Summary Basis of Decision for Victrelis ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
VictrelisTM
Boceprevir, 200 mg, Capsule, Oral
Merck Canada Inc.
Submission control no: 141556
Date issued: 2011-12-22
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02370816
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On July 29, 2011, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the drug product Victrelis™.
Victrelis™ contains the medicinal ingredient boceprevir which is a hepatitis C virus (HCV) protease inhibitor.
Victrelis™ is indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alpha (PegIFNα)/ribavirin (RBV), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Victrelis™ were primarily based on the analyses of two parallel-group, double-blind, multicentre Phase III studies conducted with Victrelis™ in combination with PegIFN alfa-2b/RBV in either treatment-naïve patients or patients who failed previous therapy. The sustained virologic response (SVR) was evaluated for all patients within both studies and was shown to have significantly increased (approximately 27% higher in treatment-naïve patients and 41% in patients who failed previous therapy) in patients who received the combination of Victrelis™ with PegIFN alfa-2b/RBV compared to PegIFN alfa-2b/RBV therapy alone. In addition, the rate of relapse, discontinuation and treatment failure were much lower in patients who received the treatment combination of Victrelis™ with PegIFN alfa-2b/RBV compared to patients who received PegIFN alfa-2b/RBV therapy alone.
Victrelis™ (200 mg, boceprevir) is presented in a capsule form. The recommended dose of Victrelis™ is 800 mg (four 200 mg capsules) administered orally three times a day taken every 7-9 hours with food. The patients must first take peginterferon alfa and ribavirin for four weeks, after which they will add Victrelis to the treatment for up to 44 weeks, depending on several factors such as the patient’s previous treatment and results of blood tests during treatment. Consultation of Victrelis™ Product Monograph prior to initiation of therapy is highly recommended for further dosing guidelines. Victrelis™ must not be used as monotherapy, but only in combination with PegIFN alfa/RBV. The Product Monographs of PegIFN alfa/RBV must be consulted prior to initiation of therapy with Victrelis™.
Victrelis™, in combination with PegIFN alpha/RBV, is contraindicated for patients with:
- known hypersensitivity to boceprevir or to any of the ingredients of the product (including the capsule);
- autoimmune hepatitis;
- hepatic decompensation [Child-Pugh score >6 (class B and C)];
- pregnant women and men whose female partners are pregnant;
- co-administration with medicines that are highly dependent on cytochrome P450 (CYP) 3A4/5 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index);
- co-administration with medicines that are potent CYP3A4/5 inducers, where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy.
Victrelis™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Victrelis™ are described in the Product Monograph.
Priority Review Status was granted for the evaluation of Victrelis™ as it appeared to provide substantial evidence of increased clinical efficacy such that the overall benefit/risk profile is improved over existing therapies.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Victrelis™ is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Boceprevir, the medicinal ingredient of Victrelis™ is a hepatitis C virus (HCV) protease inhibitor. Boceprevir blocks an enzyme called HCV NS3/4A protease. Boceprevir inhibits the cleavage of the HCV polyprotein to form the functional viral proteins required for viral propagation.
Manufacturing Process and Process Controls
Boceprevir is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of boceprevir has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from batch analysis or toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of boceprevir.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period, shelf-life, and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Victrelis™ contains the medicinal ingredient, boceprevir. The drug product is presented as hard gelatin capsules for oral administration. Each capsule has a yellowish-brown, opaque cap with the Merck logo imprinted with red ink. The opaque body of the capsule is off-white and has "314" imprinted in red ink.
Each Victrelis™ capsule contains 200 mg of boceprevir and the following inactive ingredients: croscarmellose sodium; lactose monohydrate; magnesium stearate; microcrystalline cellulose; pre-gelatinized starch; and sodium lauryl sulfate. The capsule shell consists of gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The capsule is printed with red ink containing red iron oxide and shellac.
