Drugs

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)- Organization: Gilead Sciences, Inc. Phase of Development: Bictegravir is a component of the fixed-dose combination product bictegravir/emtricitabine/tenofovir alafenamide (brand name: Biktarvy), which received marketing approval for the treatment of HIV infection by the U.S. Food and Drug Administration in February 2018.

It is unclear whether stand-alone bictegravir will be developed, although a Phase II trial of an investigational NRTI (GS-9131) will evaluate GS-9131 plus stand-alone bictegravir and boosted darunavir as an optimized ART regimen.

Chemical Image:

(Click to enlarge)
bictegravir

bictegravir

Molecular Weight: 449.3832

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Gilead Sciences press release,3 and HIV Treatment Bulletin article4)

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).5,6 The BIC-based, fixed-dose combination (FDC) tablet Biktarvy has been approved by the FDA for the treatment of HIV infection.3

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 treatment-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: The approval of Biktarvy was based on data from four Phase III trials: GS-US-380-1489 (NCT02607930) and GS-US-380-1490 (NCT02607956) in treatment-naive adults, as well as GS-US-380-1844 (NCT02603120) and GS-US-380-1878 (NCT02603107) in adults who are virologically suppressed on ART. In all four studies, no participants who received Biktarvy developed treatment-emergent resistance through Week 48. Pre-existing resistance mutations at baseline in treatment-naive participants did not affect the efficacy of Biktarvy. In the switch studies, pre-existing mutations at baseline, including FTC/TAF substitutions, did not substantially affect virologic suppression rates among those who switched to BIC/FTC/TAF.3,10,11

Additional information on in vitro and in vivo HIV resistance associated with BIC and Biktarvy is described in the FDA-approved Full Prescribing Information for Biktarvy.12


Select Clinical Trials


Bictegravir single-agent tablet

Study Identifiers: GS-US-442-4148; NCT03472326
Sponsor: Gilead Sciences
Phase: II
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The primary purpose of this study is to evaluate the efficacy of GS-9131 as functional monotherapy in participants who are receiving a failing ART regimen. Secondary objectives include evaluating the efficacy of an optimized ART regimen consisting of GS-9131, BIC, DRV, and ritonavir (RTV).
Study Population: Participants are adults with HIV who are currently receiving a failing ART regimen that contains two NRTIs and a NNRTI. Participants have never received a regimen containing an INSTI or PI. Participants have HIV RNA ≥500 copies/mL at screening.4,13

Bictegravir/emtricitabine/tenofovir alafenamide FDC tablet (Biktarvy)

Biktarvy was approved by the FDA in February 2018. Approval was based on supporting data from the following Phase III trials.3

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 evaluate the safety and efficacy of Biktarvy versus dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF; Descovy) in treatment-naive adults.
Study Population: Participants are treatment-naive adults with HIV. Participants have HIV RNA ≥500 copies/mL at screening.14
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 Biktarvy versus abacavir/dolutegravir/lamivudine (ABC/DTG/3TC; Triumeq) in treatment-naive adults.
Study Population: Participants are treatment-naive adults with HIV. Participants have HIV RNA ≥500 copies/mL at screening.15
Selected Study Results:
Study Identifiers: GS-US-380-1844; NCT02603120
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 efficacy of switching to Biktarvy versus continuing on a regimen consisting of DTG, ABC, and 3TC in adults who are virologically suppressed.
Study Population: Participants are adults with HIV who have been receiving a stable ART regimen consisting of DTG, ABC, and 3TC for at least 3 months prior to screening. Participants have HIV RNA <50 copies/mL at screening, and have had HIV RNA <50 copies/mL for at least 3 months.16
Selected Study Results:
Study Identifiers: GS-US-380-1878; NCT02603107
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 efficacy of switching to Biktarvy versus continuing on a regimen consisting of boosted atazanavir (ATV) or boosted DRV plus either emtricitabine/tenofovir DF (FTC/TDF; Truvada) or abacavir/lamivudine (ABC/3TC; Epzicom) in adults who are virologically suppressed.
Study Population: Participants are adults with HIV who have been receiving a stable ART regimen consisting of RTV-boosted or cobicistat-boosted ATV or DRV plus either Truvada or Epzicom for at least 6 months prior to screening. Participants have had HIV RNA <50 copies/mL for at least 6 months.17
Selected Study Results:
ClinicalTrials.gov lists several other planned studies, ongoing late-stage studies, or post-approval studies that are evaluating the efficacy of Biktarvy. Notably, a Phase IV study (NCT03499483) will evaluate the use of Biktarvy for the prevention of HIV infection in adults without HIV after high-risk sexual contact (non-occupational post exposure prophylaxis).18


