Summary Basis of Decision for Sunlenca

 

Clinical Pharmacology

Lenacapavir is a multistage, selective inhibitor of human immunodeficiency virus-1 (HIV–1) capsid function that directly binds to the interface between capsid protein (CA) subunits. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including:

1. capsid-mediated nuclear uptake of HIV-1 proviral deoxyribonucleic acid (by blocking nuclear import proteins binding to the capsid),
2. virus assembly and release (by binding to and destabilizing capsid precursor proteins [interfering with Gag/Gag-Pol functioning, reducing production of CA subunits]), and
3. capsid core formation (by disrupting the rate of capsid subunit association, leading to dysfunctional malformed capsids).

The clinical pharmacology of lenacapavir was assessed in nine Phase I studies, one Phase II study, and through population pharmacokinetic analysis.

Following the administration of a single intravenous dose of carbon-14 labelled lenacapavir (¹⁴C-LEN) to healthy participants, 76% of total radioactivity was recovered from feces and less than 1% from urine. Unchanged lenacapavir constituted 68.8% of circulating total radioactivity in plasma and 32.9% in feces. Lenacapavir is cleared by metabolism, excretion into bile, and intestinal secretion by P-glycoprotein (P-gp). Metabolism plays a minor role in lenacapavir elimination. Lenacapavir is metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation, primarily via cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). No single metabolite contributed more than 10% of total radioactive exposure.

Orally administered lenacapavir is absorbed rapidly with peak plasma concentrations observed after 4 to 8 hours and an absolute bioavailability of approximately 6 to 10%. Subcutaneous (SC) administration of lenacapavir results in complete absorption, however due to its long-acting properties, the absorption profile is complex with peak plasma concentrations observed 77 to 84 days post-dose. The median half-life after oral and SC administration ranges from 10 to 12 days and 8 to 12 weeks, respectively. Lenacapavir is highly bound to plasma proteins (>98.5%).

A Phase I study in healthy participants compared the safety, tolerability, and pharmacokinetics of lenacapavir dosed with the regimen used in the pivotal Phase II/III study (oral lenacapavir 600 mg daily dosing [Days 1 and 2], oral lenacapavir 300 mg dose [Day 8], and SC lenacapavir 927 mg [Day 15]) and a simplified regimen (SC lenacapavir 927 mg and oral lenacapavir 600 mg on Day 1, followed by oral lenacapavir 600 mg on Day 2). Lenacapavir exposure was generally comparable between the two dosing regimens; however, the simplified regimen group included only 14 participants, therefore the safety data is too limited to support the recommendation for slow-release SC dosing with lenacapavir on Day 1.

Based on population pharmacokinetic analysis, in heavily treatment–experienced (HTE) patients with HIV-1 infection, lenacapavir clearance was 3.62 L/h and the steady state volume of distribution was 976 L. Steady state lenacapavir exposures were 28.5% to 84.1% higher in HTE patients with HIV–1 as compared to participants without HIV-1 infection with an area under the concentration–time curve to the end of the dosing period (AUC_tau) of 3,000,000 h•ng/mL, a maximum concentration (C_max) of 97.2 ng/mL, and a trough concentration (C_trough) of 36.2 ng/mL. The pharmacokinetics of a single oral dose of lenacapavir are non-linear and less than dose–proportional over the dose range of 50 to 1,800 mg. The single dose pharmacokinetics of lenacapavir after a SC injection (309 mg/mL) are dose–proportional over the dose range of 309 to 927 mg.

Population pharmacokinetic analyses using data from adult trials did not identify any clinically relevant differences in the exposure of lenacapavir due to gender, race/ethnicity, weight, or age, however, the number of patients 65 years or older was limited (total number [n] = 5).

At supratherapeutic exposures of lenacapavir, there was no association between the observed lenacapavir plasma concentrations and changes in the corrected QT interval by Fridericia (QTcF) based on post hoc analysis of average baseline QTcF instead of the pre-specified analysis of time-matched, baseline-adjusted, and placebo-corrected QTcF.

The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a Phase I study in subjects with moderate hepatic impairment. Observed increases in the lenacapavir exposures were not considered clinically relevant. The pharmacokinetics of lenacapavir were not studied in patients with severe hepatic impairment.