Victrelis™ capsules are packaged in peelable blisters (4 capsules per blister cavity; 12 capsules per blister card).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of boceprevir with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Victrelis™ is tested to verify that its identity, appearance, content uniformity, assay, dissolution, moisture content, and levels of degradation products and drug-related impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.
The validation process is considered to be complete. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life for Victrelis™ is considered acceptable when the product is stored at refrigeration (2-8°C). A patient in-use period of up to 3 months at room temperature (15-30°C) in the original container is also acceptable.
The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Victrelis™ are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The gelatin and lactose are of animal origin. Letters of attestation confirming that the material is not from a bovine spongiform encephalopathy (BSE) and transmissible spongiform encephalopathy (TSE) affected country/area has been provided for this product indicating that it is considered to be safe for human use.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Victrelis™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Boceprevir appeared to be a potent and selective inhibitor of HCV NS3 protease with a inhibitory constant (Ki) of 14-19 nM. Boceprevir was specific for HCV genotype 1a and 1b with limited activity against genotypes 2a and 3a. The effects of interferon alpha and boceprevir appeared to be additive and suppressed the emergence of resistance variants. Boceprevir had minimal effect (<3 fold) on the antiviral activity of HIV proteases atazanavir (ATV) and ritonavir (RTV), and caused a slight decrease in the half maximal effective concentration (EC50) values of lopinavir (LPV).
Boceprevir is a mixture of two diastereomers (SCH534128 and SCH534129) that differ in stereochemical configuration at the third carbon atom from the ketoamide end of the molecule. The drug substance is an amorphous powder with a diastereomer ratio of approximately 1:1 (SCH534128:SCH534129). SCH534128 was at least 41- to 130-fold more potent than SCH534129 as an inhibitor of HCV NS3 protease. In a cell-based replicon inhibition assay, the diastereomers had equivalent activity, indicating interconversion of SCH534128 and SCH534129 to reach equilibrium. In vitro incubations of the individual diastereomers of boceprevir in plasma showed that they interconvert. In rats, epimerization of the diastereomers was observed following oral administration of SCH534128 and SCH534129 individually.
Culturing of replicon cells in the presence of boceprevir resulted in the emergence of resistant colonies. Boceprevir resistance mutations also developed during clinical studies of boceprevir. Resistance mutations with reduced susceptibility to boceprevir were characterized in biochemical and replicon assays. Overall, V170A (10), T54S+R155K (12), V36M+R155K (14), A156S (17), R155G (18), R155T (20), T54C (32), R155I (45), A156T/V (300) confers resistance to NS3 protease inhibitors with an average overall inhibition constant (Ki) fold change of 10-300.
Safety pharmacological studies of boceprevir evaluated its effects on cardiovascular, respiratory, central nervous, gastrointestinal and renal systems. The results of these studies do not raise any safety concern at clinical doses.
Non-clinical qualification studies were performed to support new specification criteria for boceprevir impurities and metabolites present in both the drug substance (boceprevir) and drug product (Victrelis™). The results of the non-clinical studies adequately supported the safety level provided by the new specification criteria.
3.2.2 Pharmacokinetics
Absorption
The pharmacokinetic (PK) attributes of boceprevir include moderate absorption and oral bioavailability. Systemic exposure to boceprevir and its diastereomers were highly variable. The maximum plasma concentration (Cmax), and area under the curve (AUC) to boceprevir, SCH 534128 (the active diastereomer), and SCH 534129 (the inactive diastereomer) increased as the doses increased.
Distribution
Boceprevir had low plasma protein binding, was widely distributed to tissues, crossed the placenta in rats, and was excreted in milk of nursing rats. The highest concentrations were in the liver, bladder wall, kidneys, various glandular tissues (adrenal, harderian, salivary, and prostate glands), digestive tract, and bone marrow.