Adverse Events


GS-US-380-1490 (NCT02607956):
In this Phase III study, 320 participants received Biktarvy and 325 participants received DTG plus Descovy. Five participants in the Biktarvy group had an adverse event (AE) that resulted in discontinuation of treatment. Among these five Biktarvy participants, three had drug-related AEs that led to discontinuation—chest pain (n = 1); abdominal distension (n = 1); and sleep disorder, dyspepsia, tension headache, depressed mood, and insomnia (n = 1).19

In both groups, the majority of AEs were Grade 1 or 2. The incidence of drug-related AEs was lower with Biktarvy (18%) than with DTG plus Descovy (26%). Some of the most common AEs that occurred during the study with either Biktarvy or DTG plus Descovy were headache (13% vs. 12%), diarrhea (12% vs. 12%), nausea (8% vs. 9%), nasopharyngitis (7% vs. 10%), and fatigue (6% vs. 8%). No discontinuations due to renal AEs and no cases of renal tubulopathy occurred in either arm. Reductions in eGFR were less pronounced with Biktarvy than with DTG plus Descovy. Changes in lipid parameters were similar in both study arms.19

GS-US-380-1489 (NCT02607930):
This was a Phase III study that evaluated Biktarvy in 314 participants and Triumeq in 315 participants. Overall, AEs were mostly mild or moderate in severity. No participants in the Biktarvy arm discontinued treatment because of an AE. Drug-related AEs occurred less frequently with Biktarvy (26%) than with Triumeq (40%). Some of the most common AEs that occurred with the use of either Biktarvy or Triumeq included diarrhea (Biktarvy 13%; Triumeq 13%), headache (Biktarvy 11%; Triumeq 14%), upper respiratory tract infection (Biktarvy 6%; Triumeq 11%), and nasopharyngitis (Biktarvy 7%; Triumeq 9%). Nausea was also common in both groups, but was significantly more common among participants taking Triumeq (23%) than those taking Biktarvy (10%). The incidence of central nervous system and psychiatric AEs was similar between groups. Insomnia occurred in 4% of Biktarvy participants versus 6% of Triumeq participants.20

No discontinuations due to renal AEs and no cases of proximal tubulopathy or Fanconi Syndrome occurred in either arm. Changes in bone mineral density (BMD) and renal markers were similar in both study arms. Changes in lipid parameters were also generally comparable between the Biktarvy and Triumeq groups, but a slight, though statistically significant, difference in the total cholesterol to HDL ratio was seen between groups.20

GS-US-380-1844 (NCT02603120):
In this Phase III study, 282 participants received Biktarvy and 281 participants received Triumeq. Six participants in the Biktarvy group discontinued treatment because of an AE. Among these six Biktarvy participants, five discontinuations were attributed to a drug-related AE: headache (n = 2), abnormal dreams (n = 1), cerebrovascular accident (n = 1), and vomiting (n = 1). The occurrence of cerebrovascular accident was classified as a drug-related serious adverse event (SAE).21

AEs that occurred during the study were mostly mild or moderate. Treatment-related AEs occurred less frequently with Biktarvy (8%) than with Triumeq (16%). A higher percentage of participants in the Triumeq group than in the Biktarvy group experienced drug-related gastrointestinal and neuropsychiatric AEs. Overall, some of the most common AEs were upper respiratory tract infection (Biktarvy 10%; Triumeq 10%), nasopharyngitis (Biktarvy 7%; Triumeq 8%), headache (Bictarvy 7%; Triumeq 7%), diarrhea (Biktarvy 9%; Triumeq 5%), and arthralgia (Biktarvy 7%; Triumeq 4%). BMD changes were comparable between these groups. No participants developed proximal tubulopathy or Fanconi syndrome, and no participants discontinued treatment due to renal AEs. Changes in lipid parameters were similar between these groups.21