The pharmacokinetics of a single 300 mg oral dose of lenacapavir were evaluated in a Phase I study in subjects with severe renal impairment. Mean lenacapavir exposures were increased (1.84-fold and 2.62-fold for AUC_inf and C_max, respectively) in patients with severe renal impairment compared to subjects with normal renal function. This increase was not considered clinically relevant; however, among the ten study participants, three achieved significant elevations in lenacapavir exposure. The pharmacokinetics of lenacapavir were not studied in patients with end-stage renal disease, including those on dialysis.

A Phase I study in healthy participants evaluated the impact of lenacapavir as a perpetrator on organic anion transporting polypeptide (OATP), breast cancer resistance protein (BCRP), and P-gp transporters; as a perpetrator on CYP3A metabolizing enzyme activities; and as a victim of P-gp, CYP3A, and UGT1A1 inhibition or induction. The study also evaluated the effect of an acid-reducing agent on the pharmacokinetics of lenacapavir. The co-administration of lenacapavir with strong CYP3A inducers (i.e., carbamazepine, phenytoin, rifampin, rifapentine and St. John’s wort) is contraindicated due to the observed/anticipated decreased plasma concentrations of lenacapavir and an increased risk of loss of therapeutic effect and development of resistance. Caution is advised if lenacapavir is co-administered with strong inhibitors of CYP3A, P-gp, and UGT1A1 together, such as atazanavir/cobicistat, due to the observed significantly increased plasma concentration of lenacapavir. Lenacapavir is a moderate inhibitor of CYP3A, therefore caution is advised if it is co-administered with sensitive CYP3A substrates with a narrow therapeutic index (e.g., dabigatran and midazolam). Based on drug interaction studies conducted with lenacapavir or potential drug interactions that may occur, no clinically significant drug interactions were observed or are expected with: atorvastatin, darunavir/cobicistat, cobicistat, famotidine, gender-affirming hormones, itraconazole, ketoconazole, oral contraceptives, pitavastatin, ritonavir, rosuvastatin, tenofovir alafenamide, and voriconazole.

The clinical pharmacology data support the use of Sunlenca for the recommended indication. For further details, please refer to the Sunlenca Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy and safety of Sunlenca in heavily treatment experienced (HTE) patients with multidrug resistant (MDR) human immunodeficiency virus-1 (HIV-1) was evaluated in the pivotal Phase II/III study GS–US–200–4625 (CAPELLA). The study design followed a multi-stage approach that included a partially randomized, double-blind, short-term functional monotherapy phase with a placebo comparator, followed by a single-arm, open-label assessment on the durability of the antiviral effect and safety at 26 and 52 weeks.

CAPELLA enrolled 72 male and female patients with MDR HIV-1 who were 18 years of age or older (all sites) or who were 12 years of age or older and weighed 35 kg or more (sites in North America and Dominican Republic). Key inclusion criteria included:

• plasma HIV-1 ribonucleic acid (RNA) ≥400 copies/mL at screening;
• resistance to two or more antiretroviral (ARV) medications from each of at least three of the four main classes of ARV medications (nucleoside reverse transcriptase inhibitors [NRTI], non-nucleoside reverse transcriptase inhibitors [NNRTI], protease inhibitors [PI] and integrase strand-transfer inhibitors [INSTI]); and
• two or less fully active ARV medications remaining at baseline from the four main classes that, in the opinion of the investigator, could be effectively combined to form a viable regimen based on resistance, intolerability, contraindication, safety, drug access, or acceptability to the participant.

The trial was composed of two cohorts. Patients were enrolled into the randomized cohort (Cohort 1) if they had a decline of <0.5 log₁₀ in HIV-1 RNA at the cohort selection visit compared to the screening visit. Patients were enrolled into the non-randomized cohort (Cohort 2) if they had a decline of ≥0.5 log₁₀ in HIV-1 RNA at the cohort selection visit compared to the screening visit, or after Cohort 1 reached its planned sample size.

In the 14-day functional monotherapy period, patients in Cohort 1 (total number [n] = 36) were randomized in a 2:1 ratio in a blinded fashion to receive either 600 mg of Sunlenca orally (two 300–mg tablets) on Days 1 and 2 and 300 mg (one 300-mg tablet) on Day 8 (Cohort 1A) or placebo (Cohort 1B) while they continued their failing regimen. This period was to establish the virologic activity of Sunlenca. After each patient completed the functional monotherapy period, their treatment assignment was unblinded. Patients who had received Sunlenca, continued Sunlenca along with an optimized background regimen (OBR). Patients who had received placebo during this period initiated Sunlenca along with an OBR. There was no comparator after the functional monotherapy period. Patients in Cohort 2 (n = 36) initiated Sunlenca and an OBR on Day 1.

