Summary Basis of Decision for Biktarvy

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Biktarvy is located below.

Recent Activity for Biktarvy

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Biktarvy

Updated: 2024-08-12

The following table describes post-authorization activity for Biktarvy a product which contains the medicinal ingredients bictegravir, emtricitabine, and tenofovir alafenamide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02478579 - Bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 25 mg, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 264207 2022-05-12 Issued NOC 2023-04-14 Submission filed as a Level I – Supplement to update the PM with long-term safety and efficacy data for antiretroviral therapy-naïve adults, based on the final results of the 96-week extension phase of the studies GS-US-380-1489 and GS-US-180-1490; and to update the inner and outer labels. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM, and corresponding changes were made to Patient Medication Information and to the package inserts. An NOC was issued.
Health product advertising incident Not applicable

Date received:

2021-11-19		 A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized products by Gilead Sciences Canada Inc. A Compliance letter was sent to request correction of non-compliance. A satisfactory response was received from the company and follow-up was completed. The material was modified/removed/discontinued.
SNDS # 250704 2021-03-16 Issued NOC 2021-11-02 Submission filed as a Level I – Supplement to add a primary container closure system and to migrate the PM to the 2020 format. As a result of the new primary container closure system, a carton and blister labels were introduced. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage Forms, Strengths, Composition and Packaging; Storage, Stability and Disposal; and Pharmaceutical Information sections of the PM, and corresponding changes were made to Patient Medication Information and to the package inserts. An NOC was issued.
SNDS # 240953 2020-06-23 Issued NOC 2021-05-21 Submission filed as a Level I – Supplement to update the PM with the clinical safety and efficacy data from clinical trials in virologically suppressed HIV-1 infected geriatric patients (≥ 65 years of age) or adult patients with end stage renal disease on chronic hemodialysis. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 237235 2020-03-18 Issued NOC 2021-02-05 Submission filed as a Level I – Supplement to update the PM with long-term safety and efficacy data from two Phase III clinical trials in HIV-1-infected treatment-naïve adult patients, GS-US-380-1489 and GS-US-380-1490. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Clinical Trials sections of the PM, and corresponding changes were made to Patient Medication Information and to the package insert. An NOC was issued.
Health product advertising incident Not applicable

Date received:

2021-01-12		 A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized claims. An explanatory letter was sent.
SNDS # 242750 2020-08-12 Issued NOC 2020-12-30 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Patient Medication Information and to the package inserts. An NOC was issued.
SNDS # 236105 2020-02-13 Issued NOC 2020-04-14 Submission filed as a Level I – Supplement to add a bottle label and package insert for an additional package size to be used as a professional sample only. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 226658 2019-04-08 Issued NOC 2020-03-02 Submission filed as a Level I – Supplement for an expanded indication, and to update the PM with long-term safety and efficacy data from Phase III clinical trials in HIV-1-infected treatment-naïve adult patients. The indication was extended to include HIV-1-infected pediatric patients weighing ≥ 25 kg with no known substitution associated with resistance to the individual components of Biktarvy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 224191 2019-01-29 Issued NOL
2019-05-10		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02478579) market notification Not applicable Date of first sale:
2018-08-08		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 203718 2017-07-26 Issued NOC
2018-07-10		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Biktarvy

Date SBD issued: 2018-10-17

The following information relates to the New Drug Submission for Biktarvy.

Bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 25 mg, tablet, oral

Drug Identification Number (DIN):

  • 02478579

Gilead Sciences Canada Inc.

New Drug Submission Control Number: 203718

 

On July 10, 2018, Health Canada issued a Notice of Compliance to Gilead Sciences Canada Inc. for the drug product Biktarvy.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Biktarvy is favourable as a complete regimen for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults with no known substitution associated with resistance to the individual components of Biktarvy.

 

1 What was approved?

 

Biktarvy, a fixed-combination drug product, is an antiretroviral agent. It was authorized as a complete regimen for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults with no known substitution associated with resistance to the individual components of Biktarvy. Biktarvy contains a new integrase strand transfer inhibitor, bictegravir, and two previously approved nucleoside/nucleotide reverse transcriptase inhibitors, emtricitabine and tenofovir alafenamide.