GS-US-380-1878 (NCT02603107):
During this Phase III study, 287 participants continued on their baseline boosted PI regimen and 290 participants switched to Biktarvy. The overall incidence of AEs was similar between groups, and AEs were mostly mild or moderate in severity. Headache (mostly mild) was more common in the Biktarvy group (12%) than in the boosted PI group (4%). Two AEs in the Biktarvy group resulted in discontinuation of treatment; one of the two AEs (schizophrenia) was considered to be related to Biktarvy.22

Drug-related AEs were mainly mild or moderate and occurred more frequently in those receiving Biktarvy (19%) than in those receiving a boosted PI (2%). A greater proportion of participants who received Biktarvy experienced certain drug-related side effects than participants who received a boosted PI; these side effects included headaches (Biktarvy 5%; boosted PI 0%), flatulence (Biktarvy 2%; boosted PI 0%), nausea (Biktarvy 2%; boosted PI 0%), and diarrhea (Biktarvy 2%; boosted PI 0%). Two participants in the Biktarvy group and no participants in the boosted PI group had a Grade 3 or 4 drug-related AE. No participants in the Biktarvy group discontinued treatment due to renal AEs, and no participants in either group developed proximal tubulopathy or Fanconi syndrome. Lipid parameters were generally improved after switching to Biktarvy from a boosted PI regimen.22

Additional AEs known to be associated with BIC and Biktarvy are described in the FDA-approved Full Prescribing Information for Biktarvy.12


Drug Interactions


BIC is an in vitro inhibitor of the renal drug transporters OCT2 and MATE1; therefore, when Biktarvy is coadministered with drugs that are OAT2 and MATE1 substrates, the plasma concentration of the coadministered drug may increase. BIC is a substrate of UGT1A1 and CYP3A4, and it does not inhibit or 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.9,12

Specific drug-drug interactions associated with Biktarvy are described in the FDA-approved Full Prescribing Information for Biktarvy.12

 