During the maintenance period, patients in Cohort 1A received a subcutaneous injection of 927 mg of Sunlenca (two 1.5 mL injections of 309 mg/mL) and initiated their optimized background regimen (OBR) on Day 1 of subcutaneous administration (i.e., 14 days after the first dose of oral Sunlenca). Patients in Cohort 1B received 600 mg of Sunlenca (two 300-mg tablets) orally on Days 15 and 16 and 300 mg of Sunlenca (one 300-mg tablet) on Day 22 in addition to initiating their OBR on Day 15. These patients received a subcutaneous injection of 927 mg of Sunlenca (309 mg/mL; 2 x 1.5 mL) on Day 1 of subcutaneous administration (i.e., 14 days after the first dose of oral Sunlenca while continuing their OBR). Eligible patients were enrolled into Cohort 2 if Cohort 1 was fully enrolled or if they did not meet the criteria for randomization into Cohort 1. Patients in Cohorts 1 and 2 received their subsequent subcutaneous injection of Sunlenca at the Week 26 visit. At the Week 52 visit, patients in both cohorts were given the option to continue in the study, receiving a subcutaneous injection of Sunlenca every 6 months (26 weeks) while continuing their OBR until Sunlenca became accessible through an access program or until the sponsor elected to discontinue the study.

The enrolled population included 36 patients in the randomized cohort (12 in the placebo group and 24 in the Sunlenca group) and 36 patients in the non-randomized cohort. The baseline demographic and disease characteristics of enrolled patients were reflective of the HTE patient population. Per the study protocol, there were specified analyses at 14 days, 26 weeks, and 52 weeks. The primary endpoint was to evaluate the proportion of participants in Cohort 1 achieving a reduction in HIV-1 RNA of ≥0.5 log₁₀ copies/mL from baseline at the end of the functional monotherapy period. The secondary endpoints were the proportions of participants in Cohort 1 with plasma HIV-1 RNA <50 copies/mL and <200 copies/mL at Weeks 26 and 52 of treatment. Other endpoints included: incidences of treatment-emergent adverse events (TEAEs) and graded laboratory abnormalities, the change from baseline in HIV-1 RNA (log₁₀ copies/mL) by visit, and the change from baseline in CD4 cell count (cells/μL) by visit. At the time of the authorization of Sunlenca, this study was ongoing.

Sunlenca met the study’s primary endpoint. A significantly greater proportion of patients who received Sunlenca had a reduction in HIV-1 RNA of ≥0.5 log₁₀ copies/mL from baseline relative to those who received placebo (87.5% versus [vs.] 16.7%, respectively; p <0.0001). Post hoc analysis of the primary efficacy endpoint with adjustment for baseline HIV-1 RNA using rank analysis of covariance confirmed the difference between the groups remained statistically significant (p = 0.0003). The mean standard deviation (SD) change from baseline in HIV-1 RNA at the end of the functional monotherapy period was greater for participants who received Sunlenca vs. placebo as follows: -1.93 (0.893) log₁₀ copies/mL for Sunlenca-treated patients vs. -0.29 (0.614) log₁₀ copies/mL for placebo-treated patients (adjusted difference in least-squares mean [LSM] by baseline log₁₀ HIV-1 RNA: -2.17 [95% confidence interval [CI]: -2.74 to -1.59]; p <0.0001). 

A key efficacy concern reflected baseline differences between the Sunlenca and placebo groups in HIV-1 RNA (log₁₀ copies/mL), HIV-1 RNA categories, CD4 cell count, and CD4 cell percentage, with the placebo group having significantly higher HIV-1 RNA and lower CD4 cell counts at baseline.

Although the group of participants with baseline CD4 cell counts <200 cells/μL was limited by small sample size, the percentage of patients with a reduction in HIV-1 RNA ≥0.5 log₁₀ copies/mL from baseline at the end of the functional monotherapy period was significantly greater in patients receiving Sunlenca than in those receiving placebo (87.5% [14/16] vs. 9.1% [1/11]; p < 0.0001).

To further address the imbalance in baseline CD4 cell count, post hoc analyses of the primary efficacy endpoint were conducted in patients with comparable or clinically relevant baseline CD4 cell counts. The difference between groups remained statistically significant among patients with baseline CD4 cell counts below the cut off (p = 0.0008) and at or above the cut off (p = 0.0001). Statistical methods were reviewed via an internal biostatistics consult and deemed appropriate, although concerns were raised regarding the small sample size population.