The safety and efficacy of Biktarvy in pediatric patients younger than 18 years of age have not been established. Clinical studies of Biktarvy did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from patients younger than 65 years of age.

Biktarvy is contraindicated in patients who are hypersensitive to bictegravir, emtricitabine, tenofovir alafenamide or to any ingredient in the formulation or component of the container. In addition, co-administration of Biktarvy is contraindicated with:

  • dofetilide (not marketed in Canada), due to the potential for increased dofetilide plasma concentrations and associated serious and/or life-threatening events;
  • rifampin, due to decreased bictegravir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to Biktarvy;
  • St. John's wort, due to the effect of St. John's wort on the bictegravir component of Biktarvy. This may result in loss of therapeutic effect and development of resistance.

Biktarvy was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) is presented as a tablet. Each tablet contains 50 mg of bictegravir (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of tenofovir alafenamide hemifumarate). In addition to the medicinal ingredients, the tablets contain croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Biktarvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Biktarvy approved?

 

Health Canada considers that the benefit-risk profile of Biktarvy is favourable as a complete regimen for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults with no known substitution associated with resistance to the individual components of Biktarvy.

Human immunodeficiency virus-1 (HIV-1) infection is a serious and life-threatening disease of major public health interest, with approximately 37 million HIV-infected individuals worldwide.

The current standard of care for HIV-1 infected patients is combination antiretroviral therapy intended to suppress viral replication to below detectable limits, allow CD4 cell counts to increase, and stop disease progression. For antiretroviral therapy-naïve HIV-infected patients, initial therapy generally consists of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) combined with a third active drug such as an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (pharmacologically boosted with ritonavir or cobicistat). With extensive use of antiretroviral drugs in HIV-infected patients, adaptive viral substitutions have been observed more commonly, and resistance-associated substitutions can be seen in many antiretroviral therapy-naïve patients. Therefore, HIV drug-resistance testing has become a routine practice before initiation of the HIV treatment to avoid treatment failure. Virologically suppressed HIV-infected patients (on a stable, effective treatment regimen) may switch to another combination antiretroviral therapy regimen from their current regimen due to safety or tolerability concerns or for regimen simplification. All these patient populations may benefit from once-daily fixed-dose combination regimens as these have been shown to provide increased adherence and improved clinical and virologic outcomes.

Biktarvy is a fixed-dose combination of bictegravir, emtricitabine and tenofovir alafenamide. Bictegravir is a new integrase strand transfer inhibitor (INSTI). Emtricitabine and tenofovir alafenamide are NRTIs and are found in previously authorized drug products. The recommended dosage of Biktarvy is a single tablet taken orally once daily with or without food.

The primary efficacy and safety evaluation of Biktarvy was based on interim 48-week data derived from three active-controlled, double-blind, non-inferiority Phase III clinical studies and one open-label study. Two of the clinical studies were conducted in antiretroviral treatment-naïve HIV-1 infected adult patients, and the other two in virologically suppressed HIV-1 infected adult patients.

In the studies with antiretroviral treatment-naïve HIV-1 infected adult patients, the primary efficacy endpoint was the proportion of patients with plasma HIV-1 ribonucleic acid (RNA) level below 50 copies/mL at Week 48 (as defined by the United States Food and Drug Administration [US FDA] snapshot algorithm) for the intent-to-treat exposed population as compared to an active control. The primary efficacy endpoint in the studies with virologically suppressed HIV-1 infected adult patients was the evaluation of the proportion of patients with HIV-1 RNA level greater than or equal to 50 copies/mL in the treatment group at Week 48 (in accordance with the snapshot algorithm) as compared to an active control. Biktarvy was demonstrated to be non-inferior to the active control groups in all four studies. Treatment failure rates were low. In all four studies, none of the HIV-1 infected patients who received Biktarvy had treatment emergent genotypic or phenotypic resistance to any of the drug components in the resistance analysis population.