References


  1. United States National Library of Medicine. ChemIDplus Advanced: bictegravir. https://chem.nlm.nih.gov/chemidplus/rn/1611493-60-7. Accessed December 24, 2018.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed December 24, 2018.
  3. Gilead: Press Release, dated February 7, 2018. U.S. Food and Drug Administration approves Gilead’s Biktarvy® (bictegravir, emtricitabine, tenofovir alafenamide) for treatment of HIV-1 infection. http://www.gilead.com/news/press-releases/2018/2/us-food-and-drug-administration-approves-gileads-biktarvy-bictegravir-emtricitabine-tenofovir-alafenamide-for-treatment-of-hiv1-infection. Accessed December 24, 2018.
  4. Collins S and Clayden P. HIV pipeline 2018: new drugs in development. HIV Treat Bull. 2018;19(1):Suppl: 1-29.
  5. White K, Cihlar T, Miller MD. Potent activity of bictegravir (BIC; GS-9883), a novel unboosted HIV-1 integrase strand transfer inhibitor (INSTI), against patient isolates with INSTI-resistance. American Society for Microbiology (ASM) Microbe; June 16-20, 2016; Boston, MA. http://www.natap.org/2016/HIV/062316_02.htm. Accessed December 24, 2018.
  6. Tsiang M, Kan E, Tsai L, et al. Antiviral activity of GS-9883, a potent next generation HIV-1 integrase strand transfer inhibitor. American Society for Microbiology (ASM) Microbe; June 16-20, 2016; Boston, MA. http://www.natap.org/2016/HIV/062016_04.htm. Accessed December 24, 2018.
  7. Gallant J, Thompson M, Mills T, et al. Novel INSTI GS-9883 10 day monotherapy in HIV-1 infected subjects. American Society for Microbiology (ASM) Microbe; June 16-20, 2016; Boston, MA. http://natap.org/2016/HIV/062016_01.htm. Accessed December 24, 2018.
  8. Zhang H, Custodio JM, Wei X, et al. Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13–16, 2017; Seattle, WA. Abstract 40. http://www.croiconference.org/sessions/clinical-pharmacology-hiv-integrase-strand-transfer-inhibitor-bictegravir. Accessed December 24, 2018.
  9. Joseph M. Custodio. Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13–16, 2017; Seattle, WA. http://www.croiwebcasts.org/console/player/33377?mediaType=slideVideo&. Accessed December 24, 2018.
  10. White K, Kulkarni R, Willkom M, et al. Pooled Week 48 efficacy and baseline resistance: B/F/TAF in treatment-naive patients. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2018; Boston, MA. Poster 532. https://www.croiconference.org/sites/default/files/posters-2018/1430_White_532.pdf. Accessed December 24, 2018.
  11. Andreatta K, Willkom M, Martin R, et al. Resistance analyses of bictegravir/emtricitabine/tenofovir alafenamide switch studies. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2018; Boston, MA. Poster 506. https://www.croiconference.org/sites/default/files/posters-2018/1430_Andreatta_506.pdf. Accessed December 24, 2018.
  12. Gilead Sciences, Inc. Biktarvy: full prescribing information, September 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=664cb8f0-1f65-441b-b0d9-ba3d798be309. Accessed December 24, 2018.
  13. Gilead Sciences. A Phase 2 study to evaluate the efficacy of GS-9131 functional monotherapy in HIV-1-infected adults failing a nucleos(t)Ide reverse transcriptase inhibitor-containing regimen with nucleos(t)Ide reverse transcriptase inhibitor resistant virus, followed by continued treatment with a GS-9131+bictegravir+darunavir+ritonavir regimen. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 8, 2018. NLM Identifier: NCT03472326. https://clinicaltrials.gov/ct2/show/NCT03472326. Accessed December 24, 2018.
  14. Gilead Sciences. A Phase 3, randomized, double-blind study to evaluate the safety and efficacy of GS-9883/emtricitabine/tenofovir alafenamide versus dolutegravir + emtricitabine/tenofovir alafenamide in HIV-1 infected, antiretroviral treatment-naive adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 10, 2015. NLM Identifier: NCT02607956. https://clinicaltrials.gov/ct2/show/NCT02607956. Accessed December 24, 2018.
  15. Gilead Sciences. A Phase 3, randomized, double-blind study to evaluate the safety and efficacy of GS-9883/emtricitabine/tenofovir alafenamide versus abacavir/dolutegravir/lamivudine in HIV-1 infected, antiretroviral treatment-naive adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 10, 2015. NLM Identifier: NCT02607930. https://clinicaltrials.gov/ct2/show/NCT02607930. Accessed December 24, 2018.
  16. Gilead Sciences. A Phase 3, randomized, double-blind study to evaluate the safety and efficacy of switching from a regimen of dolutegravir and ABC/3TC, or a fixed-dose combination (FDC) of ABC/DTG/3TC to a FDC of GS-9883/F/TAF in HIV-1 infected subjects who are virologically suppressed. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 10, 2015. NLM Identifier: NCT02603120. https://clinicaltrials.gov/ct2/show/NCT02603120. Accessed December 24, 2018.
  17. Gilead Sciences. A Phase 3, randomized, open-label study to evaluate the safety and efficacy of switching from regimens consisting of boosted atazanavir or darunavir plus either emtricitabine/tenofovir or abacavir/lamivudine to GS-9883/emtricitabine/tenofovir alafenamide in virologically suppressed HIV-1 infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 10, 2015. NLM Identifier: NCT02603107. https://clinicaltrials.gov/ct2/show/NCT02603107. Accessed December 24, 2018.
  18. Fenway Community Health. A Phase IV open-label evaluation of safety, tolerability, and acceptability of a fixed-dose formulation of bictegravir, emtricitabine/tenofovir alafenamide (B/F/TAF) for non-occupational prophylaxis following potential exposure to HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 9, 2018. NLM Identifier: NCT03499483. https://clinicaltrials.gov/ct2/show/NCT03499483. Accessed December 24, 2018.
  19. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, Phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073-2082. doi:10.1016/S0140-6736(17)32340-1
  20. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, Phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063-2072. doi:10.1016/S0140-6736(17)32299-7
  21. Molina J-M, Ward D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, Phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e357-e365. doi:10.1016/S2352-3018(18)30092-4
  22. Daar ES, DeJesus E, Ruane P, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, Phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e347-e356. doi:10.1016/S2352-3018(18)30091-2


Last Reviewed: December 24, 2018