = 36 n = 34

Baseline CD4+ (cells/mm3)< 200 78% (21/27) 78% (21/27) 58% (15/26)≥ 200 89% (8/9) 100% (9/9) 88% (7/8)

Baseline INSTI resistance profile

With INSTI resistance 85% (23/27) 81% (22/27) 62% (16/26)

Without INSTI resistance 63% (5/8) 88% (7/8) 71% (5/7)

Number of fully active ARV agents in the OBR0 67% (4/6) 67% (4/6) 67% (4/6)1 86% (12/14) 79% (11/14) 58% (7/12)≥ 2 81% (13/16) 94% (15/16) 69% (11/16)

Use of DTG and/or DRV in the OBR

With DTG and DRV 83% (10/12) 83% (10/12) 58% (7/12)

With DTG, without DRV 83% (5/6) 83% (5/6) 60% (3/5)

Without DTG, with DRV 78% (7/9) 89% (8/9) 67% (6/9)

Without DTG or DRV 78% (7/9) 78% (7/9) 75% (6/8)

ARV = antiretroviral; DRV = darunavir; DTG = dolutegravir; INSTI = integrase strand-transfer inhibitor; OBR = optimisedbackground regimena 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 was81 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 participantsachieved HIV-1 RNA < 50 copies/mL, respectively, and the mean change from baseline in CD4+ cellcount was 98 cells/mm3 (range: -103 to 459), 113 cells/mm3 (range: -124 to 405), and 173 cells/mm3(range: -168 to 455), respectively.

The European Medicines 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 (seesection 4.2 for information on paediatric use).

Lenacapavir exposures (AUCtau, Cmax and Ctrough) were 29% to 84% higher in heavily treatmentexperienced participants with HIV-1 infection as compared to participants without HIV-1 infectionbased on population pharmacokinetics analysis.

Lenacapavir is completely absorbed following subcutaneous administration. Due to slow release fromthe site of subcutaneous administration, the absorption profile of subcutaneously administeredlenacapavir is complex with peak plasma concentrations occurring 84 days postdose.

Lenacapavir is absorbed following oral administration with peak plasma concentrations occurringapproximately 4 hours after administration of Sunlenca. Absolute bioavailability following oraladministration of lenacapavir is low (approximately 6 to 10%). Lenacapavir is a substrate of P-gp.

Lenacapavir AUC, Cmax and Tmax 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 beadministered without regard to food.

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

Table 7: Pharmacokinetic parameters of lenacapavir following oral and subcutaneousadministration

Parameter Day 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC)

Mean (%CV)a Day 1 to Day 15 Day 15 to end of month 6 Steady state

Cmax(ng/ mL) 69.6 (56) 87 (71.8) 97.2 (70.3)

AUCtau(h*ng/mL) 15,600 (52.9) 250,000 (66.6) 300,000 (68.5)

Ctrough(ng/mL) 35.9 (56.8) 32.7 (88) 36.2 (90.6)

CV = Coefficient of Variation; SC = subcutaneousa Simulated exposures utilizing population PK analysis.

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

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

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

The median half-life following oral and subcutaneous administration ranged from 10 to 12 days, and8 to 12 weeks, respectively. Lenacapavir clearance was 3.62 L/h in heavily treatment experiencedparticipants with HIV-1 infection based on population pharmacokinetic analysis.

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

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

Other special population

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 oflenacapavir due to age, gender, race/ethnicity or weight.

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). Lenacapavirmean exposures (total and unbound) were 1.47- to 2.84-fold and 2.61- to 5.03-fold higher for AUCinfand Cmax, respectively in participants with moderate hepatic impairment (Child-Pugh B) compared toparticipants with normal hepatic function. However, this increase is not considered clinically relevantbased on lenacapavir exposure-response. The pharmacokinetics of lenacapavir have not been studiedin patients with severe hepatic impairment (Child-Pugh C) (see section 4.2).

The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a dedicated studyin participants with severe renal impairment (estimated creatinine clearance ≥ 15and < 30 mL/minute). Lenacapavir exposures were increased (84% and 162% for AUCinf and Cmax,respectively) in participants with severe renal impairment compared with participants with normalrenal function; however, the increase was not considered clinically relevant. The pharmacokinetics oflenacapavir 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 toalter exposures of lenacapavir.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, 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 to300 mg/kg/dose once every 13 weeks, which resulted in exposures approximately 60 times theexposure in humans at the recommended human dose (RHD).

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

In offspring from rat and rabbit dams treated with lenacapavir during pregnancy, there were notoxicologically significant effects on developmental endpoints.

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

Macrogol (E1521)

Water for injections

Not applicable.

3 years

This medicinal product does not require any special temperature storage conditions. Store in theoriginal 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 andphysical 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 anelastomeric butyl rubber closure and aluminum overseal with flip off cap;

* 2 vial access devices, 2 disposable syringes, and 2 injection safety needles for subcutaneousinjection (22-gauge, 12.7 mm).

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

Use aseptic technique. Visually inspect the solution in the vials for particulate matter and discolorationprior to administration. Sunlenca injection is a yellow to brown solution. Do not use Sunlencainjection if the solution is discoloured or if it contains particulate matter. Once the solution iswithdrawn 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. Two1.5 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).

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/22/1671/002

Date of first authorisation: 17 August 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.