Metabolism
Boceprevir was extensively metabolized in vitro following incubations with rat, dog, monkey, and human hepatocytes; human liver microsomes; and mouse, monkey, and human liver fractions, as well as in vivo. The most common metabolic pathways included oxidation, reduction, and a combination of oxidation and reduction. All metabolites detected in humans were also observed in animals. Based on the results of in vitro and in vivo studies, the aldo-ketoreductase (AKR) 1C isoforms and the cytochrome P450 (CYP) isozymes 3A4/5 are the primary enzymes responsible for boceprevir metabolism.
Boceprevir caused direct and time-dependent inhibition of CYP 3A4/5, and co-administration with the CYP 3A4/5 substrate midazolam in human subjects increased exposure to midazolam. Boceprevir is also a substrate and inhibitor of P-gp.
Co-administration with ketoconazole, a CYP 3A4/5 inhibitor and a P-gp inhibitor, increased the exposure to boceprevir.
Excretion
Excretion of boceprevir-derived material was mainly via the biliary/faecal route in animals.
3.2.3 Toxicology
Single-Dose Toxicity
The no-observed-adverse-effect level (NOAEL) after a single, oral dose was 2,000 mg/kg in female rats and 1,000 mg/kg in male rats. The NOAEL in males was based on a decrement in body weight gain.
The NOAELs for monkeys and dogs were 250 mg/kg and 100 mg/kg, respectively. Clinical signs of toxicity included emesis and abnormal stool findings.
Repeat-Dose Toxicity
The repeat-dose toxicity findings tend to be dose-related and/or species-specific in nature; and occur at exposures that are slightly higher than or similar to the clinical therapeutic dose. Targets identified in the non-clinical studies consisted of the gall bladder; liver; reproductive tract; and the activated partial thromboplastin time (APTT) coagulation parameter, and were primarily observed in rodents.
Grossly discolored gall bladder was observed in the 2-year mouse carcinogenicity study. The finding has no histopathologic correlate, no inflammation, no evidence of concretions, and no gall bladder tumours. In the 3-month dose range-finding study, clinical pathology parameters indicated no changes in alkaline phosphatase and no evidence for cholestasis. These findings were not observed in a 3-month study in mice and were not observed in monkeys.
Multifocal neutrophilic infiltration of the liver associated with necrotic hepatocytes, and Kupffer cell hypertrophy were observed in mice. Minimal to mild increases in aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in mice, but there was no direct correlation in affected individuals between neutrophilic liver infiltrates and increased liver enzymes. In a 2-year carcinogenicity study in mice, increased incidences of hepatocellular adenomas in the liver of female mice at 650 mg/kg as compared to controls was considered related to boceprevir administration. There were also increased incidences of hepatocyte necrosis and minimal to moderate pigment accumulation in macrophages.
Scattered foci of multinucleated hepatocytes occurred in a dose-related manner in rats dosed at ≥50 mg/kg in several studies. Associated with the liver findings were minimal to mild increases in ALT/AST levels, but there appeared to be no direct correlation between elevated liver enzymes and multinucleated hepatocytes in the affected animals. Single cell necrosis of hepatocytes was seen in 3 dead females with 2 having elevated ALT/AST.
Increases in APTT were observed in monkeys in several studies in the absence of clinical observations. There were no changes in other clinical pathology parameters suggestive of haemorrhage, or gross pathology evidence of haemorrhage that would indicate a defect in haemostasis [NOAEL of 25 mg/kg which represented a monkey-to human exposure multiple of <1 at a human dose of 800 mg three times a day (TID)]. Convincing increases in APTT were only observed with optical detection methods or at high doses, and there was considerable variability of magnitude and sensitivity of the effect depending on the dose, instrument, or reagent manufacturer.
Genotoxicity
Boceprevir was not genotoxic in the in vitro bacterial mutagenicity assay and human peripheral blood lymphocyte assay, as well as in the in vivo mouse bone marrow erythrocyte micronucleus assay.
