Bictegravir-Lenacapavir (Bixlenvo)

The BIXLENVO dosing schedule in adults requires a two-day initiation regimen of BIXLENVO tablets plus SUNLENCA tablets taken orally, followed by a maintenance regimen of one tablet of BIXLENVO taken orally once daily (Table 1). BIXLENVO must be taken with SUNLENCA during the two-day initiation period. BIXLENVO and SUNLENCA tablets may be taken with or without food [see Clinical Pharmacology (12.3)].

Missed Initiation Dose

During the initiation period, if the Day 1 or Day 2 doses of BIXLENVO or SUNLENCA are missed, patients should take them as soon as possible (see Table 1). Patients should not take Day 1 and Day 2 doses of SUNLENCA on the same day.

Missed Maintenance Dose

If a maintenance dose of BIXLENVO is missed, patients should take it as soon as possible. If more than 7 days have elapsed since the last maintenance dose, restart the initiation dosage regimen from Day 1, if clinically appropriate to continue BIXLENVO treatment (see Table 1).

Lower exposures of BIC were observed during pregnancy; therefore, viral load should be monitored closely in pregnant individuals [see Drug Interactions (7.4), Use in Specific Populations (8.1), and Clinical Pharmacology (12.3)].

The concomitant use of BIXLENVO with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4), and Drug Interactions (7.4)]:

• Loss of therapeutic effect of BIXLENVO and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during BIXLENVO therapy; review concomitant medications during BIXLENVO therapy; and monitor for the adverse reactions associated with the concomitant drugs.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The primary safety assessment of BIXLENVO in virologically suppressed adults with HIV-1 was based on 48-week data from participants in two Phase 3 randomized active-controlled clinical trials, ARTISTRY-1 (N=557) and ARTISTRY-2 (N=574) [see Clinical Studies (14)]. ARTISTRY-1 was an open-label trial that enrolled participants who had been on a stable baseline regimen for at least 6 months and were randomized to receive BIXLENVO or to continue their stable baseline regimen. ARTISTRY-2 was a blinded trial that enrolled participants who had been on BIKTARVY for at least 6 months at baseline and were randomized to receive BIXLENVO or to continue BIKTARVY.

The most common adverse reactions (all grades) reported in greater than or equal to 2% of participants in any treatment group from ARTISTRY-1 and ARTISTRY-2 through Week 48 are presented in Table 2. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Laboratory Abnormalities

Changes in Serum Creatinine

BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology 12.2].

ALT and AST Elevations

ALT and AST abnormalities from ARTISTRY-1 and ARTISTRY-2 trials are presented in Table 3.

The following adverse reactions have been identified during postmarketing experience in patients receiving a bictegravir-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders

Angioedema, urticaria, and Stevens-Johnson syndrome/toxic epidermal necrolysis

Investigations

Weight increased

Because BIXLENVO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)].

Bictegravir (BIC), a component of BIXLENVO, inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Coadministration of BIC with drugs that are substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations (see Table 4).

Lenacapavir (LEN), a component of BIXLENVO, is a moderate inhibitor of CYP3A and a P-gp inhibitor. Coadministration of LEN with sensitive substrates of CYP3A or P-gp may increase the concentrations of these substrates and result in the increased risk of their adverse events. See the prescribing information of these sensitive substrates for dosing recommendations or appropriate monitoring of safety.

BIC is a substrate of CYP3A and UGT1A1. LEN is a substrate of P-gp, UGT1A1, and CYP3A.

Strong or Moderate CYP3A Inducers

A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC. Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of LEN [see Clinical Pharmacology (12.3)]. Strong or moderate CYP3A inducers may result in loss of therapeutic effect of BIXLENVO and development of resistance.

Concomitant administration of BIXLENVO with strong CYP3A inducers is contraindicated [see Contraindications (4)]. Concomitant administration of BIXLENVO with moderate CYP3A inducers is not recommended.

Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors

Combined UGT1A1 and strong CYP3A inhibitors may significantly increase plasma concentrations of BIC. Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of LEN. Concomitant administration of BIXLENVO with combined P-gp, UGT1A1, and strong CYP3A inhibitors is not recommended.

Table 4 provides a listing of established or potentially clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with the components of BIXLENVO (BIC or LEN) as individual agents, or are drug interactions that may occur with BIXLENVO [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to BIXLENVO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from observational studies and the APR with BIC use during pregnancy have not established a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from the APR show no statistically significant difference in the overall risk of major birth defects for BIC compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%.

BIC safety has also been evaluated in an open-label trial in individuals with HIV-1 that demonstrated safety findings that were consistent with other trials in adults (see Data).