Biktarvy is a well-tolerated regimen. The most common side effects are diarrhea, headache, nausea, fatigue, dizziness and abnormal dreams. Death is rare and none of the death incidents in the clinical trials have been associated with study drugs. Biktarvy demonstrated favourable bone and renal safety profiles during the 48-week study period. However, the long-term bone and renal safety are not known. Due to lack of relevant safety data, Biktarvy is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). Also, it is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL/min).

There is a potential risk of severe acute exacerbation of hepatitis B virus (HBV) infection in patients who are co-infected with HIV-1 and HBV and have discontinued Biktarvy. This risk has been specifically highlighted in a Serious Warnings and Precautions box in the Biktarvy Product Monograph, including recommendations for appropriate monitoring after discontinuation of Biktarvy in patients co-infected with HIV-1 and HBV.

There exists a potential risk that some HIV-1 strains may be resistant to the individual components of Biktarvy. As specified in the authorized indication, the target patient population encompasses HIV-1 infected adults with no known substitution associated with resistance to the individual components of Biktarvy. Therefore, a pre-treatment resistance evaluation is necessary to ensure there is no present or past evidence of viral resistance to the INSTI class, emtricitabine or tenofovir alafenamide.

Established or potential drug-drug interactions with use of Biktarvy have been identified and appropriate recommendations for dose adjustments of the co-administered drug, avoidance of co-administration, or contraindications have been included in the Biktarvy Product Monograph.

A Risk Management Plan (RMP) for Biktarvy was submitted by Gilead Sciences Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Biktarvy Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Biktarvy was accepted.

Based on the data submitted, Health Canada considers that the anticipated benefits of Biktarvy outweigh the potential risks in the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Biktarvy Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Biktarvy?

 

Submission Milestones: Biktarvy

Submission Milestone Date
Submission filed: 2017-07-26
Screening  
Screening Acceptance Letter issued: 2017-09-14
Review  
Biopharmaceutics Evaluation complete: 2018-07-05
Quality Evaluation complete: 2018-07-09
Clinical Evaluation complete: 2018-07-10
Review of Risk Management Plan complete: 2018-02-21
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-07-09
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2018-07-10

 

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Biktarvy?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Biktarvy is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Biktarvy is a fixed-dose combination drug product and a single-tablet, once-daily regimen of the antiviral drugs bictegravir, emtricitabine and tenofovir alafenamide.

Bictegravir (as bictegravir sodium) is a new active substance in Canada. Bictegravir is an integrase strand transfer inhibitor (INSTI) that binds to the integrase active site and blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the human immunodeficiency virus (HIV) replication cycle. Bictegravir has activity that is specific to HIV-1 and HIV-2.

The other two active substances, emtricitabine and tenofovir alafenamide (as tenofovir alafenamide hemifumarate) are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). They are found in previously authorized drug products. Both emtricitabine and tenofovir alafenamide exert activities that are specific to HIV-1 and HIV-2, and hepatitis B virus.

The pharmacokinetics of bictegravir is dose proportional across the dose range of 25 mg to 100 mg.

In the clinical trials with Biktarvy (described in the Clinical Efficacy section), the mean trough concentration (Ctau) of bictegravir (percentage coefficient of variation [% CV]) was found to be much higher than the protein-adjusted 95% effective concentration against wild type HIV-1 virus. Exposures of emtricitabine and tenofovir alafenamide were found to be consistent with historical data for these approved drugs in HIV-infected individuals.

Bictegravir is a substrate of cytochrome P450 (CYP) 3A (CYP3A) and uridine-5'-diphosphate glucuronosyltransferase (UGT) 1A1 (UGT1A1). Co-administration of bictegravir and drugs that potently induce both CYP3A and UGT1A1 may significantly decrease plasma concentrations of bictegravir, which may result in loss of therapeutic effect of Biktarvy and development of resistance. Co-administration of bictegravir with drugs that potently inhibit both CYP3A and UGT1A1 may significantly increase plasma concentrations of bictegravir. Established or potential drug-drug interactions for Biktarvy and relevant contraindications are included in the Biktarvy Product Monograph.

