Summary Basis of Decision for Genvoya

Clinical Pharmacology

Genvoya is a fixed-dose combination of antiviral drugs elvitegravir (boosted by the pharmacokinetic enhancer cobicistat), emtricitabine and tenofovir alafenamide (TAF). Elvitegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor. Integrase is an HIV-1 encoded enzyme that is required for viral replication. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication. Tenofovir alafenamide is efficient in loading tenofovir (TFV) into peripheral blood mononuclear cells (including lymphocytes and other HIV target cells) and macrophages. Intracellular TFV is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate which inhibits HIV replication.

The pharmacokinetic profiles of Genvoya and its components were well established in HIV-1 infected patients and special populations. Elvitegravir and TFV exposures in adolescents treated with Genvoya were similar to that in adults. Exposure of TAF in adolescents was consistent with the range of exposure associated with antiviral activity in adults, despite being lower than that in the adult comparator. Emtricitabine exposure in adolescents was consistent with adult data. Cobicistat exposure in adolescents was lower compared to the adult comparator, but was consistent with historical data and within the range of exposure associated with robust pharmacoenhancement.

Patients with estimated glomerular filtration rate (eGFR) values by the Cockcroft-Gault method (eGFRCG) of <50 mL/min had a similar safety profile compared to patients with an eGFRCG values of ≥50 mL/min, therefore no dose adjustment of Genvoya is required in patients with renal impairment with an eGFR ≥30 mL/min. Mild and moderate hepatic impairment did not meaningfully affect TAF and TFV exposures.

Population pharmacokinetics analysis of HIV-infected patients in Phase II and Phase III studies of Genvoya indicated that the covariates of body weight, age, gender, renal function and race did not have a clinically relevant effect on exposures of TAF.

Tenofovir alafenamide may have clinically relevant drug interactions with potent inducers of cytochrome P450 (CYP) enzyme, CYP3A4, and inhibitors of P-glycoprotein and breast cancer resistance protein. This information is labelled in the Genvoya Product Monograph.

Overall, the clinical pharmacological data support the use of Genvoya for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Genvoya was evaluated in antiretroviral treatment (ART)-naïve and virologically suppressed ART-experienced HIV-1 infected patients. A total of 2,394 patients were randomized or enrolled and received at least one dose of Genvoya in the six clinical studies submitted in support of the new drug submission. Across these studies, 88 patients (3.7%) discontinued Genvoya prematurely with the most common reasons for the discontinuations being adverse event (1.2%, 29 patients), lost to follow-up (0.9%, 22 patients), and withdrawal of consent (0.8%, 19 patients).

A total of 1,032 ART-naïve patients were enrolled, randomized, and received at least one dose of Genvoya in the following five studies: 866 adult patients in the pivotal Phase III studies (GS-US-292-0104 and GS-US-292-0111), 112 adult patients in the Phase II study (GS-US-292-0102), 6 adult patients with mild to moderate renal impairment in the Phase III study GS-US-292-0112, and 48 adolescent patients in the Phase II/III study GS-US-292-0106. In both pivotal studies (GS-US-292-0104 and GS-US-292-0111), patients were randomized in a 1:1 ratio to receive either Genvoya once daily or the active comparator Stribild once daily.

A total of 1,362 virologically suppressed, ART-experienced adult patients across three studies were randomized or enrolled and received at least one dose of Genvoya as follows: 959 patients in the Phase III study GS-US-292-0109; 161 patients in the extension phase of the Phase II study GS-US-292-0102; and 242 patients with mild to moderate renal impairment in the Phase III study GS-US-292-0112. In the Phase III study GS-US-292-0109, the efficacy and safety of switching from either Atripla, Truvada plus atazanavir (boosted by either cobicistat or ritonavir), or Stribild to Genvoya were evaluated.

The demographic and baseline characteristics were generally comparable between the treatment arms in each of the studies. The median age ranged from 33 to 41 years in ART-naïve or virologically suppressed patients. The median age for patients with renal impairment in study GS-US-292-0112 was 54 years in the ART-naïve cohort, and 58 years in the virologically suppressed cohort. There were 87 patients who were ≥65 years of age across the studies. The median age of the adolescent patients in study GS-US-292-0106 was 15 years (range, 12 to 17). The percentage of women in the pivotal studies with ART-naïve and virologically suppressed patients ranged from 10-15%, was approximately 20% in the population with renal impairment, and 58% among the adolescent population. Most of the adult patients across the studies were Caucasian (approximately 55% to 70%) and Black (approximately 20% to 30%) whereas the majority of adolescent patients were Black (87.5%) and the remaining 12.5% were Asian.