Available data from a randomized, controlled trial with LEN use during pregnancy in individuals without HIV-1 have not identified a drug-associated risk for miscarriage, or adverse maternal or fetal outcomes when compared to an active control (see Data). The rate of major birth defects in LEN-exposed pregnancies did not exceed the background prevalence rates. The risk estimates are imprecise due to small numbers of exposed pregnancies (see Data).

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with BIC at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD) (see Data). During organogenesis, systemic exposures (AUC) to BIC were approximately 24 (rats) and 0.39 times (rabbits) the exposure at the RHD of BIXLENVO. In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 20 times (BIC) the exposure in humans at the RHD.

In animal reproduction studies, no adverse developmental effects were observed when LEN was administered to rats and rabbits at exposures (AUC) ≥3 times the exposure in humans at the RHD of BIXLENVO (see Data).

Data

Human Data

Bictegravir

A BIC-containing regimen was evaluated in an open-label clinical trial of 33 virologically suppressed (HIV-1 RNA < 50 copies/mL) pregnant adults with HIV-1 and no known substitutions associated with resistance to BIC. Pregnant adults were administered a BIC-containing regimen once daily from the second or third trimester through postpartum. Exposures of BIC were lower during pregnancy as compared to postpartum. All 32 adult participants who completed the study maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum. The median CD4⁺ cell count at baseline was 558 cells/µL, and the median change in CD4⁺ cell count from baseline to Week 12 postpartum was 159 cells/μL. All 29 neonate participants had negative/nondetectable HIV-1 PCR results at birth and/or at 4 to 8 weeks post-birth. The safety findings in this trial were consistent with other trials of BIC-containing regimens in adults.

Based on prospective reports to the APR of over 500 exposures to a BIC-containing regimen during pregnancy resulting in live births (including 423 exposed in the first trimester and 113 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.3% (95% CI: 2.5% to 6.6%) and 1.8% (0.2%, 6.2%) following first and second/third trimester exposure, respectively, to a BIC-containing regimen.

Lenacapavir

In a randomized, controlled trial of individuals without HIV-1 in Uganda and South Africa, there were 208 pregnancies exposed to LEN received via injection with known outcomes and 132 deliveries (both live and non-live). In the active control arm of this study, there were 109 pregnancies with known outcomes and 61 deliveries (both live and non-live). The adverse pregnancy outcomes of spontaneous abortion, stillbirth, preterm birth, and small for gestational age were similar across both treatment groups.

There were two major birth defects in the LEN arm. Both were ventricular septal defects. This resulted in a rate of major birth defects that fell within the background prevalence rate for major birth defects.

Concentrations of LEN received via injection during each trimester of pregnancy and postpartum were comparable to those in non-pregnant participants.

Animal Data

Bictegravir

BIC was administered orally to pregnant rats (5, 30, or 300 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) on gestation days 7 through 17, and 7 through 19, respectively. No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (AUC) of up to approximately 24 (rats) and 0.39 (rabbits) times the exposure in humans at the RHD of BIXLENVO. Spontaneous abortion, increased clinical signs [fecal changes, thin body, and cold-to-touch], and decreased body weight were observed at a maternally toxic dose in rabbits (1000 mg/kg/day; approximately 0.90 times higher than human exposure at the RHD).

In a pre/postnatal development study, BIC was administered orally to pregnant rats (up to 300 mg/kg/day) from gestation days 6 to lactation/post-partum day 20. No significant adverse effects were observed in the offspring exposed daily from before birth (in utero) through lactation at maternal and pup exposures (AUC) of approximately 20 and 7.3 times higher, respectively, than human exposures at the RHD.

Lenacapavir

LEN was administered intravenously to pregnant rabbits (up to 20 mg/kg/day on gestation days (GD) 7 to 19), orally to rats (up to 300 mg/kg/day on GD 6 to 17), and subcutaneously to rats (up to 300 mg/kg on GD 6). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at exposures (AUC) approximately ≥3 times (rats) and 75 times (rabbits) the exposure in humans at the RHD of BIXLENVO.

Risk Summary

Bictegravir

Data from the published literature reports on the presence of BIC in human milk. There are no data on the effects of BIC on the breastfed child. There is no data on the effects of BIC on milk production.

Lenacapavir

LEN is present in human milk. LEN was detected at very low levels in infants who were breastfed by individuals who became pregnant while receiving LEN via injection (see Data). No adverse effects of LEN in breastfed infants have been observed. It is not known if LEN affects milk production.

Potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1–negative infants; (2) developing viral resistance in HIV-1–positive infants; and (3) adverse reactions in a breastfed infant similar to those seen in adults.

Data

Human data

Lenacapavir

The median LEN concentration in human breast milk to maternal plasma ratio in participants (n=8) who received LEN via injection was 0.63 (range: 0.29 to 1.90). The median infant-to-mother plasma ratio for LEN in infants (n=10) who were breastfed by individuals receiving LEN via injection from 0 to less than 13 weeks after delivery was 0.06 (range: 0.01 to 0.20). Data are not available in breastfeeding individuals receiving LEN orally.

The safety and effectiveness of BIXLENVO have not been established in patients less than 18 years of age.

Clinical studies included 159 (21%) participants 65 years and over who received BIXLENVO. Of the total number of BIXLENVO-treated patients in these studies, 148 (93%) were ages 65 to 74, and 11 (7%) were 75 to 84 years of age. No overall differences in safety or effectiveness were observed between participants 65 years of age and older and adult participants less than 65 years of age and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment of BIXLENVO is recommended in patients with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). BIXLENVO has not been studied in patients with end-stage renal disease (ESRD; estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)].

No dosage adjustment of BIXLENVO is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. BIXLENVO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

BIXLENVO does not have activity against hepatitis B virus (HBV). Patients with HBV coinfection who switch to BIXLENVO from an antiretroviral regimen with activity against HBV, and patients on BIXLENVO who are newly diagnosed with HBV coinfection, should be closely monitored and specific anti-HBV therapy should be considered, as clinically appropriate.

BIXLENVO is a fixed dose combination of the antiretroviral drugs bictegravir (BIC) and lenacapavir (LEN) [see Microbiology (12.4)].

Cardiac Electrophysiology

BIC at exposures of 3-times those at the recommended dose of BIXLENVO did not affect the QT/QTc interval and did not prolong the PR interval. LEN at exposures of 10.8-times those at the recommended dose of BIXLENVO did not prolong the QTcF interval to any clinically relevant extent.

Effects on Serum Creatinine

Mean change from baseline in serum creatinine in healthy participants who received BIC 75 mg once daily with food for 14 days was 0.1 mg per dL on Days 7 and 14 compared to placebo. BIC did not have a significant effect on the estimated creatinine clearance or on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol).

Exposure-Response

In a Phase 2 trial evaluating lenacapavir over a dose range of 0.5-1 times the recommended dose of lenacapavir (in combination with the approved dose of bictegravir), no exposure-response relationship for efficacy was identified for lenacapavir.

The pharmacokinetic (PK) properties of BIXLENVO are provided in Table 5. The PK parameter estimates of the components of BIXLENVO following administration of the recommended BIXLENVO treatment regimen with or without food in adults with HIV-1 are provided in Table 6.

Specific Populations

Patients with Renal Impairment

Bictegravir: No clinically relevant differences in the pharmacokinetics of BIC were observed between participants with severe renal impairment (creatinine clearance of 15 to less than 30 mL/min, estimated by Cockcroft-Gault method) and participants with normal renal function. In a study of virologically-suppressed participants with ESRD (estimated creatinine clearance less than 15 mL/min, by Cockcroft-Gault method) receiving chronic hemodialysis who were receiving a BIC-containing regimen, median BIC C_trough values were lower compared to participants with normal renal function. Despite significantly lower BIC C_trough values in this population, virologic suppression was maintained in this study.

Lenacapavir: There were no clinically significant differences in the pharmacokinetics of LEN in participants with severe renal impairment. The effect of end-stage renal disease (including dialysis) on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Clinically relevant changes in the pharmacokinetics of BIC and LEN were not observed in participants with moderate (Child-Pugh Class B) hepatic impairment [see Use in Specific Populations (8.7)].

Hepatitis B and/or Hepatitis C Virus Coinfection

The pharmacokinetics of BIC and LEN have not been evaluated in participants with hepatitis B and/or C virus.

Age, Race, Gender and Body Weight

There were no clinically significant differences in the pharmacokinetics of BIC and LEN based on age (18 to 84), sex, ethnicity (Hispanic or non-Hispanic), race (White, Black, Asian, or Other), or body weight (44 kg to 164 kg).

Pregnancy

Plasma exposures (C_trough and AUC_tau) of orally administered BIC were lower during pregnancy as compared to postpartum. The exposure changes during pregnancy are not considered clinically significant in virologically suppressed pregnant individuals [see Drug Interactions (7.4)]. Pregnancy was not shown to have a clinically significant impact on LEN exposure in individuals receiving LEN via injection. Pharmacokinetic data for oral LEN in pregnant individuals are limited.

