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Bictegravir

Other Names: BIC, GS-9883, bictegravir sodium
Drug Class: Integrase Inhibitors
Molecular Formula: C21 H18 F3 N3 O5
Registry Number: 1611493-60-7 (CAS)
Chemical Name: 2,5-Methanopyrido(1',2':4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-
Company: Gilead Sciences, Inc.
Phase of Development: Bictegravir, as part of a fixed-dose combination product containing bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), is in Phase III development. An application for marketing approval of BIC/FTC/TAF for the treatment of HIV infection was submitted to the U.S. Food and Drug Administration in June 2017.
Patent Version Content

Pharmacology


Mechanism of Action: HIV-1 integrase strand transfer inhibitor (INSTI). Bictegravir (BIC) inhibits strand transfer of viral DNA into the host genome and thereby prevents HIV-1 replication. It is a novel INSTI that can be dosed once daily without boosting. In vitro, BIC has demonstrated potent antiviral activity against HIV-2 and diverse subtypes of wild-type HIV-1, and it has shown synergistic effects when combined with other ARVs, including tenofovir alafenamide (TAF), emtricitabine (FTC), and darunavir (DRV). Currently, BIC is being developed for HIV treatment as part of a fixed-dose combination (FDC) product containing BIC/FTC/TAF.5,6

 Half-life (T½): In a 10-day dose-ranging study (NCT02275065) of BIC monotherapy (5 mg to 100 mg) administered once daily in adults who were treatment-naive and -experienced (but INSTI-naive and off ART), the median half-life of BIC ranged from 15.9 hours to 20.9 hours.7

Metabolism/Elimination: BIC is cleared primarily through UGT1A1 glucuronidation and CYP3A4 oxidation, with each pathway contributing equally to BIC metabolism. Recovered radioactivity was approximately 60% in feces and 35% in urine after a single dose of radiolabeled BIC 100 mg in healthy participants. Approximately 1% of the BIC dose was excreted in urine as unchanged drug.8,9

Resistance: In vitro resistance studies indicate that BIC has a better profile than raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG). BIC was found to have greater potency than RAL, EVG, and DTG against a panel of patient-derived HIV-1 isolates with high-level INSTI resistance-associated mutations (including combinations of mutations such as E92Q + N155H or G140A/C/S + Q148R/H/K). In addition, BIC was shown to retain full activity against clonal isolates from individuals with INSTI resistance after virologic failure on elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF; Stribild), as well as against virus resistant to approved NRTIs, NNRTIs, and PIs.5,10

BIC has a high barrier to resistance emergence, higher than that of EVG and similar to that of DTG. In cell culture, BIC selected for virus that had low-level resistance and contained the R263K and M50I integrase mutations. Low-level cross-resistance to RAL and DTG and intermediate cross-resistance to EVG was seen among the BIC-selected viruses; these viruses, however, remained susceptible to other ARV drug classes.10

In a 10-day dose-ranging study (NCT02275065) of BIC monotherapy in 20 adults who were treatment-naive and -experienced (but INSTI-naive and off ART), no primary resistance mutations in integrase emerged during the study.7

A Phase II study (NCT02397694) is evaluating BIC versus DTG, each with emtricitabine/tenofovir alafenamide (FTC/TAF; Descovy), in adults who are treatment-naive. No participants in the BIC arm have developed INSTI or NRTI treatment-emergent resistance through 48 weeks of the study. A single participant in the DTG arm, who had poor adherence to study medications, developed a transient T97A integrase mutation.11

Two Phase III trials (NCT02607930 and NCT02607956) are evaluating BIC/FTC/TAF in adults who are treatment-naive. Through 48 weeks of both studies, there has been no resistance to any study medications.12,13


Clinical Trials


Study Identifiers: GS-US-141-1219; NCT02275065
Sponsor: Gilead Sciences
Phase: Ib
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety, pharmacokinetics, and antiviral activity of BIC monotherapy.
Study Population: Participants were adults with HIV who were treatment-naive and -experienced. (Treatment-experienced participants were INSTI-naive and off ART for at least 12 weeks prior to screening.) Participants had HIV RNA ≥10,000 copies/mL but ≤400,000 copies/mL at screening and CD4 counts >200 cells/mm3.
Dosing: Participants received either BIC monotherapy (5, 25, 50, or 100 mg) or placebo administered orally and once daily over 10 days. Participants were then followed for an additional 7 days for safety purposes.7,14,15
Selected Study Results:

