Summary Basis of Decision for Edurant ™

3.3.1 Pharmacodynamics

Three clinical Phase I studies were submitted to examine the effects of rilpivirine on the QT/QTc interval in healthy subjects.

One of the Phase I studies was a thorough QTc study. Rilpivirine at supratherapeutic doses of 75 mg daily (q.d.) and 300 mg q.d. was studied in a double-blind, double-dummy, randomized, placebo and active controlled, 3-way crossover study in healthy adult volunteers (number = 40, 22 females/19 males), with 13 electrocardiogram (ECG) recordings over 24 hours on Day 1 and Day 11 of treatment. On Day 11 of treatment, the maximum QTcF interval prolongation (baseline- and placebo-adjusted) was mean 10.7 [90% confidence interval (CI) 6.1, 15.3] ms at 16 hours post-dosing in the 75 mg q.d. treatment group and mean 23.3 (90% CI 18.0, 28.7) ms at 4.5 hours post-dosing in the 300 mg q.d. treatment group.

The other two Phase I studies evaluated the impact of the therapeutic dose (25 mg q.d.) of rilpivirine in healthy subjects. Although rilpivirine was not associated with a statistically significant prolongation of the QTc interval in healthy subjects treated for 11 days, there were isolated cases of significant ECG abnormalities, including QTc prolongation, which were attributed to the study drug by the investigator. One female subject had a prolonged QTcF interval (>460 ms) following treatment with 25 mg q.d. rilpivirine. One male subject in the rilpivirine 25 q.d. group had an abnormal increase in QTcF (>60 ms) that led to an abnormal value of 499 ms. These events had a delayed onset which is consistent with the observations of a delayed onset of dose-related QTc prolongation in the Phase IIB and Phase III studies. The duration of the Phase I studies may have been insufficient to detect any delayed effects of rilpivirine on the QTc interval.

3.3.2 Pharmacokinetics

Absorption

The rate of rilpivirine absorption was independent of the dose with a median T_max between 4 and 5 hours. In several healthy subjects, multiple absorption peaks and/or an increase in absorption between 12 and 24 hours post-dose were observed. The underlying mechanism(s) for these observations is unknown. The median elimination half-life of rilpivirine was between 45 and 50 hours in the Phase I studies.

The absolute bioavailability of rilpivirine was not investigated.

The exposure of rilpivirine was approximately 40% and 50% lower when administered under fasted conditions and with only a protein-rich nutritional drink, respectively, as compared to a regular or high-fat meal. Rilpivirine should always be taken with a meal.

Distribution

In vitro, rilpivirine was approximately 99.7% bound to plasma protein, mainly albumin. The distribution of rilpivirine into compartments other than plasma was not investigated in humans.

Metabolism

In vitro experiments indicated that rilpivirine primarily undergoes oxidative metabolism mediated by the CYP 3A system.

Excretion

In studies with radiolabelled rilpivirine, an average of 85% of the administered radioactivity was recovered in the faeces and 6.1% was recovered in the urine. Unchanged rilpivirine accounted for on average 25% of the radioactivity in the faeces. The recovered metabolites were consistent with CYP3A-mediated metabolism of rilpivirine.

Drug Interactions

Rilpivirine is primarily metabolized by CYP3A. Drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of rilpivirine and drugs that induce CYP3A or increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the NNRTI class of antiretrovirals. Co-administration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.

Rilpivirine at 150 mg q.d. was a moderate inducer of CYP3A4 (atorvastatin, norethindrone) and CYP2C19 (omeprazole). Rilpivirine at either 25 mg q.d. or 150 mg q.d. had no significant effects on the CYP2C9- and CYP3A4-mediated metabolism of ethinylestradiol. Rilpivirine had a modest or no effect on the metabolism of: norethindrone at 25 mg q.d., sildenafil (CYP3A4) at 75 mg q.d. and chlorzoxazone (CYP2E1) at 150 mg q.d. CYP3A4 inducers rifampin and rifabutin, decreased the mean rilpivirine exposure by 80% and 46%, respectively. Since a reduction in rilpivirine exposure could decrease the therapeutic effect and increase the risks of virologic failure and development of resistance to NNRTIs, rilpivirine use should be contraindicated with CYP3A inducers.