Drug Interaction Studies

As BIXLENVO is a complete regimen for the treatment of HIV-1 infection, comprehensive information regarding potential drug-drug interactions with other HIV-1 antiretroviral agents is not provided.

Drug interaction studies were conducted with the components of BIXLENVO (BIC or LEN). Table 7 summarizes the pharmacokinetic effects of other drugs on BIC and Table 8 summarizes the pharmacokinetic effect of BIC on other drugs. Table 9 summarizes the pharmacokinetic effects of other drugs on LEN and Table 10 summarizes the pharmacokinetic effect of LEN on other drugs.

Based on drug interaction studies conducted with bictegravir, no clinically significant drug interactions have been observed or are expected with: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

Based on drug interaction studies conducted with lenacapavir, no clinically significant drug interactions have been observed or are expected with: atorvastatin, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: BIC is a substrate of CYP3A and is not an inhibitor of CYP (including CYP3A). LEN is a substrate and moderate inhibitor of CYP3A. LEN is not a substrate, inducer, or inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. LEN is not an inducer of CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: BIC and LEN are substrates of, and not inhibitors of, UGT1A1.

Transporter Systems: BIC is an inhibitor of organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporter (MATE) 1. BIC is not an inhibitor of hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, or renal transporters OAT1 and OAT3. LEN is a substrate and inhibitor of P-gp. LEN is also an inhibitor of BCRP. LEN is not an inhibitor of organic anion transporter 1 (OAT1), OAT3, OCT1, OCT2, MATE1, or MATE 2-K. LEN is not a substrate of BCRP, OATP1B1, or OATP1B3.

Mechanism of Action

Bictegravir: BIC inhibits the strand-transfer activity of HIV-1 integrase (integrase strand-transfer inhibitor; INSTI) with a 50% inhibitory concentration (IC₅₀) value of 7.5 nM. Inhibition of integrase prevents the integration of linear HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the virus.

Lenacapavir: LEN is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (K_D) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

Antiviral Activity in Cell Culture

The combination of BIC and LEN was not antagonistic with respect to antiviral activity in cell culture.

Bictegravir: The antiviral activity of BIC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4⁺ T-lymphocytes. In MT-4 cells (human lymphoblastoid T-cell line) acutely infected with HIV-1 IIIB, the mean 50% effective concentration (EC₅₀) value was 2.4±0.4 nM, and the protein-adjusted EC₉₅ value was 361 nM (0.162 micrograms per mL).

BIC displayed antiviral activity in activated PBMCs against clinical isolates of HIV-1 representing groups M, N, and O, including subtypes A, B, C, D, E, F, and G, with a median EC₅₀ value of 0.55 nM (range <0.05 to 1.71 nM). The EC₅₀ value against a single HIV-2 isolate was 1.1 nM.

Lenacapavir: LEN has antiviral activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2). The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4⁺ T-lymphocytes with EC₅₀ values ranging from 30 to 190 pM.

Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, F1, G, H with EC₅₀ values ranging from 20 and 160 pM. The median EC₅₀ value for subtype B isolates (n=8) was 40 pM. Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.

Resistance

In Cell Culture

Bictegravir: HIV-1 isolates with reduced susceptibility to BIC have been selected in cell culture. In one selection with BIC, a virus pool emerged expressing amino acid substitutions M50I and R263K in the HIV-1 integrase. M50I, R263K, and M50I+R263K substitutions, when introduced into a wild-type virus by site-directed mutagenesis, conferred 1.3-, 2.2-, and 2.9-fold reduced susceptibility to BIC, respectively. In a second selection, emergence of amino acid substitutions T66I and S153F was detected, and 0.4-, 1.9-, and 0.5-fold reductions in BIC susceptibility were observed with T66I, S153F, and T66I+S153F, respectively. In addition, S24G and E157K substitutions emerged during the selection process.

Lenacapavir: HIV-1 variants with reduced susceptibility to LEN have been selected in cell culture. Resistance selections with LEN identified 7 substitutions in capsid: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination that conferred 4- to >3,226-fold reduced phenotypic susceptibility to LEN relative to wild-type (WT) virus. The M66I substitution alone or in combination conferred >3,226-fold decreased susceptibility to LEN in a single-cycle infectivity assay; substitutions Q67H and T107N, conferred 4- to 6.3-fold decreased susceptibility; K70N, N74D and Q67H/N74S conferred 22- to 32-fold decreased susceptibility; and L56I conferred 239-fold decreased susceptibility.