The primary efficacy endpoint in ART-naïve and virologically suppressed adults was the percentage of patients with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 using the United States Food and Drug Administration (FDA) snapshot algorithm in the Full Analysis Set (FAS). Based on pooled data in ART-naïve patients from pivotal studies GS-US-292-0104 and GS-US-292-0111, Genvoya was non-inferior to Stribild with 92% of patients in the Genvoya treatment group achieving the primary efficacy endpoint as compared to 90% of patients in the Stribild group [95% confidence interval (CI): -0.7, 4.7%]. The percentage of patients experiencing virologic failure and the reasons for failure were comparable between the Genvoya and Stribild treatment groups (3.6% and 4.0%, respectively). The rates of virologic failure were approximately 1% for each treatment group.

The primary efficacy endpoint in the open-label studies in adults or adolescent patients with renal impairment was the percentage of patients with HIV-1 RNA <50 copies/mL at Week 24 using the FDA snapshot algorithm in the FAS. The percentage of virologically suppressed patients with mild to moderate renal impairment who achieved the primary efficacy endpoint after switching treatment to Genvoya in study GS-US-292-0112 was 95.0% regardless of baseline eGFRCG (<50 mL/min or ≥50 mL/min). Three patients (1.2%) experienced virologic failure. In ART-naïve adolescents, 21 of the 23 patients (91.3%) achieved the primary efficacy endpoint. Two patients (8.7%) had virologic failure at Week 24, however both had HIV-1 RNA <50 copies/mL at later study visits.
 
The primary endpoint in ART-naïve adults from pivotal studies GS-US-292-0104 and GS-US-292-0111 was assessed for the following subgroups: age (<50 years and ≥50 years), gender, race (Black and non-Black), baseline CD₄ count (<200 and ≥200 cells/µL), baseline viral load (HIV RNA ≤100,000 and >100,000 copies/mL), region (United States and ex-United States) and study drug adherence (<95% and ≥95%). Subgroup analysis in virologically suppressed adults did not include baseline viral load or baseline CD₄ count and included primary efficacy endpoint and change from baseline in CD₄ cell count by prior treatment regimen. In patients with renal impairment who were virologically suppressed, subgroup analysis did not include baseline viral load or baseline CD₄ count and no subgroup analysis was performed in adolescents. No significant differences in the efficacy of Genvoya were observed between the subgroups in the pooled analysis of the two pivotal studies in ART-naïve adults, in virologically suppressed patients or in patients with renal impairment.
 
The secondary endpoints included the percentage of adult patients with HIV-1 RNA <20 copies/mL, percentage of patients with HIV-1 RNA<50 copies/mL, changes from baseline in plasma HIV-1 RNA in ART-naïve patients, and changes from baseline in CD₄ cell counts. The percentages of patients achieving the secondary efficacy endpoints were similar between Genvoya and active comparators in ART-naïve patients and in virologically suppressed patients. 

In a pooled analysis of treatment-naïve patients with confirmed virologic failure, the development of one or more primary elvitegravir, emtricitabine, or tenofovir alafenamide resistance-associated mutations was observed in 0.7% of patients treated with Genvoya and in 0.8% of patients treated with Stribild. The mutations that emerged in the Genvoya group were M184V [number of patients (N) = 7] and K65R (N = 1) in reverse transcriptase, and T66T/A/I/V (N = 2), E92Q (N = 2), Q148Q/R (N = 1) and N155H (N = 1) in integrase. The mutations that emerged in the Stribild group were M184V/I (N = 7) and K65R (N = 2) in reverse transcriptase, and E92E/Q (N = 3) and Q148R (N = 2) in integrase. All patients who developed resistance mutations to elvitegravir developed resistance mutations to both emtricitabine and elvitegravir.

There were 4 patients in the Genvoya group (4/14, 29%) and 4 patients in the Stribild group (4/15, 27%) whose HIV-1 isolates showed reduced susceptibility to elvitegravir, and 6 patients (43%) in the Genvoya group had reduced susceptibility to emtricitabine compared with 5 patients (33%) in the Stribild group. No patients in either group had isolates with a reduced susceptibility to tenofovir. One virologically suppressed patient with emergent resistance to Genvoya had the M184M/I mutation. Cross-resistance was not observed for elvitegravir-resistant HIV-1 isolates and emtricitabine or tenofovir, or for emtricitabine- or tenofovir-resistant isolates and elvitegravir.

