Summary Basis of Decision for Rukobia

 

Clinical Pharmacology

Fostemsavir is a prodrug without significant biochemical or antiviral activity. Upon cleavage of a phosphonooxymethyl group in vivo, fostemsavir is hydrolyzed to the active moiety, temsavir, a human immunodeficiency virus type 1 (HIV-1) attachment inhibitor. Temsavir binds directly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and cellular CD4 receptors. This prevents the attachment and subsequent entry of the virus into host cells, thereby preventing infection.

Following the administration of Rukobia, the pharmacokinetics of temsavir is similar between healthy subjects and patients with an HIV-1 infection. Fostemsavir is not generally detectable in the plasma following oral administration as it is hydrolyzed to temsavir by alkaline phosphatases within the small intestine. Under fasting conditions, temsavir is readily absorbed with a median time to maximum plasma concentration (T_max) of 2 hours. Increases in plasma temsavir exposure, as measured by maximum plasma concentration (C_max) and the area under the concentration-time curve over the dosing interval (AUC_tau), appeared dose-proportional or slightly greater than dose-proportional, over the range of 600 mg to 1,800 mg of Rukobia.

In vivo data indicate that temsavir is approximately 88% bound to human plasma proteins. Human serum albumin is the major contributor to plasma protein binding of temsavir in humans. The free fraction of temsavir in plasma was approximately 12% to 18% in healthy subjects, 23% in subjects with severe hepatic impairment, 19% in subjects with severe renal impairment, and 12% in HIV-1-infected patients.

Temsavir is primarily metabolised via esterase hydrolysis (36.1% of administered dose) and secondarily by cytochrome P450 (CYP) 3A4-mediated oxidative pathways (21.2% of administered dose). Temsavir is extensively metabolised, accounting for the fact that only 3% of the administered dose is recovered in human urine and faeces. Following oral administration of ¹⁴C-labelled fostemsavir in a human mass balance study, 51% and 33% of the radioactivity was retrieved in the urine and faeces, respectively.

The terminal half-life of temsavir was approximately 11 hours. The plasma temsavir clearance rate following intravenous administration was 17.9 L/hr, and the apparent clearance (CL/F) after oral dosing was 66.4 L/hr.

Significant prolongation of the corrected QT (QTc) interval was observed following a supratherapeutic dose of Rukobia, corresponding to four times the recommended daily dose. Based on this finding, Rukobia should be used with caution in patients with a history of QTc interval prolongation. In addition, caution should be used when co-administering Rukobia with a drug with a known risk of Torsade de Pointes or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

The concomitant use of Rukobia with certain other drugs may result in known or potentially significant drug interactions. The co-administration of Rukobia with strong CYP3A4 inducers (e.g., rifampin) is contraindicated, as it may lead to loss of the therapeutic effect of Rukobia and the possible development of resistance due to reduced exposure of temsavir. The co-administration of Rukobia with inhibitors of CYP3A4, P-glycoprotein (P-gp), or breast cancer resistance protein (BCRP) may increase temsavir exposure. A detailed description of important drug interactions can be found in the Rukobia Product Monograph. The potential for drug interactions should be considered prior to and during therapy with Rukobia, and patients should be monitored for adverse reactions associated with the concomitantly administered drugs.

Patients co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) at baseline had a higher incidence of post-baseline emergent elevations in hepatic transaminases as compared to patients with neither co-infection. Therefore, monitoring of liver chemistries is recommended in patients co-infected with HBV and/or HCV.

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

Clinical Efficacy

Evidence of the clinical efficacy of Rukobia was provided through the results of the partially randomized Phase III clinical BRIGHTE study, conducted in heavily treatment-experienced (HTE) adult patients with HIV-1. At baseline, all patients had a viral load of 400 copies/mL or greater, and no more than two classes of antiretroviral medications remaining due to resistance, intolerability, contraindication, or other safety concerns. The BRIGHTE study was double-blind, placebo-controlled, and partially randomized, with patients enrolled in either a randomized or a non-randomized cohort.

Randomized Cohort

Data from the 272 patients in the randomized cohort provided the primary evidence of efficacy. Patients in this cohort were taking a maximum of two fully active and available antiretroviral agents at screening, which could be combined as part of an efficacious background regimen. For the first eight days of the study, patients received either 600 mg Rukobia twice daily (number [n] = 203) or placebo (n = 69), in addition to their current failing regimen. Beyond Day 8, patients received 600 mg Rukobia twice daily (open-label), plus investigator-selected optimized background therapy (OBT).

The primary endpoint analysis was based on the adjusted mean decline in HIV-1 ribonucleic acid (RNA) from Day 1 to Day 8 in the randomized cohort. In the intent-to-treat exposed (ITT-E) population, Rukobia was superior with adjusted mean declines in HIV-1 RNA levels of 0.79 log₁₀ copies/mL relative to 0.17 log₁₀ copies/mL in the placebo group (p<0.0001).