The clinical pharmacology data support the use of Biktarvy for the recommended indication.

For further details, please refer to the Biktarvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Biktarvy was evaluated in antiretroviral treatment-naïve HIV-1 infected patients, as well as in virologically suppressed HIV-1 infected patients who switched to Biktarvy.

Clinical trials in antiretroviral treatment-naïve HIV-1 infected patients (Studies 1489 and 1490)

Studies 1489 and 1490 were randomized, double-blind, active-controlled, non-inferiority Phase III trials conducted in previously untreated HIV-1 infected adult patients. In Study 1489, patients randomized in a 1:1 ratio received Biktarvy (number of patients, [n] = 314) or abacavir/dolutegravir/lamivudine (600/50/300 mg) (n = 315) once daily. In Study 1490, patients randomized in a 1:1 ratio received Biktarvy (n = 320) or dolutegravir + emtricitabine/tenofovir alafenamide (50 + 200/25 mg) (n = 325) once daily.

In both studies, patients were stratified by baseline HIV-1 ribonucleic acid (RNA) levels (below or equal to 100,000 copies/mL, greater than 100,000 copies/mL to below or equal to 400,000 copies/mL, or greater than 400,000 copies/mL), by CD4 cell count (below 50 cells/µL, 50 to 199 cells/µL, or greater than or equal to 200 cells/µL), and by region (United States or countries other than the United States).

In both studies, the primary efficacy endpoint was the proportion of participants with plasma HIV-1 RNA levels below 50 copies/mL at Week 48 (as defined by the United States Food and Drug Administration [US FDA] snapshot algorithm), with a prespecified non-inferiority margin of -12%. The snapshot algorithm defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

In Study 1489, an HIV-1 RNA level below 50 copies/mL was achieved in 92.4% (290/314) of patients in the Biktarvy group and 93.0% (293/315) of patients in the abacavir/dolutegravir/lamivudine group (treatment difference of -0.6%, 95% confidence interval [CI]: -4.8% to 3.6%). In Study 1490, 89.4% (286/320) of patients in the Biktarvy group had HIV-1 RNA levels below 50 copies/mL as compared to 92.9% (302/325) of patients treated with dolutegravir + emtricitabine/tenofovir alafenamide (treatment difference of -3.5%, 95% CI: -7.9% to 1.0%). Since the lower bound of the two-sided 95% CI of the difference between treatment groups was greater than the prespecified non-inferiority margin of -12%, Biktarvy was determined to be non-inferior in achieving HIV-1 RNA levels below 50 copies/mL at Week 48 when compared to abacavir/dolutegravir/lamivudine and dolutegravir + emtricitabine/tenofovir alafenamide, respectively. None of the patients developed treatment-emergent resistance to any study drug. In both studies, the CD4 cell count and CD4 cell percentage increased and were comparable between the two treatment groups during study period. Treatment outcomes were similar among treatment groups, across subgroups by age, sex, race, baseline viral load, and baseline CD4 cell count.

Clinical trials in virologically suppressed HIV-1 infected patients who switched to Biktarvy (Study 1844 and Study 1878)

Study 1844 and Study 1878 were active-controlled, non-inferiority trials conducted in virologically suppressed (i.e., with HIV-1 RNA levels below 50 copies/mL) HIV-1 positive adult patients who had been on a stable, effective antiretroviral treatment regimen for at least 3 months (Study 1844) or 6 months (Study 1878) before one of the two randomized groups switched to Biktarvy. The active control group for the double-blind Study 1844 was comprised of patients on abacavir/dolutegravir/lamivudine regimen. In the open-label Study 1878, the active control group included patients on a regimen containing atazanavir (given with cobicistat or ritonavir) or darunavir (given with cobicistat or ritonavir) plus either emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine (hereafter referred to as atazanavir- or darunavir-based regimen).

In both studies, the primary efficacy endpoint was the evaluation of the proportion of patients with HIV-1 RNA levels greater than or equal to 50 copies/mL at Week 48 (using the US FDA snapshot algorithm).

