Sunlenca

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 EC 50 and selectivity (CC 50 /EC 50 ) 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 EC 95 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 + 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 log 10 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 log 10 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 lenacapavir 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 log 10 copies/mL (range 2.33 to 5.40) and 127 cells/mm 3 (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 log 10 copies/mL (range 1.28 to 5.70) and 195 cells/mm 3 (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 log 10 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 log 10 decrease in viral load (Cohort 1) Sunlenca (n = 24) Placebo (n = 12) Proportion of participants achieving a ≥ 0.5 log 10 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 26 a , 52 b and 156 c with Sunlenca plus OBR in the CAPELLA trial (Cohort 1) Sunlenca plus OBR Week 26 n = 36 Week 52 n = 36 Week 156 n = 34 d HIV-1 RNA < 50 copies/mL HIV-1 RNA < 200 copies/mL 81% 89% 83% 86% 65% e 68% f HIV-1 RNA ≥ 50 copies/mL g HIV-1 RNA ≥ 200 copies/mL g 19% 11% 14% 11% 18% 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 < 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 or 52 window; participants who discontinued early due to lack or loss of efficacy; participants who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL 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) Sunlenca plus OBR Week 26 n = 36 Week 52 n = 36 Week 156 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) Baseline CD4+ (cells/mm 3 ) < 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 OBR 0 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 = 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/mm 3 (range: ‑101 to 522), 82 cells/mm 3 (range: ‑194 to 467), and 157 cells/mm 3 (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/mm 3 (range: ‑103 to 459), 113 cells/mm 3 (range: -124 to 405), and 173 cells/mm 3 (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).