 

Study Identifiers: GS-US-141-1475; NCT02397694
Sponsor: Gilead Sciences
Phase: II
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of BIC versus DTG, each administered in combination with Descovy in adults who are treatment-naive.
Study Population: Participants are adults with HIV who are treatment-naive. Participants have HIV RNA ≥1,000 copies/mL and CD4 counts 200 cells/mm3 at screening.
Dosing: Participants will be randomized to 1 of the following 2 groups to receive once-daily oral treatments for 48 weeks:

  • BIC (75 mg) + Descovy (200/25 mg), plus matching placebos
  • DTG (50 mg) + Descovy (200/25 mg), plus matching placebos

Following unblinding of treatments, participants will be given the option to receive a BIC/FTC/TAF single-tablet regimen in an open-label rollover extension.11,16,17

Selected Study Results:

 

Study Identifiers: GS-US-380-1490; NCT02607956
Sponsor: Gilead Sciences
Phase: III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evalute the safety and efficacy of a BIC/FTC/TAF single-tablet regimen versus DTG plus Descovy in adults who are treatment-naive.
Study Population: Participants are adults with HIV who are treatment-naive. Participants have HIV RNA ≥500 copies/mL at screening.
Dosing: Participants will be randomized to 1 of the following 2 groups to receive once-daily oral treatments for at least 96 weeks:

  • BIC/FTC/TAF (50/200/25 mg) single-tablet regimen, plus matching placebos
  • DTG (50 mg) + Descovy (200/25 mg), plus matching placebo

Following unblinding of treatments, participants may have the option to receive BIC/FTC/TAF in an open-label extension phase.13,18

Selected Study Results:

 
Study Identifiers: GS-US-380-1489; NCT02607930
Sponsor: Gilead Sciences
Phase: III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of a BIC/FTC/TAF single-tablet regimen versus abacavir/dolutegravir/lamivudine (ABC/DTG/3TC; Triumeq) in adults who are treatment-naive.
Study Population: Participants are adults with HIV who are treatment-naive. Participants have HIV RNA ≥500 copies/mL at screening.
Dosing: Participants will be randomized to 1 of the following 2 groups to receive once-daily oral treatments for at least 96 weeks:
  • BIC/FTC/TAF (50/200/25 mg) single-tablet regimen, plus matching placebo
  • Triumeq (600/50/300 mg), plus matching placebo

Following unblinding of treatments, participants may have the option to receive BIC/FTC/TAF in an open-label extension phase.12,19

Selected Study Results:

 

In addition, 3 ongoing Phase III switch studies (NCT02603120; NCT02652624; NCT02603107) are evaluating the safety and efficacy of switching to a BIC/FTC/TAF single-tablet regimen versus continuing on a stable ART regimen in participants who are virologically suppressed.20-22 A fourth Phase III switch study (NCT03110380), which is currently recruiting participants, will investigate the efficacy of switching from a regimen of either DTG plus Descovy or DTG plus emtricitabine/tenofovir DF (FTC/TDF; Truvada) to a regimen of BIC/FTC/TAF.23


Adverse Events


In the Phase Ib dose-ranging study (NCT02275065) of BIC monotherapy, no serious adverse events (SAEs), clinically significant laboratory abnormalities, or discontinuations due to an adverse event (AE) were reported. BIC was reported as being well-tolerated by participants at all dose levels.7,24

In the Phase II study (NCT02397694), 98 total participants were randomized, with 65 receiving BIC plus Descovy and 33 receiving DTG plus Descovy. Analysis up to Week 48 showed there were no treatment-related SAEs or deaths. One participant in the BIC group discontinued treatment after Week 24 because of drug-related urticaria. Treatment-emergent AEs were experienced by 85% of participants in the BIC group and 67% of participants in the DTG group. The most common AEs included diarrhea (BIC 12%; DTG 12%) and nausea (BIC 8%; DTG 12%).11