With respect to the secondary endpoints, the percentages of patients in Cohort 1 with HIV-1 RNA <50 and <200 copies/mL at Week 26 using the United States Food and Drug Administration (FDA)-defined snapshot algorithm were 80.6% (29 of 36 patients) and 88.9% (32 patients), respectively. At Week 52, the percentages of patients in Cohorts 1 and 2 with HIV-1 RNA <50 and <200 copies/mL using the FDA-defined snapshot algorithm were 77.8% (35 of 45 patients) and 82.2% (37 of 45 patients), respectively. The results were consistently seen in patients who had suboptimal baseline OBR with a low overall susceptibility score, no or one fully active agent, INSTI resistance, or no dolutegravir or darunavir. 

There were clinically meaningful increases in CD4 cell count from baseline to Week 26 and Week 52. The mean (SD) baseline CD4 cell count value of patients in Cohorts 1 and 2 at baseline was 212 (226.2) cells/µL. At Week 26, the mean (SD) change from baseline was 89 (106.7) cells/µL. At Week 52, the mean (SD) change from baseline was 94 (121.5) cells/µL.

The percentage of patients who experienced virologic failure through the Week 52 analysis was 11.1% (8 of 72). The virologic profiles of these eight patients suggested they were at high risk of developing Sunlenca resistance due to lack of fully active antiretroviral in the OBR (n = 4) or due to inadequate adherence to OBR (n = 4). Therefore, Sunlenca may have been the only active ARV at the time of virologic failure. No cross resistance between Sunlenca and other ARVs was demonstrated.

Of concern, the sample size in the pivotal study was very small. Although the primary endpoint was met, a small sample size raises concerns about wider confidence intervals with more imprecise treatment effect estimates, imbalanced randomization (as seen with the differences in baseline HIV RNA and CD4 cell counts), and subgroup analysis numbers being too small to allow treatment effect to be compared reliably. Additionally, compared to larger studies, small studies may be at risk of overestimating the treatment effect and/or producing false-positive results due to the fluctuation of one or two responders. As per the biostatistics consultation, for the primary efficacy endpoint for Cohort 1 in the CAPELLA study, one more responder in the placebo arm would lead the treatment effect to be decreased by 8.3%.

Despite the limitations of a small sample size, the magnitude and duration of the results support the efficacy of Sunlenca in combination with other fully active ARV agents for the treatment of MDR HIV-1 infection in HTE adults who have a high unmet medical need.

 

 

Indication

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

Sunlenca (lenacapavir), in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 35 kg with multidrug resistant HIV–1 infection failing their current antiretroviral regimen due to resistance, intolerance or safety considerations.

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

Sunlenca (lenacapavir), in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance or safety considerations.

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

Clinical Safety

The clinical safety of Sunlenca was evaluated based on data from the pivotal Phase II/III study (CAPELLA) described in the Clinical Efficacy section with additional data provided from the supportive Phase II study GS-US-4334 (CALIBRATE). The overall safety population reflects exposure to Sunlenca in 229 patients with human immunodeficiency virus (HIV). The primary safety analysis was based on the pivotal CAPELLA study (total number [n] of patients = 72), which was conducted in heavily treatment experienced (HTE) adult patients with HIV who received Sunlenca through Week 26 (median duration on study of 32 weeks) and Week 52 (median duration on study of 54 weeks). Supportive data in treatment-naïve adult patients with HIV was provided from the CALIBRATE study. Data was provided through Week 28 (median duration of exposure of 43 weeks) and Week 54 (median duration on study of 66 weeks). The Sunlenca regimens used in both studies were generally well tolerated.

In the pivotal CAPELLA study, oral Sunlenca was well tolerated during the functional monotherapy period. The percentages of patients who experienced adverse events (AEs) was higher in the Sunlenca group with 37.5% (9 of 24) of patients experiencing an AE versus (vs.) 25.0% (3 of 12) of patients in the placebo group. No deaths, serious adverse events (SAEs), AEs leading to discontinuation of study drug, or Grade 3 or higher AEs were reported in either group. Nausea was the only AE reported in more than one patient (3 patients treated with Sunlenca [12.5%] versus [vs.] 0% in placebo). Nausea was considered to be related to the study drug in two patients (8.3%) in the Sunlenca group. All AEs were Grade 1 or 2 in severity.

