Summary Basis of Decision for Incivek ™

3.3.1 Pharmacodynamics

A QT/QTc study was conducted in healthy volunteers to thoroughly evaluate the effect of telaprevir on QT/QTc intervals and cardiac safety. Incivek was tested at a dose of 750 mg every eight hours (q8h) for Days 1 to 4, and a single 750 mg morning dose on Day 5, as well as a 1,875 mg 8qh on Days 1 to 4, with a single 1,875 mg morning dose on Day 5. The 1,875 mg dose in healthy volunteers closely matched the plasma concentrations of the target patient population receiving the 750 mg dose (in combination with Peg-IFNalpha/ RBV). According to the optimal study population-specific non-linear heart rate correction, 1,875 mg q8h was associated with statistically significant QTc prolongation from 1 to 6 hours on Day 5, with a maximum difference compared to placebo of mean 8.0 milliseconds at 5 hours post-dosing. The maximum magnitude of QTc prolongation with telaprevir 1,875 mg was comparable to that observed with the positive control treatment, moxifloxacin 400 mg which produced a peak effect of 9.6 milliseconds (mean values) at 6 hours post-dosing. Statistically significant QRS prolongation was also evident from 1 to 24 hours, with a maximum difference compared to placebo of 2.6 milliseconds (mean values) at 6 hours post-dosing. Additionally, statistically significant PR interval prolongation was observed from 4 to 6 hours with a maximum difference compared to placebo of mean 5.0 milliseconds (mean values) at 6 hours postdosing. At the 1,875 mg q8h dose, all respiration rate derived heart rate was not significantly increased at any time post-dose time point, with a maximum effect of 7.9 beats per minute observed at 8 hours post-dosing. Electrocardiogram results collected from a Phase 2 study and Phase 3 study also confirmed similar observations for QTc prolongation during telaprevir treatment.

3.3.2 Pharmacokinetics

Absorption

Maximum plasma concentrations following a single dose of Incivek were generally achieved within 4 to 5 hours post-dose. In vitro studies performed on human Caco-2 cells revealed that telaprevir is a substrate of P-gp. Exposure to telaprevir is higher during coadminstration of Peg-IFN-alfa/RBV than after administration of Incivek alone.

A food study conducted in healthy volunteers revealed that the fat content of a meal significantly affects exposure to telaprevir. When compared with administration following a standard meal (21 grams of fat), exposure to telaprevir decreased by 19%, 42%, and 73% when administered with meals that were successively less in fat [that means (i.e.) 9 grams of fat, 3.6 grams of fat, and fasting condition]. Following this trend, telaprevir exposure increased by 36% when administered with a high-fat (56 grams of fat) meal, compared to a standard meal. Similarly, the maximum concentration of telaprevir followed this trend with the change in amount of fat in meals. Based on this study, to achieve optimal telaprevir exposure, Incivek should be taken with food.

Distribution

Telaprevir is approximately 59% to 76% bound to human plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding is concentration dependent, decreasing with increasing concentrations of telaprevir. Following oral administration, the typical apparent volume of distribution of telaprevir was approximately 252 litres, with an inter-individual variability of 72%.

Metabolism

Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in the faeces, plasma, and urine; but no new unique human metabolites were observed other than those noted in the non-clinical species. Following repeated-oral administration, R-diastereomer of telaprevir, pyrazinoic acid, and a metabolite that underwent reduction at the alpha-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir.

In vitro studies using recombinant human CYP isoforms indicated that CYP3A4 was the major isoform responsible for telaprevir metabolism. However, non-CYP mediated metabolism likely plays a role after multiple dosing of telaprevir.

Excretion

Incivek is predominantly eliminated through the faeces. Following administration of a single dose of radiolabelled Incivek, the median recovery of the administered radioactive dose was approximately 82% in faeces, 9% in exhaled air and 1% in urine.

Biopharmaceutics

A comparative bioavailability study was conducted in healthy volunteers to evaluate the bioequivalence of an uncoated telaprevir tablet (used within the Phase III clinical studies) and a film-coated telaprevir tablet proposed for market. Results from this study showed the rate and extent of telaprevir absorption from the uncoated (clinical) 375 mg tablet was comparable to the coated 375 mg tablet under fed conditions. Therefore, the comparative data was determined to be acceptable.