Co-administration of rilpivirine at 150 mg q.d. with CYP3A inhibitors such as ketoconazole (400 mg q.d.) and ritonavir-boosted protease inhibitors (PIs) such as lopinavir/ritonavir (400 mg/100 mg q.d.) and darunavir/ritonavir (800 mg/100 mg q.d.) resulted in increased mean exposures of rilpivirine (1.49; 1.52-fold; and 2.3-fold, respectively). In a subset of subjects (31%), darunavir/ritonavir increased the mean exposure of rilpivirine from 2.7-fold to 3.8-fold. Based on these findings, caution should be exercised when rilpivirine is co-administered with CYP3A inhibitors. The mean exposure of ketoconazole was decreased by 24% when co-administered with rilpivirine 150 mg q.d. thus clinical monitoring for breakthrough infections should be recommended when azole antifungals are used concomitantly with rilpivirine. In subjects on stable methadone therapy, rilpivirine at 25 mg q.d. decreased the mean exposure of methadone by 16% however there were two cases of methadone withdrawal symptoms reported and clinical monitoring for withdrawal symptoms is recommended.

In healthy subjects, co-administration of a single 150 mg dose of rilpivirine with drugs which increase intragastric pH (omeprazole and famotidine) resulted in significant decreases in rilpivirine exposure (56% and 76%, respectively). Rilpivirine should not be used with proton pump inhibitors. Co-administration of rilpivirine with H2-receptor antagonists, antacids or didanosine (which must be administered under fasting conditions) should be scheduled to allow for sufficient temporal separation of drug intakes to ensure optimal rilpivirine absorption and exposure.

Special Populations

Hepatic Impairment

Rilpivirine is primarily metabolized and eliminated by the liver. Following administration of 25 mg q.d. rilpivirine, the mean steady-state C_max and area under the curve over 24 hours (AUC_24h) were 1.27- and 1.47-fold higher, respectively in subjects with mild hepatic impairment as compared to healthy subjects, at steady-state. In subjects with moderate hepatic impairment, the mean C_max and AUC_24h values after a single dose of rilpivirine were decreased by 30% and 24%, respectively, as compared to those of healthy controls, whereas the mean steady-state C_max and AUC_24h values were comparable between the two groups. The mean terminal half-life of rilpivirine was increased by approximately 20.2 hours and 34.5 hours in subjects with mild and moderate hepatic impairment, respectively, as compared to healthy subjects. The effects of severe hepatic impairment on exposure to rilpivirine were not studied.

Renal Impairment

Rilpivirine was not studied in subjects with renal impairment. Hepatic drug metabolism is frequently altered secondary to renal dysfunction in individuals with acute renal impairment/end stage renal disease.

3.3.3 Clinical Efficacy

The proposed 25 mg dose of Edurant™ (rilpivirine) is based on the results from a Phase IIb trial which tested three different doses (25 mg, 75 mg and 150 mg, each administered once daily) against a comparator in combination with a fixed background regimen of tenofovir and emtricitabine. Initially, rilpivirine 75 mg q.d. was selected for further development based on the 48-week results of this study. However, results from a thorough QT study using rilpivirine doses of 75 mg and 300 mg identified cardiovascular safety issues including the prolongation of QTc interval. As a result, based on the comparable efficacy of the 25 mg and 75 mg q.d. doses, rilpivirine 25 mg q.d. was selected for further development in Phase III.

The evidence of efficacy of Edurant™ 25 mg q.d. is based on the analyses of 48-week data from two, Phase III, randomized, double-blind, active-controlled studies (C209 and C215) in adult, antiretroviral treatment-naïve HIV-1 infected patients. The two studies are identical in design with the exception of the background regimen (BR) used. In study C209, the BR was fixed to a combination of tenofovir (TDF) and emtricitabine (FTC). In study C215, the BR included one of the following three: abacavir/lamivudine (ABC/3TC); zidovudine/lamivudine (AZT/3TC); or TDF/FTC. Patients with plasma HIV-1 RNA ≥5,000 copies/mL, who were screened for susceptibility to nucleoside (tide) reverse transcriptase inhibitors [N(t)RTIs] and for absence of specific non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs) were included in the studies. Both of the studies excluded patients at high risk for cardiovascular risk factors. The two studies are ongoing with additional analyses planned for 96-week data.

A total of 1,895 patients were screened, of whom 527 did not meet inclusion criteria. The most common reason for screening failure was HIV-1 viral load <5,000 copies/mL (165, 31.3%) and having at least one NNRTI RAM from the protocol exclusion list (148, 28.1%). The remaining patients were randomized and treated. Of these, 686 received Edurant™ 25 mg q.d. and 682 received the comparator. Baseline demographics and disease characteristics were balanced between the Edurant™ group and the comparator group.

The primary efficacy endpoint was the proportion of patients with plasma viral load <50 copies/mL at Week 48 (virological responders). In study C209, the proportions of virologic responders in the intent-to-treat population were 82.9% and 82.8% for the Edurant™ and control groups, respectively, and in study C215, these were 85.6% and 81.7%, respectively. Analysis of the per-protocol population confirmed these results. Thus both studies demonstrated non-inferiority of Edurant™ compared to the comparator. Analyses of the secondary endpoints showed similar results.

