Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

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 wild-type 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’), 29% (21/72) of heavily treatment experienced-patients 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 analysed for lenacapavir-associated mutation emergence. Lenacapavir-associated capsid mutations were found in 11.1% (n = 8) of these patients. The M66I CA mutation was observed in 8.3% (n = 6) of patients, alone or in combination with other Sunlenca-associated capsid mutations including N74D, Q67Q/H/K/N, K70K/N/R/S, T107T/C, and T107A. One patient had a K70H CA mutation emerging along with T107T/N, and one patient had emergence of both Q67H and K70R in CA.

Phenotypic analyses indicated that the M66I and K70H mutations were associated with an average decrease in lenacapavir susceptibility of 234-fold and 265-fold, respectively, when compared to WT.
The Q67H + K70R CA resistance pattern was associated with a 15-fold decrease in lenacapavir susceptibility.

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 HIV-1 infected, heavily treatment experienced patients with multidrug resistance is based on 52-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 patients with multiclass resistant HIV-1. Patients 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. Patients 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. Patients 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. Patients 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, patients 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, patients who had received Sunlenca continued on Sunlenca along with an OBR; patients who had received placebo during this period initiated Sunlenca along with an OBR.

The majority of patients 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 patients had no fully active agents within their initial failing regimen.

Patients in cohort 2 initiated Sunlenca and an OBR on Day 1.

The majority of patients 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 patients 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 patients 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 patients achieving a ≥ 0.5 log10 decrease in viral load (Cohort 1) 
Sunlenca                          Placebo
(n = 24)                         (n = 12)
Proportion of patients achieving a ≥ 0.5 log10
87.5%                            16.7% decrease in viral load
Treatment difference (95% CI); p-value                                70.8% (34.9% to 90.0%); p < 0.0001 
The results at Weeks 26 and 52 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 and 52b with Sunlenca plus OBR in the CAPELLA trial (Cohort 1)

Sunlenca plus OBR
(n= 36)
Week 26         Week 52
HIV-1 RNA < 50 copies/mL                                                               81%             83% HIV-1 RNA < 200 copies/mL                                                              89%             86% HIV-1 RNA ≥ 50 copies/mLc                                                              19%             14% HIV-1 RNA ≥ 200 copies/mLc                                                             11%             11% No virologic data in week 26 or week 52 Window                                          0               3% Discontinued study drug due to AE or death d                                            0                0 Discontinued study drug due to other reasons e and last available HIV- 0                    3%
1 RNA < 50 copies/mL or < 200 copies/mL
Missing data during window but on study drug                                               0                      0 a     Week 26 window was between Days 184 and 232 (inclusive).
b     Week 52 window was between Days 324 and 414 (inclusive).
c     Includes patients who had ≥ 50 copies/mL or ≥ 200 copies/mL, respectively, in the Week 26 or 52 window; patients who discontinued early due to lack or loss of efficacy; patients 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.


d     Includes patients 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 patients 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 26a and 52b with Sunlenca plus OBR in the CAPELLA trial (Cohort 1)

Sunlenca plus OBR
(n = 36)
Week 26          Week 52
Baseline plasma viral load (copies/mL)
≤ 100,000                                                                        86% (25/29)            86% (25/29) > 100,000                                                                         57% (4/7)              71% (5/7) Baseline CD4+ (cells/mm3)
< 200                                                                            78% (21/27)            78% (21/27) ≥ 200                                                                             89% (8/9)              100% (9/9) Baseline INSTI resistance profile
With INSTI resistance                                                            85% (23/27)            81% (22/27) Without INSTI resistance                                                          63% (5/8)              88% (7/8) Number of fully active ARV agents in the OBR
0                                                                                 67% (4/6)              67% (4/6) 1                                                                                86% (12/14)            79% (11/14) ≥2                                                                               81% (13/16)            94% (15/16) Use of DTG and/or DRV in the OBR
With DTG and DRV                                                                 83% (10/12)            83% (10/12) With DTG, without DRV                                                             83% (5/6)              83% (5/6) Without DTG, with DRV                                                             78% (7/9)              89% (8/9) Without DTG or DRV                                                                78% (7/9)              78% (7/9) 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).


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 83 cells/mm3 (range: -194 to 467).

In cohort 2, at Week 26, 81% (29/36) of patients achieved HIV-1 RNA < 50 copies/mL and the mean change from baseline in CD4+ cell count was 98 cells/mm3 (range: -103 to 459).

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Lenacapavir exposures (AUCtau, Cmax and Ctrough) were 29% to 84% higher in heavily treatment experienced patients with HIV-1 infection as compared to subjects without HIV-1 infection based on population pharmacokinetics analysis.

Absorption

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, 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 be administered without regard to food.



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.

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

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

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
69.6 (56)                     87 (71.8)              97.2 (70.3)
(ng/ mL)
AUCtau
15,600 (52.9)                 250,000 (66.6)          300,000 (68.5)
(h•ng/mL)
Ctrough
35.9 (56.8)                    32.7 (88)              36.2 (90.6)
(ng/mL)
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 patients 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 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. Lenacapavir clearance was 3.62 L/h in heavily treatment experienced patients 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 patients (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 subjects 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 AUCinf and Cmax, respectively in patients with moderate hepatic impairment (Child-Pugh B) compared to subjects 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 subjects with severe renal impairment (estimated creatinine clearance ≥ 15 and < 30 mL/minute).
Lenacapavir exposures were increased (84% and 162% for AUCinf and Cmax, respectively) in subjects with severe renal impairment compared with subjects 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.