3.3.3 Clinical Efficacy

The efficacy of Incivek was evaluated primarily in three Phase III studies in genotype 1 hepatitis C-infected patients. Among these three studies, two were conducted in treatment-naïve patients, and the third study was conducted in previously treated patients (relapsers, partial responders, and null responders). All patients enrolled had compensated liver disease, detectable hepatitis C virus ribonucleic acid (HCV-RNA) particles, and liver histopathology consistent with chronic hepatitis C. The methodology used to assess efficacy was that of plasma HCV-RNA measurements through the use of the COBAS® TaqMan® HCV test (version 2.0). The assay had a lower limit of quantitation of 25 IU/mL. The primary outcome measure for all three studies was the sustained virologic response (SVR). SVR was defined as undetectable HCV RNA 24 weeks after the end of treatment and is considered a virologic cure. The lower limit of detection was 10 IU/mL. Undetectable HCV RNA was used to determine SVR.

Treatment-naïve Patients

The first Phase III study, herein known as "Advance", was a randomized, double-blind, parallel-group, placebo-controlled study conducted in treatment-naïve patients who had not received any prior hepatitis C treatment, including INF or Peg-INF monotherapy. This study sought to explore whether Incivek, in combination with Peg-IFN-alfa/RBV would be superior in efficacy compared to Peg-IFN-alfa/RBV treatment alone. In addition, this study also sought to explore whether a shortened dosing regimen for Incivek (8-week treatment) would offer an improved tolerability as compared to the proposed 12-week Incivek dosing regimen while not compromising efficacy.

The study design consisted of either administering Incivek for 8 weeks in combination with Peg-IFN-alfa/RBV (T8/PR regimen) for either 24 or 48 weeks; or administering Incivek for 12 weeks in combination with Peg-IFN-alfa/RBV (T12/PR regimen) for either 24 or 48 weeks. The duration of Peg-IFN-alfa/RBV administration was determined through a response-guided therapy determined by the presence or absence of an extended Rapid Virologic Response (eRVR). Patients who demonstrated presence of an eRVR (eRVR⁺); that being an undetectable HCV-RNA at either Week 4 or Week 12, received a shortened 24-week Peg-IFN-alfa/RBV dosing regimen. Patients who demonstrated absence of an eRVR (eRVR^-); that being who did not have undetectable HCV-RNA at either Week 4 or Week 12, received a 48-week Peg-IFN-alfa/RBV dosing regimen. The control group (Pbo/PR48 regimen) received a matched-placebo for the first 12 weeks along with a Peg-IFN-alfa/RBV dosing for 48 weeks.

Results from the Advance study demonstrated significant improvement in SVR rates in both Incivek treatment groups (T12/PR = 74.7% and T8/PR = 68.7%) compared to the placebo treatment group (Pbo/PR48 = 43.8%). Furthermore, relapse rates were lower in both Incivek treatment groups compared to the placebo group, as were on-treatment virologic failure rates. Incivek-treated patients in both groups achieved comparable eRVR rates which were much higher than in the placebo group. However, for patients which achieved eRVR⁺, the SVR rates were higher in the placebo-treated patients compared to the Incivek-treated patients, suggesting no additional efficacy was achieved with Incivek treatment among eRVR⁺ patients. For patients who failed to achieve an eRVR (i.e., eRVR^-), SVR rates in the Incivek treatment groups were also higher compared to the placebo group.

When study results were compared between T12/PR and T8/PR treatment regimens, T12/PR achieved favourable efficacy outcomes, namely higher SVR rates, lower relapse rates and lower on-treatment virologic failure rates. Although eRVR rates were comparable, the eRVR to SVR rates were higher in T12/PR. In conclusion, results from the Advance study showed that Incivek administration, in combination with Peg-IFNalfa/RBV treatment, demonstrated superiority in efficacy when compared to Peg-IFNalfa/RBV treatment alone (placebo + Peg-IFN-alfa/RBV) in treating chronic hepatitis C treatment-naïve patients. Furthermore, the 12-week Incivek dosing regimen was more favourable than the 8-week Incivek dosing regimen.

A second Phase III study, herein known as "Illuminate", was a randomized, activecontrolled, open-label study also conducted in treatment-naïve patients. This study was designed as a supportive study to determine whether a 24-week Peg-IFN/RBV duration was non-inferior to a 48-week Peg-IFN/RBV duration in patients who achieved eRVR (i.e., eRVR⁺). Patients received 12 weeks of Incivek in combination with Peg-IFN/RBV (T12/PR). Patients with eRVR⁺ were randomized at Week 20 to complete either 24 or 48 weeks of treatment. Patients who did not achieve eRVR (i.e., eRVR^-) were assigned to receive a total of 48 weeks of Peg-IFN/RBV.