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

Indication

The New Drug Submission for Genvoya was filed with the following indication:

Genvoya (150 mg elvitegravir/150 mg cobicistat/200 mg emtricitabine/10 mg tenofovir alafenamide) is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1 infection) in adults and pediatric patients 12 years of age and older with no known mutations associated with resistance to the individual components of Genvoya.

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

Genvoya (150 mg elvitegravir/150 mg cobicistat/200 mg emtricitabine/10 mg tenofovir alafenamide) is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 12 years of age and older (and weighing ≥35 kg) and with no known mutations associated with resistance to the individual components of Genvoya.

Clinical Safety

The clinical safety of Genvoya was evaluated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older (weighing ≥35 kg (title tag – kilograms)). A safety assessment was based on Week 48 pooled data from two comparative, pivotal, Phase III studies, GS-US-292-0104 and GS-US-292-0111, where a total of 866 ART-naïve adults received Genvoya once daily. Virologically suppressed patients were assessed for new adverse events (AEs) in an open-label clinical study GS-US-292-0109 where patients switched from a tenofovir disoproxil fumarate (TDF) -containing combination regimen to Genvoya (N = 959). Genvoya was also evaluated through 24 weeks in an open-label clinical study GS-US-292-0112 in 248 HIV-1 infected patients who were either treatment-naïve (N = 6) or virologically suppressed (N = 242) with mild to moderate renal impairment (eGFR_CG 30-69 mL/min). The safety of Genvoya in HIV-1 infected, treatment naïve pediatric patients aged 12 to <18 years was evaluated through 24 weeks in an open-label clinical study GS-US-292-0106. For more information about the clinical studies, see the Clinical Efficacy section).

The safety profiles of Genvoya were generally similar in HIV-1 infected adults who were ART-naïve, virologically suppressed, renally impaired, or in ART-naïve adolescents (ages 12 to <18 years of age). In ART-naïve adults, the most commonly reported AEs were diarrhea, nausea, headache, and upper respiratory tract infection. Grade 2 to 4 AEs related to study drug and reported in ≥1% of patients in either the Genvoya or Stribild treatment group were diarrhea, nausea, fatigue and headache. The proportion of patients who discontinued the study drug due to an AE was 0.9% in the Genvoya group and 1.5% in the Stribild group.

A total of 7 deaths were reported during the Phase II and Phase III studies. There were 5 deaths reported for the ART-naïve patients; 2 patients in the Genvoya group (embolic stroke and alcohol poisoning) and 3 patients in the Stribild group (cardiac arrest, recreational drug use and alcohol overdose, and acute myocardial infarction). Two virologically suppressed patients in the Genvoya group died during the study (septic shock and Stage 4 lung adenocarcinoma). None of the deaths were considered related to study drug by the investigator.

Genvoya resulted in significantly lower bone and renal toxicity as compared to Stribild when mean percentage changes in hip and spine bone mineral density (BMD) or in serum creatinine, eGFR, and treatment-emergent proteinuria were compared.

In ART-naïve adults, fewer patients in the Genvoya group as compared to the Stribild group, had clinically significant (>3%) decreases from baseline in hip BMD (17% and 50%, respectively) and in spine BMD (26% and 46%, respectively). Since there was a substantial percentage of patients in the Genvoya group with a clinically significant decrease in BMD from baseline, it was recommended that the sponsor continue monitoring bone effects of Genvoya as part of the Risk Management Plan. In studies in virologically suppressed patients, improvements in BMD were observed in patients who switched from a tenofovir disoproxil fumarate (TDF) based regimen. In patients with renal impairment, hip and spine BMD increased for patients following a switch to Genvoya. The mean standard deviation (SD) changes from baseline in BMD in adolescents, as expressed in height-age adjusted spine and total body less head (TBLH) Z-scores were -0.08 (0.391) and -0.10 (0.256), respectively, however 4 patients experienced a worsening of their BMD Z-scores at Week 24. At Week 48, 2 of the patients showed improvements in BMD, no data was available for one patient and the fourth patient experienced a further worsening in the Z-score. In the context of limited exposure and small sample size, these observations were considered significant. A cautionary statement about the effect of Genvoya on BMD in adolescents was added to the Genvoya Product Monograph in the Warnings and Precautions, Adverse Reactions and Clinical Trials sections. Across all studies, the incidence of fractures was low, balanced between treatment groups and the events were not considered as related to study drug by the investigator and did not result in permanent discontinuation of study drugs.