In the Phase III GS-US-380-1490 study (NCT02607956), 645 participants were randomized and treated (BIC/FTC/TAF n = 320; DTG plus Descovy n = 325). Week 48 results found that no participants discontinued treatment because of lack of efficacy. Five participants receiving BIC/FTC/TAF and 1 participant receiving DTG plus Descovy discontinued the study because of an AE. One death occurred in the BIC/FTC/TAF arm and 2 occurred in the DTG plus Descovy arm. The most common AEs included headache (BIC/FTC/TAF 12.5%; DTG plus Descovy 12.3%) and diarrhea (BIC/FTC/TAF 11.6%; DTG plus Descovy 12.0%). Reductions in estimated glomerular filtration rate (eGFR) were less with BIC/FTC/TAF than with DTF plus Descovy. No discontinuations due to renal AEs and no cases of proximal tubulopathy occurred in either arm. Changes in lipid parameters were similar in both study arms.13

In the Phase III GS-US-380-1489 study (NCT02607930), 629 participants were randomized and treated (BIC/FTC/TAF n = 314; Triumeq n = 315). Results from analysis at Week 48 showed that no participants in the BIC/FTC/TAF arm and 4 participants in the Triumeq arm discontinued treatment because of an AE. There were no deaths reported in either study arm. The most common AEs included diarrhea (BIC/FTC/TAF 12.7%; Triumeq 13.0%) and headache (BIC/FTC/TAF 11.5%; Triumeq 13.7%). Nausea was also frequently reported in both groups, but was significantly more common with Triumeq than with BIC/FTC/TAF (BIC/FTC/TAF 10.2%; Triumeq 22.9%). Gastrointestinal, neuropsychiatric, and sleep-related AEs were more common in participants receiving Triumeq than in participants receiving BIC/FTC/TAF. Changes in bone mineral density (BMD), lipid parameters, and renal markers were similar in both study arms. No discontinuations due to renal AEs and no cases of proximal tubulopathy occurred in either arm.12


Drug Interactions


BIC is a substrate of UGT1A1 and CYP3A4, and it does not inhibit nor induce either enzyme. Inhibition of both CYP3A4 and UGT1A1 by a coadministered drug could potentially lead to significant increases in BIC exposure, while potent induction of these enzymes may significantly reduce BIC exposure.9

Voriconazole and darunavir/cobicistat (CYP3A4 inhibitors) have been shown to increase BIC AUC by 61% to 74%. However, atazanavir and atazanavir/cobicistat (potent inhibitors of both CYP3A4 and UGT1A) increased BIC AUC 4 times more than what was seen with voriconazole and darunavir/cobicistat. When BIC was coadministered with rifampin (potent CYP3A4, UGT1A1, and P-gp inducer), BIC AUC was reduced by 75%. Rifabutin (moderate CYP3A4 and P-gp inducer) coadministration resulted in a 38% reduction in BIC AUC.8

BIC is described to have low potential to cause PK alterations in coadministered drugs. When coadministered with midazolam, norgestimate/ethinyl estradiol, or ledipasvir/sofosbuvir, BIC was shown to have no effect on the AUC of the coadministered agent.9 The coadministration of BIC/FTC/TAF with sofosbuvir/velpatasvir/voxilaprevir has also been shown to be acceptable, as no clinically relevant PK changes were observed when these agents were concomitantly administered in a Phase I study.25

When BIC/FTC/TAF was coadministered with metformin, metformin exposure was increased by 39%, but the pharmacodynamics of metformin were not significantly altered. Therefore, when coadministered with BIC/FTC/TAF, dose adjustment of metformin is not required.26

BIC exposure is affected by cation-containing antacids; therefore, administration of BIC and an antacid should be separated by at least 2 hours.9

 


References


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  23. Gilead Sciences. A Phase 3, randomized, double-blind study to evaluate the safety and efficacy of switching from a regimen of dolutegravir and either emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate to a fixed dose combination of bictegravir/ emtricitabine/tenofovir alafenamide in HIV-1 infected subjects who are virologically suppressed. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 7, 2017. NLM Identifier: NCT03110380. Available at: https://clinicaltrials.gov/ct2/show/NCT03110380. Last accessed on August 11, 2017.
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Last Reviewed: August 16, 2017