In the Illuminate study, SVR rates were 92% in T12/PR24/eRVR⁺ patients and 87.5% in T12/PR48/eRVR⁺ patients, demonstrating that the T12/PR24 regimen was non-inferior to the T12/PR48 regimen among eRVR⁺ patients. Moreover, relapse rates were lower among eRVR⁺ patients randomized to T12/PR48 compared to all other treatment groups. Although the number of cirrhotic patients was limited, eRVR⁺ cirrhotic patients randomized to the T12/PR48 regimen achieved a much higher SVR rate (91.7%) than those eRVR⁺ cirrhotic patients randomized to the shorter T12/PR24 regimen (SVR rate 66.7%). This leads to suggest eRVR⁺ cirrhotic patients may benefit from a longer Peg- IFN-alfa/RBV dosing (i.e., 48 weeks). In conclusion, the efficacy results of the Illuminate study were consistent with the results seen within the Advance study. In addition, results from the Illuminate study also demonstrated overall non-inferior efficacy in eRVR⁺ patients with genotype 1 chronic hepatitis C who received the T12/PR24 treatment regimen as apposed to the extended Peg-IFN-alfa/RBV 48-week dosing regimen (T12/PR48). Moreover, cirrhotic patients with eRVR⁺ also showed a clinical benefit from the 48-week Peg-IFN-alfa/RBV dosing treatment as opposed to the 24-week Peg-IFNalfa/RBV dosing treatment.

Treatment-failure Patients

The third Phase III study, herein known as "Realize", was a randomized, double-blind, placebo-controlled, three-arm study conducted in patients who did not achieve SVR through prior treatment with either Peg-IFN-alfa-2a/RBV or Peg-IFN-alfa-2b/RBV. This study sought to demonstrate the superiority of Incivek treatment in combination with Peg-IFN-alfa/RBV therapy compared to a placebo and Peg-IFN-alfa/RBV therapy alone in achieving SVR in prior relapsers, prior partial responders, and prior null responders. In addition, this study also sought to evaluate whether a delayed start (DS) of Incivek offered an efficacy advantage by reducing the emergence of Incivek-resistant variants and thus on-treatment virologic failures.

The study enrolled prior relapsers (patients with HCV-RNA undetectable at end of treatment with a Peg-IFN-based regimen, but HCV-RNA detectable within 24 weeks of treatment follow-up) and prior non-responders (patients who did not have undetectable HCV-RNA levels during or at the end of a prior course of at least 12 weeks of treatment). The non-responder population included 2 sub-groups: prior partial responders (greater than or equal to 2-log₁₀ reduction in HCV-RNA at week 12, but not achieving HCV-RNA undetectable at end of treatment with Peg-IFN-alfa/RBV); and prior null responders (less than 2-log₁₀ reduction in HCV-RNA at week 12 of prior treatment with Peg-IFNalfa/RBV).

Patients were randomized in a 2:2:1 ratio to one of three treatment groups. In two of the treatment groups patients received Incivek for 12 weeks in combination with Peg-IFNalfa/RBV for 48 weeks; one group started the treatment regimens simultaneously (T12/PR48), and the other had a 4-week delayed start of Incivek (T12-DS/PR48) to examine the impact on relapse and resistance. The third treatment group received a placebo for 16 weeks in combination with Peg-IFN-alfa/RBV dosing for 48 weeks (Pbo16/PR48).

The proportion of patients achieving SVR was significantly higher in each of the Incivek treatment groups compared to placebo. For the prior relapser population, in the Incivek treatment groups, SVR rates were 83.4% to 87.9%, respectively compared to 23.5% for the placebo group. For prior non-responder population, SVR rates were 41.3% and 41.5% respectively, in the Incivek treatment groups compared to 9.4% in the placebo group. Sustained virologic rates were also significantly higher in each of the prior non-responder subgroups: prior null; and prior partial responders. For the prior null responder population, SVR rates were 29.2% and 33.3%, respectively for the Incivek groups, compared to 5.4% in the placebo group. For prior partial responders, SVR rates were 59.2% and 54.2%, respectively, for the Incivek groups compared to 14.8% for the placebo group. In conclusion, Incivek met its primary objective of demonstrating superior efficacy when combined with Peg-IFN-alfa/RBV compared to Peg-IFNalfa/RBV therapy alone (standard treatment) in patients with genotype 1 chronic hepatitis C infection who previously failed treatment with Peg-IFN-alfa/RBV. Further, the delayed start of Incivek treatment did not result in an added clinical benefit relative to simultaneous start of Incivek and Peg-IFN-alfa/RBV.