At Day 8, 131 of the 203 patients (65%) who received Rukobia had a reduction in viral load greater than 0.5 log₁₀ copies/mL relative to baseline, compared to 13 of the 69 patients (19%) who received the placebo. Ninety-three of the 203 patients (46%) who received Rukobia had a reduction in viral load greater than 1 log₁₀ copies/mL, compared to seven of the 69 patients (10%) who received the placebo.

At Day 8, randomized patients with a baseline HIV-1 RNA level greater than 1,000 copies/mL achieved a median decline of 1.015 log₁₀ copies/mL in viral load, while patients treated with the placebo had a median decline of 0.00 log₁₀ copies/mL in viral load. Patients with a baseline HIV-1 RNA level of 1,000 copies/mL achieved a median decline of 0.14 log₁₀ copies/mL in viral load, while patients treated with the placebo had a median decline of 0.06 log₁₀ copies/mL in viral load.

There was considerable variability in the number of antiretrovirals (fully active and otherwise) included in OBT regimens. The majority of patients (84%) received dolutegravir as a component of OBT, of which approximately half (51% overall) also received darunavir with ritonavir or cobicistat. Virologic outcomes by ITT-E snapshot analysis at Week 48 were consistent with those observed at Weeks 24 and 96.

Based on the ITT-E snapshot algorithm, HIV-1 RNA levels below 40 copies/mL were achieved in 53% of patients at Week 24, 54% of patients at Week 48, and 60% of patients at Week 96. Levels below 200 copies/mL were achieved in 68% of patients at Week 24, 69% of patients at Week 48, and 64% of patients at Week 96. Levels below 400 copies/mL were achieved in 75% of patients at Week 24, 70% of patients at Week 48, and 64% of patients at Week 96.

Relative to baseline measurements, mean changes in the CD4+ cell count continued to increase over time with gains of 90 cells/mm³ at Week 24, 139 cells/mm³ at Week 48, and 205 cells/mm³ at Week 96. Results from a subgroup analysis indicated that over time, patients with the lowest baseline CD4+ cell counts (less than 20 cells/mm³) had a similar increase in the CD4+ cell count as patients with higher baseline CD4+ cell counts (greater than 50, 100, or 200 cells/mm³).

Non-Randomized Cohort

Ninety-nine patients were enrolled in the non-randomized cohort who had no fully active and approved antiretroviral agents available at screening. These patients were treated with Rukobia 600 mg twice daily (open-label) and OBT from Day 1 onward.

At Weeks 24, 48, and 96, the proportions of patients who achieved HIV-1 RNA levels below 40 copies/mL were 37%, 38%, and 37%, respectively, based on the ITT-E snapshot algorithm. At the same time points, the proportions of patients with less than 200 copies/mL HIV-1 RNA were 42%, 43%, and 39%, respectively, and the proportions of patients with less than 400 copies/mL HIV-1 RNA were 44%, 44%, and 40%, respectively. Relative to baseline measurements, mean changes in the CD4+ cell count increased over time (41 cells/mm³ at Week 24, 64 cells/mm³ at Week 48, and 119 cells/mm³ at Week 96).

Virologic Failure

Virologic failure is defined as:

• a confirmed HIV-1 RNA level of 400 copies/mL or greater after a prior confirmed suppression to fewer than 400 copies/mL;
• a confirmed HIV-1 RNA level of 400 copies/mL or greater at the last available measurement prior to discontinuation; or
• an increase in HIV-1 RNA level greater than 1 log₁₀ copies/mL at any time above nadir level (40 copies/mL or greater)

Virologic failure occurred in 69 of the 272 patients (25%) in the randomized cohort and 50 of the 99 patients (51%) in the non-randomized cohort through the Week 96 analysis.

In the randomized cohort, 27 of 53 evaluable patients (51%) with virologic failure had treatment-emergent genotypic substitutions in the HIV-1 envelope glycoprotein gp120 at the four key positions: S375, M426, M434, and M475. At virologic failure, the median fold-change in the half maximal effective concentration (EC50) of temsavir (the active moiety of fostemsavir) was 1,755-fold in the evaluable isolates with emergent gp120 substitutions and 3.6-fold in the evaluable isolates without emergent gp120 substitutions. Out of 69 cases of virologic failure in the randomized cohort, genotypic or phenotypic resistance to at least one drug in the OBT was detected in 21 (30%) cases at screening. Out of 64 cases of virologic failure with post-baseline data, emergent resistance to at least one drug in the OBT was detected in 31 (48%) cases.