In Study 1844, at Week 48, 1.1% (3/282) of patients in the Biktarvy treatment group had HIV-1 RNA levels greater than or equal to 50 copies/mL versus 0.4% (1/281) of patients in the active control group (treatment difference of 0.7%, 95% CI: -1.0% to 2.8%). In Study 1878, the proportion of patients with HIV-1 RNA greater than or equal to 50 copies/mL was 1.7% in both the Biktarvy-treated group (5/290) and the active control group (5/287) (treatment difference of 0.0%, 95% CI: -2.5% to 2.5%). For both studies, the upper bound of the two-sided 95% CI of the difference between treatment groups was lower than the prespecified non-inferiority margin of 4%. Thus, in both studies, switching to Biktarvy was shown to be non-inferior to remaining on the respective baseline antiretroviral regimen (abacavir/dolutegravir/lamivudine or an atazanavir- or darunavir-based regimen) for the primary efficacy endpoint of the proportion of patients with HIV-1 RNA greater than or equal to 50 copies/mL at Week 48.

Switching to Biktarvy was also shown to be non-inferior with respect to the percentage of patients who maintained HIV-1 RNA levels below 50 copies/mL. The CD4 cell count and CD4 cell percentage were maintained in each treatment group.

Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region.

Indication

The New Drug Submission for Biktarvy was filed by the sponsor with the following proposed indication:

  • Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults.

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) is indicated as a complete regimen for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults with no known substitution associated with resistance to the individual components of Biktarvy.

For more information, refer to the Biktarvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Treatment-Naïve Adults: The primary safety assessment of Biktarvy was based on Week 48 pooled data from 1,274 patients in two randomized, double-blind, active-controlled trials conducted in antiretroviral treatment-naïve HIV-1 infected adult patients (Study 1489 and Study 1490, described in the Clinical Efficacy section). A total of 634 patients received one tablet of Biktarvy once daily.

Biktarvy and the comparators were well tolerated through a median of over 48 weeks of exposure to study drugs.

In Study 1489, adverse drug reactions were reported in 26.1% (number of patients [n] = 82) of patients in the Biktarvy group and 40.3% (n = 127) of patients in the abacavir/dolutegravir/lamivudine group. A higher incidence of gastrointestinal disorders was observed in the comparator group, i.e., 14% in the Biktarvy group versus 27% in the abacavir/dolutegravir/lamivudine group. Adverse drug reactions that occurred with an incidence of ≥2% were nausea, diarrhea, headache, fatigue, abnormal dreams, dizziness and insomnia.

In Study 1490, adverse drug reactions were reported in 17.8% (n = 57) of patients in the Biktarvy group and 25.5% (n = 83) of patients in the group treated with dolutegravir + emtricitabine/tenofovir alafenamide. Adverse drug reactions with incidence of ≥2% were similar to those reported in Study 1489 except for the fewer neurological adverse drug reactions reported in Study 1490.

No study drug-related deaths were reported in either study. The incidence of serious adverse events considered related to Biktarvy was low in Study 1489 (0.3%, n = 1) (including generalized tonic-clonic seizure [Grade 3]) and in Study 1490 (0.6%, n = 2) (including chest pain [Grade 3] and suicide attempt [Grade 4]). No discontinuations due to adverse events were reported in the Biktarvy group in Study 1489. In Study 1490, five discontinuations due to adverse events were reported in the Biktarvy group and were due to cardiac disorders (in 1 patient), paranoia (in 1 patient), chest pain (a serious adverse event in 1 patient) abdominal distension (in 1 patient), and sleep disorder, dyspepsia, tension headache, depressed mood, and insomnia (in 1 patient).

Hepatic adverse events were reported with similar low incidences in each study and most of these events were not considered related to study drugs. None of the hepatic adverse events resulted in discontinuation of study drugs. There were no clinically relevant changes from baseline in median values of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase at Week 48 in any treatment group. Total bilirubin abnormalities were reported in a higher percentage of patients in the Biktarvy group (12.4% in Study 1489 and 10.9% in Study 1490) than in the comparator group in both studies. Most bilirubin abnormalities were of Grade 1 or 2. In Study 1489, Grade 3 total bilirubin abnormalities occurred in 1 patient in each treatment group, although their transaminases and alkaline phosphatase results were normal throughout the study. None of the patients in either study had Grade 4 bilirubin abnormalities. In addition, none of the patients in either study met Hy's Law criteria.