In Clinical Studies

In ARTISTRY-1, two of 371 (0.5%) participants in the BIXLENVO group met the criteria for resistance testing (HIV-1 RNA ≥ 200 copies/mL at confirmed virologic failure or last visit on study drugs) through Week 48. Resistance analyses showed that one of these participants had no detectable resistance in either capsid or integrase. The other participant had no detectable resistance in capsid and had transient emergence of a Q148R substitution in integrase at low level (13% mutant) at Week 24 that conferred a 1.2-fold reduction in bictegravir susceptibility; this substitution was not detected at Week 48.

In ARTISTRY-2, two of 383 (0.5%) participants in the BIXLENVO group met the criteria for resistance testing (HIV-1 RNA ≥ 200 copies/mL at confirmed virologic failure or last visit on study drugs) through Week 48. In one participant, no lenacapavir resistance substitutions were detected in capsid and a R263K substitution in integrase was detected that had 2-fold reduction in susceptibility to bictegravir in comparison to wild-type. The second participant had no detectable emergence of resistance in capsid or integrase.

Cross-Resistance

Bictegravir: Cross-resistance has been observed among INSTIs. The susceptibility of BIC was tested against 64 clinical isolates expressing known INSTI resistance-associated substitutions listed by IAS-USA (20 with single substitutions and 44 with 2 or more substitutions). Isolates with a single INSTI-resistance substitution including E92Q, T97A, Y143C/R, Q148R, and N155H showed less than 2-fold reduced susceptibility to BIC. All isolates (n=14) with more than 2.5-fold reduced susceptibility to BIC (above the biological cutoff for BIC) contained G140A/C/S and Q148H/R/K substitutions; the majority (64.3%, 9/14) had a complex INSTI resistance pattern with an additional INSTI-resistance substitution L74M, T97A, or E138A/K. Of those evaluated isolates containing G140A/C/S and Q148H/R/K substitutions in the absence of additional INSTI-resistance substitutions, 38.5% (5/13) showed more than 2.5-fold reduction. In addition, site-directed mutant viruses with G118R (dolutegravir and raltegravir treatment-emergent substitution) and G118R+T97A had 3.4- and 2.8-fold reduced susceptibility to BIC, respectively. BIC showed no cross-resistance in mutants with resistance to LEN or other ARV classes (NNRTIs, NRTIs, PIs).

Lenacapavir: The antiviral activity in cell culture of LEN was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the four main classes of anti-retroviral agents (INSTI, NNRTI, NRTI, and PI; n=58), as well as to viruses resistant to the gp120-directed attachment inhibitor fostemsavir, the CD4⁺-directed post-attachment inhibitor ibalizumab, the CCR5 co-receptor antagonist maraviroc, and the gp41 fusion inhibitor enfuvirtide (n=42). These data indicated that LEN remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of LEN in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms and substitutions at protease cleavage sites.

Carcinogenesis

Bictegravir: BIC was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females. BIC was not carcinogenic in a 2-year rat study at doses up to 300 mg/kg/day, which resulted in exposures of approximately 21 times the exposure in humans at the recommended dose of BIXLENVO.

Lenacapavir: LEN was not carcinogenic in a 6-month rasH2 transgenic mouse study in males or females at doses of up to 300 mg/kg/dose once every 13 weeks.

A 104-week carcinogenicity study was conducted in male and female rats at lenacapavir doses of 0, 102, 309, or 927 mg/kg by subcutaneous injection once every 13 weeks. A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg). This dose in rats resulted in an exposure approximately 19 times the human exposure at the RHD of BIXLENVO, based on AUC. These tumors are considered to be a secondary response to chronic tissue irritation and granulomatous inflammation, due to the depot effect of lenacapavir following subcutaneous injection. No findings of clinical relevance to orally administered BIXLENVO were observed in this study.

Mutagenesis

Bictegravir: BIC was not genotoxic in the bacterial reverse mutation assay (Ames test), chromosome aberration test in human lymphocytes or rat micronucleus assay.

Lenacapavir: LEN was not mutagenic in a battery of in vitro and in vivo genotoxicity assays, including the bacterial reverse mutation assay (Ames test), chromosome aberration test in human peripheral blood lymphocytes, and in in vivo rat micronucleus assay.

Impairment of Fertility

Bictegravir: BIC did not affect fertility, reproductive performance or embryonic viability in male and female rats at 24 times the exposures (AUC) than in humans at the recommended dose of BIXLENVO.

Lenacapavir: There were no effects on fertility, mating performance or early embryonic development when LEN was administered to rats at systemic exposures (AUC) ≥3 times the exposure in humans at the RHD of BIXLENVO.