The non-randomized cohort had a higher proportion of patients with emergent gp120 resistance-associated substitutions at the time of virologic failure compared to the randomized cohort. At virologic failure, the median fold-change in the EC50 of temsavir was 4,216-fold in the 33 evaluable isolates with emergent gp120 substitutions and 767-fold in the 12 evaluable isolates without emergent gp120 substitutions. Out of 50 cases of virologic failure in the non-randomized cohort, genotypic or phenotypic resistance to at least one drug in the OBT was detected in 45 (90%) cases at screening. Out of 49 cases of virologic failure with post-baseline data, emergent resistance to at least one drug in the OBT was detected in 27 (55%) cases.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Rukobia (fostemsavir extended release tablets) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced (HTE) adults.

Rukobia (fostemsavir extended release tablets) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1 for whom it is otherwise not possible to construct a suppressive anti-viral regimen due to resistance, intolerance or safety considerations.

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

Clinical Safety

The clinical safety of Rukobia was primarily established through data from the pivotal Phase III BRIGHTE study, described in the Clinical Efficacy section. In this study, Rukobia was generally well tolerated in the 370 patients (271 randomized and 99 non-randomized) who received at least one dose, with a dosing regimen of 600 mg twice daily.

The majority of adverse reactions reported with Rukobia (81%) were mild or moderate in severity. At Week 96, 7% of patients had discontinued treatment with Rukobia due to an adverse event (5% of patients in the randomized cohort and 12% of patients in the non-randomized cohort). The most common adverse events leading to discontinuation were related to infections which were reported in 3% of patients receiving Rukobia. Serious adverse reactions occurred in 3% of patients, and included three cases of severe immune reconstitution inflammatory syndrome (IRIS). Adverse reactions of all grades that were reported in at least 2% of patients at Week 96 included nausea (9%); diarrhea (5%); fatigue, headache, and rash (3% each); abdominal pain; vomiting; dyspepsia; IRIS; and somnolence and dizziness (2% each).

An assessment of the long-term safety of Rukobia in the BRIGHTE study was confounded by the uncontrolled study design and the complex comorbidities and concomitant medications of the study population. The data provided with this submission covered a median follow-up period of approximately 100 weeks. The most commonly reported adverse events were diarrhea, nausea, and headache, the majority of which were Grade 1 or 2 in severity and resolved without interruption of study medication. Infection and the progression of HIV disease accounted for the majority of Grade 3 and 4 adverse events, serious adverse events, and deaths through Week 96. Approximately one third of patients experienced a serious adverse event, with pneumonia as the most commonly reported event.

Twenty-nine deaths were reported during the study, including 18 deaths which were caused by events related to acquired immunodeficiency syndrome (AIDS), IRIS, or acute infections, consistent with the advanced HIV disease of the study population. The median baseline CD4+ T cell count among the 29 patients was 11 cells/mm³. In the randomized cohort, the total number of class C AIDS-defining conditions (based on the Centers for Disease Control classification) decreased over time, with 22 events in the first 24 weeks, 9 events from Week 24 to Week 48, and 3 events from Week 48 to Week 96. Through Week 96, no new clinically relevant toxicities were identified due to emergent laboratory abnormalities.

Patients with HBV or HCV co-infection at baseline had a higher incidence of elevations in hepatic transaminases which emerged post-baseline as compared to patients with neither co-infection.

The observed treatment-emergent Grade 3 or 4 elevations in serum creatinine were confounded by advanced HIV disease and other comorbidities, as well as concomitant medications known to cause increases in serum creatinine without affecting renal glomerular function. Grade 3 elevations of direct bilirubin were also reported in the study and were similarly confounded by unrelated serious liver events, viral hepatitis co-infection, and/or other relevant medical history or concomitant medication. All other reported increases were minor, transient, and asymptomatic, and were resolved without interruption of treatment. Reports of adverse events of special interest included eight cases of IRIS, three of which were serious.

Through Week 96, seven patients met the criteria for protocol discontinuation due to prolongation of the corrected QT (QTc) interval (a QT interval corrected by Fridericia’s formula [QTcF] confirmed to be greater than 470 ms for female patients or greater than 450 ms for male patients). Six of the seven patients transitioned to the fostemsavir early access program in order to continue treatment. None of these patients experienced a corresponding symptomatic cardiovascular event or had any evidence of ventricular tachyarrhythmia.

Adverse events within the Skin and Subcutaneous Tissue Disorders system organ class, including rash, were predominantly Grade 1 or 2 in severity and resolved with continued treatment with fostemsavir. One event of rash and one serious event of rhabdomyolysis were each considered related to fostemsavir. Both events resulted in permanent discontinuation from the study. A comprehensive review of creatinine phosphokinase elevations and musculoskeletal events in the study was conducted. The review showed that most of these events were Grade 1 or 2 in severity and resolved without interruption of treatment with fostemsavir.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Rukobia, and to promote its safe and effective use. Overall, the benefit-harm-uncertainty profile of Rukobia is favourable for the approved indication. For more information, refer to the Rukobia Product Monograph, approved by Health Canada and available through the Drug Product Database.