In Study 1489, the mean percentage changes from baseline in bone mineral density for the hip or spine were similar in Biktarvy and the comparator (abacavir/dolutegravir/lamivudine) group through Week 48.

Bictegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Serum creatinine showed an increase at Week 4 and remained stable through Week 48 in both treatment groups in both studies. Consistent with the results for serum creatinine, decreases from baseline in median estimated glomerular filtration rate (eGFR) values according to the Cockcroft-Gault formula (eGFRCG) were observed by Week 4 for each treatment group and remained stable through Week 48 in both studies.

Patients with HIV and hepatitis B virus (HBV) co-infection were excluded from Study 1489. There were no patients with HIV and hepatitis C virus (HCV) co-infection at baseline in the Biktarvy group of Study 1489.

In Study 1490, at baseline, in the Biktarvy group, there were 2.5% of patients with HIV and HBV co-infection and 1.6% of patients were HIV/HCV co-infected.

In either study, no incident HBV infection was found in the Biktarvy group. There was one confirmed incident HBV infection in the comparator group in Study 1489.

In Study 1489, no incident HCV infection was detected in the Biktarvy group and three patients had potential incident HCV infection in the control group. In Study 1490, six patients had potential incident HCV infection (three in each group). Five of these six patients had reported adverse event of acute HCV infection. None of the adverse events of acute HCV infection were serious or resulted in discontinuation of study drugs.

Virologically Suppressed Adults: The safety of Biktarvy in virologically suppressed adults was based on Week 48 data from 282 subjects in a randomized, double-blind, active-controlled trial (Trial 1844, described in the Clinical Efficacy section) and Week 48 data from 290 subjects in an open-label, active-controlled trial (Trial 1878, described in the Clinical Efficacy section). Overall, the safety profile in virologically suppressed adult subjects in Trials 1844 and 1878 was similar to that in subjects with no antiretroviral treatment history.

Appropriate warnings and precautions are in place in the approved Biktarvy Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box is included to highlight that severe acute exacerbations of HBV infection have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of Biktarvy.

For more information, refer to the Biktarvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical studies provided in this submission are pertinent to bictegravir, a new active substance. The other two medicinal ingredients in Biktarvy, emtricitabine and tenofovir alafenamide underwent evaluation in previous submissions.

The pharmacology studies provided mechanistic support for the development of bictegravir as an agent for the treatment of HIV-1 infection, characterized the in vitro resistance profile of bictegravir, and evaluated the potential of bictegravir for drug-drug interactions.

The general toxicity of bictegravir was evaluated in mice and rats for up to 26 weeks, and in monkeys for up to 39 weeks. Due to low severity and/or relatively high margins of exposure with respect to the recommended therapeutic dose of bictegravir, there were no adverse effects that would be considered of human relevance.

Bictegravir had no effects on reproduction and development in the rat studies at exposures that were approximately 36 times the human exposure from the recommended therapeutic dose. In rabbits, abortions and decreased fetal body weight were noted at maternally toxic exposures that were approximately 1.4 times the human exposure at the recommended therapeutic dose. This information is presented in the Biktarvy Product Monograph. Biktarvy should not be used during pregnancy unless the potential benefits outweigh the potential risks to the fetus.

Bictegravir was shown to be non-mutagenic in vitro and non-clastogenic in vitro and in vivo. The carcinogenicity studies with bictegravir in mice and rats did not report any neoplastic findings.

Overall, the non-clinical studies for bictegravir meet relevant regulatory requirements. The results of the non-clinical studies as well as the potential risks to humans have been included in the Biktarvy Product Monograph. In view of the intended use of Biktarvy there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Biktarvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Biktarvy has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the drug product should be stored below 30oC.

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients used in the formulation of Biktarvy is of human or animal origin.

 

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