During the functional monotherapy period of CAPELLA, the majority of patients had at least one graded laboratory abnormality (75.0% of Sunlenca patients [18/24] and 75.0% of placebo patients [9/12]). The majority of abnormalities were Grade 1 or 2 in severity. Grade 3 laboratory abnormalities were reported for three patients (12.5%) in the Sunlenca group (increased creatinine, hyperglycemia [non–fasting], and increased lipase) and no patients in the placebo group. There were no Grade 4 laboratory abnormalities.

The assessment of the long–term safety of Sunlenca in the CAPELLA study was limited by the uncontrolled study design and complex comorbidities and concomitant medications of the study population. Furthermore, the small clinical safety database limits the ability to detect less common adverse events.

Adverse events that occurred were generally consistent with those expected in patients with advanced HIV/acquired immunodeficiency syndrome (AIDS) or with the subcutaneous administration of a drug product. As of the 52-week data cut-off, 93.1% of participants had experienced a treatment–emergent adverse event (TEAE). Excluding injection site reactions, the most common AEs were diarrhea and nausea (9 patients each, 12.5%); coronavirus disease 2019 (COVID-19; 8 patients, 11.1%); abdominal distension, constipation, and cough (7 patients each, 9.7%); arthralgia, back pain headache, pyrexia, and urinary tract infection (6 patients each, 8.3%); rash (5 patients, 6.9%); and dizziness, fatigue, oral candidiasis, and vomiting (4 patients, 5.6% each). The majority of these events were Grade 1 or Grade 2 and resolved without discontinuation or interruption of study medication. Adverse reactions determined to be related by the study investigator occurred in 48 patients (66.7%). Common adverse reactions were injection site reactions and nausea.

Injection site reactions were expected from the Sunlenca depot formation, and included injection site swelling, injection site erythema, and injection site pain as well as longer lasting injection site induration and injection site nodules. Overall, 45 patients (62.5%) experienced a study drug-related injection site reaction. All were Grade 1 or 2 in severity except for two participants (2.8%) who experienced a Grade 3 injection site reaction that resolved after a few days. The three most commonly reported study-drug related injection site reactions were injection site pain and injection site swelling (30.6%, 22/72 patients each), and injection site erythema (25.0%, 18/72 patients). Three patients (4.2%) experienced an injection site reaction attributed to enfuvirtide. One patient discontinued the study drug in the extension phase due to a Grade 1 injection site reaction. 

Through the clinical development, concerns were raised regarding the compatibility of the Sunlenca injection solution formulation with Type I borosilicate glass vials, including the potential presence of subvisible glass particulates in the lenacapavir injection solution. Although the possibility exists that this may have contributed to the amount and severity of injection site reactions, there is limited published evidence that subvisible particles injected subcutaneously are associated with adverse effects. Irrespective, this risk is considered minimal in ongoing administration with the aluminosilicate vials proposed in this submission.

Serious adverse events (SAEs) occurred in eight patients (11.1%). None were considered related to the study drug. There was one occurrence of immune reconstitution inflammatory syndrome (IRIS) which was not unexpected given the high HIV load of the patient population. There was one death in the study due to malignancy which was thought to be unrelated to the study drug.

The majority of the patients had at least one graded laboratory abnormality (97.2%, 70/72 patients) as expected in a complex patient population with significant polypharmacy. The majority of abnormalities were Grade 1 or 2 in severity. Grade 3 laboratory abnormalities were reported for 16 patients (22.2%) and Grade 4 laboratory abnormalities were reported for five patients (6.9%). These laboratory abnormalities were either transient, returned to baseline, improved on subsequent visits despite continued exposure to the study drug, or occurred in patients with underlying conditions expected in the population (e.g., diabetes, alcohol abuse, viral hepatitis).

The supportive CALIBRATE study was limited in its ability to be extrapolated to the intended population given the study was carried out in treatment–naïve patients. Furthermore, nearly all patients were male, and the majority were young, limiting extrapolation to female patients and older or geriatric patients.

The major limitations of the safety database for Sunlenca included the small study numbers and limited long-term follow-up, with limited safety data available for Sunlenca beyond 28 weeks of treatment. Therefore, rare adverse drug reactions and adverse drug reactions associated with long exposure, long latency and cumulative effects are not well characterized. Most adverse events were tolerable and self-limited and there were few concerns identified in the clinical pharmacology/non-clinical data sets. These uncertainties are manageable through labelling and pharmacovigilance.

Overall, the safety profile of Sunlenca (lenacapavir) is considered acceptable given the significant risks associated with unsuppressed viral load in the patient population. Appropriate warnings and precautions are in place in the approved Sunlenca Product Monograph to address the identified safety concerns.

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