It is worthy to note that response-guided therapy was not evaluated in the Realize clinical study in the treatment-failure population. However, data from the Phase II studies indicated that the treatment-failure population was not uniform. Prior relapsers and prior non-responders are quite distinct, and the prior relapse population appears to have more similarities to the treatment-naïve population than to the prior non-responders (particularly prior null responders), based on rapidity of the antiviral response and on SVR rates. The primary benefit of response-guided therapy is that there is a shortened duration of therapy from 48-weeks to 24-weeks which is likely to improve the safety profile due to a reduced exposure to Peg-IFN-alfa/RBV.

3.3.4 Clinical Safety

The overall safety profile of Incivek was based mainly on the three Phase III studies previously described in section 3.3.3 Clinical Efficacy, in addition to supportive safety data derived from two Phase II studies.

The most frequent adverse events (AEs) in patients who received Incivek in combination with Peg-IFN-alfa/RBV were fatigue; pruritus; nausea; influenza-like illness; rash; anaemia; insomnia; diarrhoea; and pyrexia. The most frequent adverse drug reactions (ADRs) in patients who received Incivek in combination with Peg-IFN-alfa/RBV were pruritus; rash; nausea; anaemia; diarrhoea; vomiting; hemorrhoids; and proctalgia (i.e., pain in anal or rectal region). Serious ADRs occurred in 3.9% of patients in the T12/PR treatment group compared to 0.7% in the Pbo/PR group. The most frequent serious adverse events (SAEs) were anaemia and rash. A total of 10.4% of patients discontinued the study due to ADRs; with rash, anaemia, pruritus, nausea, and vomiting being the most frequent ADRs leading to discontinuation.

Pooled safety data from the Phase II and Phase III studies identified a total of nine deaths. Among these deaths, five occurred in patients randomized to Incivek therapy and four occurred in patients who received Peg-IFN-alfa/RBV therapy alone. None of the deaths in the Incivek treatment group occurred while administering Incivek. One death, confirmed to be malignant neoplasm of the lung, was diagnosed 96 days after the last dose of Incivek was administered and was considered by the site investigator as possibly related to Incivek. This patient had however, a history of smoking 15 to 20 cigarettes per day for over a 40-year period.

Anorectal ADRs (e.g., hemorrhoids, anorectal discomfort, anal pruritus and rectal burning) were reported more frequently in the T12/PR group than in the Pbo/PR group [26.2% versus (vs.) 5.4%]. Serious anorectal events, events of at least Grade 3 or leading to discontinuation were infrequent (<1.0%) in the T12/PR group and did not occur in the Pbo/PR group.

Safety Issues of Interest

QT, QRS and PR Prolongation

Healthy volunteers that received Incivek at a dose concentration of 1,875 mg every 8 hours demonstrated a modest effect on QTc, QRS and PR interval prolongation. Exposure at this dose was comparable to the exposure in hepatitis C-infected patients dosed at 750 mg every 8 hours in combination with Peg-IFN-alfa/RBV. Caution is therefore recommended when prescribing Incivek concurrently with drugs known to induce QT prolongation and which are CYP3A substrates (such as erythromycin, ketoconazole, haloperidol, tacrolimus, and salmeterol). Incivek may increase concentrations of the co-administered drug which may result in an increased risk of their associated cardiac AEs. In the event that co-administration of such drugs with Incivek is judged strictly necessary, clinical monitoring, including electrocardiogram (ECG) assessments, should be considered. Additionally, monitoring and correction of electrolyte disturbance (e.g., hypokalemia, hypomagnesemia, and hypocalcemia) should be considered prior to initiation and during Incivek therapy.