Virologic failure rates were higher in the Edurant™ group [10.5% versus (vs.) 5.7% in the Edurant™ and control groups, respectively in the pooled analysis]. This difference was more marked in study C209 (11.0% vs. 4.5% in the Edurant™ group vs. the control group). Among virologic failures with Edurant™, 62.9% developed NNRTI mutations, 67.7% had N(t)RTI mutations and 50.0% lost susceptibility to Edurant™. Among Edurant™-treated virologic failures with resistance to Edurant™, cross-resistance developed against efavirenz (EFV) (87.1%), etravirine (ETR) (90.3%) and nevirapine (NVP) (45.2%).

In the pooled Phase III clinical studies, the most frequently emerging mutations were V90I, L100I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. The E138K mutation emerged most frequently on Edurant™ treatment and commonly in combination with M184I, which can confer lamivudine and emtricitabine resistance.

Considering all of the available cell culture and clinical data, any of the following mutations, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E; K101P; E138A; E138G; E138K; E138R; E138Q; V179L; Y181C; Y181I; Y181V; H221Y; F227C; M230I; or M230L.

3.3.4 Clinical Safety

The clinical safety of Edurant™ was based on the data from 660 non HIV-1 infected subjects in the Phase I studies and 965 HIV-1 infected patients in the Phase II and III studies. In the Phase III studies, 611 patients received the 25 mg q.d. formulation for at least 48 weeks and the median duration of exposure was 55.7 weeks. Long-term safety data (192 weeks) was obtained from a Phase IIb study in HIV-1 infected, antiretroviral treatment-naïve adult patients.

The most common adverse events (AEs) observed with Edurant™ in the Phase III studies were headache (13.8%), nausea (13.4%), diarrhea (11.4%) and nasopharyngitis (10.1%). The most common treatment-related AEs in the Edurant™ group were nausea (10.1%), dizziness (8.0%), abnormal dreams (6.3%), and headache (6.1%). The incidence of grade 3 or 4 AEs was 13.3%.

Adverse events leading to permanent discontinuation occurred in 3.4% of Edurant™ treated patients. The most common adverse drug reaction (ADR) leading to permanent discontinuation were psychiatric disorders (10, 1.0%). The proportion of patients in the Edurant™ group experiencing at least 1 ADR was 51.6%. The most common ADRs of at least grade 2 reported with Edurant™ treatment were depression (3.5%), insomnia (2.9%), headache (2.6%), increased transaminases (2.5%), and rash (2.2%).

The incidence of grade 3 or 4 laboratory abnormalities was 10.9% with Edurant™. The most common grade 3 and 4 laboratory abnormalities were increased pancreatic amylase (2.9%), increased aspartate aminotransferase (AST) (2.0%), and increased alanine aminotransferase (ALT) (1.4%). The following grade 4 abnormalities were reported: AST 5 (0.7%); and ALT 3 (0.4%).

Statistically significant prolongation of the QTc interval was observed with 25, 75 and 150 mg doses of Edurant™ in the Phase II study. In the two Phase III studies, which excluded patients with high risk for proarrythmic conditions, Edurant™ at the 25 mg once daily dose showed a gradual increase in the mean QTc change from baseline over time.

Pooled data from the two Phase III studies showed QTc prolongation that was statistically significant from Week 2 to Week 48, inclusive. The increase was gradual over the 48 week study period, with no evidence of a plateau. At Week 48, the increase was mean 11.4 (95% CI 10.1, 12.8) ms in the Edurant™ 25 mg q.d. group and 13.0 (95% CI 11.7, 14.3) ms in the comparator group. The magnitude of the effect was numerically higher in the comparator group, but the differences between the two treatments were not statistically significant.

The adrenal gland was identified as one of the primary organs of toxicity in the non-clinical studies. In the Phase III clinical studies, a mean decrease of -13.1 nmol/L from baseline in basal cortisol was observed. At 48 weeks, the mean change from baseline in adrenocorticotropic hormone (ACTH) stimulated cortisol increase was smaller in the Edurant™ group compared to the comparator group. Monitoring of adrenal function is recommended.

In the non-clinical studies, rilpivirine was shown to induce benign and malignant tumours in liver of mice and rats. It also caused benign and malignant tumours of the thyroid follicular cells in rats. Monitoring of these tumours is recommended.

Long-term data from 183 subjects treated with Edurant™ for at least 192 weeks in the Phase IIb study indicated that no new clinically relevant or drug-related events emerged with Edurant™ administered for at least 192 weeks.

In conclusion, Edurant™ 25 mg q.d. treatment was generally safe and well-tolerated when administered for at least 48 weeks to HIV-infected, antiretroviral treatment-naïve adults, in combination with TDF/FTC, AZT/3TC or ABC/3TC. No new or unexpected safety signals were observed with long-term treatment with Edurant™ for at least 192 weeks.