Across the Phase III studies in adults with normal renal function, 10% or less of the patients had Grade 1, 2, or 3 proteinuria at baseline. In patients with mild to moderate renal impairment, 9.5% of virologically suppressed patients had Grade 2 proteinuria by urinalysis (dipstick), and 23.1% of patients had Grade 1 proteinuria at baseline. Among adolescents, <5% had proteinuria at baseline. Across studies in ART-naïve adults, increases from baseline in serum creatinine, and proteinuria (by dipstick) were smaller in the Genvoya group as compared to the Stribild group. Decreases from baseline in proteinuria and albuminuria were observed in the Genvoya group as compared to increases from baseline in these markers observed in the Stribild group. In studies where virologically suppressed patients switched from a TDF-based regimen to Genvoya, the changes from baseline in serum creatinine and eGFR at Week 48 were minimal and there were decreases in proteinuria (by dipstick) and tubular proteinuria. In renally impaired patients, decreases from baseline in proteinuria, albuminuria, and tubular proteinuria were noted following a switch to Genvoya from a TDF-containing regimen. In renally impaired patients who switched from a non-TDF containing regimen, the mean (SD) increase in serum creatinine was 0.05 (0.28) mg/dL however there were significant improvements in proteinuria, albuminuria, and tubular proteinuria. Data from an isohexol substudy in renally impaired patients who switched to Genvoya demonstrated no change in actual GFR (aGFR) through 24 weeks, regardless of baseline eGFRCG or pre-switch TDF use. In adolescents, initial changes in serum creatinine and eGFR were consistent with cobicistat-mediated inhibition on renal tubular creatinine secretion, which results in an increase in serum creatinine and a decrease in eGFR without an effect on aGFR. Across all the studies, there were no cases of proximal renal tubulopathy, including Fanconi Syndrome, or laboratory findings consistent with subclinical renal tubulopathy reported for Genvoya.

Across all studies, ocular adverse events (AEs) were uncommon, balanced between treatment groups and considered by the investigator as unrelated to the study drugs. In patients receiving Genvoya, there were no AEs in the eye disorder System Organ Class indicative of posterior uveitis. One adult patient discontinued study drugs due to 3 eye disorder AEs, all of which were unrelated to study drugs by the investigator. One adolescent patients had an AE of intermediate uveitis that was considered related to study drug by the investigator but the event was resolving while the patients continued the study drug without interruption.

Approximately 20% of adults across all studies and 8% of adolescents experienced a Grade 3 or 4 laboratory abnormality. The most common ones were abnormal creatinine kinase, fasting low density lipoproteins, and lipase parameters (among patients who had serum amylase >1.5 the upper limit of normal). Across all studies, adult and adolescent patients receiving Genvoya experienced increases from baseline in serum lipids. In the pivotal studies with ART-naïve patients, these changes were higher as compared to those experienced by patients receiving Stribild. This safety information was implemented in the Adverse Reactions section of the Genvoya Product Monograph. No clinically relevant changes from baseline in median values for hematology or clinical chemistry parameters were observed across the studies.

Across the studies in adults, there were 10 patients with clinically significant electrocardiogram (ECG) findings and 29 patients with clinically significant ECG abnormalities reported as an AE. All of the ECG AEs were non-serious and none resulted in discontinuation of the study drug. Two AEs were assessed as related to the study drug by the investigator; supraventricular extrasystoles and atrial fibrillation reported for a virologically suppressed patient who switched to Genvoya, and intermittent palpitations reported for a renally impaired ART-naïve subject receiving Genvoya.

The reported AEs and laboratory test abnormalities associated with Genvoya treatment were not affected by sex, age, race, HIV-1 RNA level, CD₄ cell count, prior treatment regimen, or region. Patients with eGFR_CG <50 mL/min had a similar safety profile compared with patients with eGFR_CG ≥50 mL/min; therefore, no dose adjustment of Genvoya is required in renally impaired patients with an eGFR ≥30 mL/min.

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