Use of Incivek should be avoided in patients with: congenital QT prolongation; or a family history of congenital QT prolongation; or sudden death. In the event that treatment with Incivek in such patients is judged clinically necessary, consideration should be given to monitoring, including ECG assessments. Incivek should be used with caution in patients with: a history of acquired QT prolongation; a history of arrhythmias (especially ventricular arrhythmias or atrial fibrillation); a history of heart failure with reduced leftventricular ejection fraction; myocardial ischemia or infarction; cardiomyopathy; conduction system disease; or a requirement for drugs known to prolong the QT interval without CYP3A4 involvement by telaprevir (e.g., methadone).

Syncope

Administration of Incivek was observed to be associated with an increased incidence of syncope. In the pooled safety data from the Phase II and III placebo-controlled studies, the incidence of syncope, syncope vasovagal, and loss of consciousness was three-times higher for patients treated with Incivek 750 mg every 8 hours than the placebo. The possibility does exist that either the QT prolongation, PR interval prolongation, or increased heart rate may be related to the syncope. In the absence of further ECG data, it is difficult to assess whether electrocardiographic effects contributed to this event, but the possibility cannot be ruled out. Other electrocardiographic AEs which occurred at a higher rate in Incivek-treated patients compared to placebo included atrial/cardiac flutter and bundle branch block.

Anaemia

In the Phase II and III studies, Peg-IFN-alfa/RBV therapy has been observed to be a cause of decreased haemoglobin concentrations, thereby leading to anaemia. The noted frequency of anaemia ADRs reported during Incivek treatment compared to placebo was higher within the T12/PR group (31.8%) than in the Pbo/PR group (14.8%). The severity of anaemia events was also higher in the T12/PR treatment group than in the Pbo/PR group. Anaemia events of at least Grade 3 occurred in 4.9% (T12/PR) versus 0.8% (Pbo/PR), of patients. Serious anaemia events were reported in 1.6% of patients in the T12/PR group, respectively, compared to <1.0% of patients in the placebo/PR group. Anaemia events leading to permanent discontinuation of the study drug alone and all study drugs were reported in 2.7% and <1.0% of patients in the T12/PR group, respectively, compared to <1.0% in each group, respectively, in patients in the placebo/PR group.

Skin Rash

The overall incidence and severity of skin rash increased when Incivek was coadministered with Peg-IFN-alfa/RBV. During the Incivek treatment phase, rash ADRs (all grades) were reported in 48.7% of patients who received Incivek in combination Peg- IFN-alfa/RBV compared to 28.0% of patients who received Peg-IFN-alfa/RBV treatment alone. More than 90% of skin rashes were of mild or moderate severity and were typically pruritic or eczematous in nature and involved less than 30% of the body surface area. The most common time for a rash to begin was during the first 4 weeks following initiation of Incivek treatment, however rashes could also occur at any other time during therapy. Improvement of the rash normally occurred after Incivek dosing was completed or discontinued; however, some rashes may take longer for complete resolution.

Due to the incidence of severe rash, the sponsor created a dermatology assessment panel to assess the cases of severe rash. The dermatology assessment panel reviewed a total of 221 cases, and found a number of serious skin reactions, including drug rash with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson Syndrome (SJS). The DRESS and SJS events were reported in the clinical development programme, at a rate of <1% of patients who received Incivek in combination with Peg-INF-alfa/RBV, compared to none who received Peg-INF-alfa/RBV alone. There were no deaths, and no cases of toxic epidermal necrolysis; however all serious skin reactions did require hospitalization for resolution.

The incidence of pruritus ADRs was noted to be higher in Incivek-treated patients compared to placebo-treated patients, 51.5% vs. 26.4% respectively. Discontinuation of Incivek or the placebo due to pruritus was infrequent in both groups, but higher in the T12/PR group than in the placebo group (1.0% vs. 0.1%). The incidence of pruritus was highest during the first 4 weeks of treatment and remained higher among patients receiving Incivek therapy. After Week 12, the incidence of pruritus was comparable between groups.

Hepatic Impairment

Incivek is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥7) or patients with decompensated liver disease. However, no dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5-6).

Pregnancy

Ribavirin is a known teratogen. Therefore, Incivek treatment in combination with Peg-INF-alfa/RBV should not be started unless a negative pregnancy test has been obtained immediately prior to initation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Female patients of childbearing potential and their male partners and male patients and their female partners of childbearing potential must use two effective methods of contraception during treatment, and for six months afterwards. Female patients should have monthly pregnancy tests during treatment. Hormonal contraceptives may not be reliable during Incivek treatment. Therefore, during this time, and for two months following treatment, female patients of childbearing potential should use two non-hormonal methods of contraception.