Carcinogenicity
In a two-year carcinogenicity study in mice, an increased incidence of hepatocellular adenomas was observed in female mice at 650 mg/kg compared to control female mice. The exposure at the 650 mg/kg dose in female mice was 5.7-fold the human exposure at the recommended 800 mg TID clinical dose. There were no increases in mortality or malignancy associated with the hepatocellular adenomas. This finding is considered gender- and species-specific to female mice and not clinically relevant. In the 2-year rat carcinogenicity study, there were no adenomas/carcinomas. The exposure at highest dose was approximately 0.9-fold the human exposure at 800 mg TID.
Reproductive and Developmental Toxicity
Fertility effects were observed in male and female rats but no embryo-foetal toxicity was observed. Boceprevir decreased fertility and early embryonic development in female rats with an NOAEL of 75 mg/kg. Decreased fertility was also observed in male rats, most likely as a consequence of testicular/epididymal degeneration (NOAEL of 15 mg/kg which represents a rat-to-human exposure multiple of <1 at a human dose of 800 mg TID). A trend towards functional recovery in the testes was observed during a 2-month post-dose interval following 3-months of boceprevir dosing. This finding was not observed in either mice or monkeys and appeared to be species-specific to rats. Additionally, clinical monitoring of the surrogate marker inhibin-B, as well as semen analysis revealed no evidence that these findings are clinically relevant to human patients.
When neonatal and juvenile rats were administered single daily oral doses of 25, 75, or 150 mg/kg from post-natal days (PNDs) 7-91, followed by a 4-week post dose period, the NOAEL for first filial generation (F1) systemic toxicity was 25 mg/kg (a rat-to-human exposure multiple of <1). The mean age of attainment of balanopreputial separation was significantly higher for the 150 mg/kg group males versus controls, and was associated with testicular findings on PND 92. Hyperplasia of thyroid gland follicular cells and higher liver weights were noted in the 75 and 150 mg/kg group males and the 150 mg/kg group females on PND 92. The thyroid hyperplasia was not present at the end of the post-dose period. Except for the juvenile rat-specific thyroid hyperplasia, findings from the juvenile studies were similar to those observed in adult animals.
3.2.4 Summary and Conclusion
The non-clinical studies for this drug submission are considered acceptable. The non-clinical pharmacology and toxicology program for Victrelis™ (boceprevir) demonstrated that the compound is relatively safe for humans. There are no pharmacological/toxicological issues within the submission which preclude approval of the requested product indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
A QT/QTc study was conducted to thoroughly evaluate the effect of boceprevir on QT/QTc intervals and cardiac safety in a well-controlled setting. This assessment was in-line with the identified assessment of ICH E14. The study utilized a positive control, consisting of a single dose (400 mg) of moxifloxacin, to ensure that the assay was capable of prolonging the mean QT/QTc interval by approximately 5 ms, which is close to the mean QT/QTc effect representative of regulatory concern. The study incorporated two objectives, a primary and a secondary objective.
The primary objective was to evaluate the effect of both a therapeutic (800 mg TID) and a supra-therapeutic (1,200 mg TID) dose of boceprevir at steady-state on the QT interval, corrected with Fridericia’s method (QTcF), as measured by the largest upper bound of the 95% one-sided confidence interval for mean change from time-matched baseline electrocardiogram (ECG) recordings compared with placebo.
The secondary objective was to evaluate the effect of boceprevir on cardiac adverse events, PR interval, and heart rate at both the therapeutic dose (800 mg TID) and a supratherapeutic (1,200 mg TID) dose after multiple dosing for 5 days.
The following conclusions are based on the administration of multiple, oral, therapeutic (800 mg) and supratherapeutic (1,200 mg) doses of boceprevir.
- The results from the moxifloxacin treatment group as a positive control validated the study design, that is (i.e.) prolongation of mean QT/QTc was seen for this treatment.
- Boceprevir does not prolong the QT interval at 1,200 mg or 800 mg relative to placebo, as determined by QTcF analysis, the primary endpoint.
- Analyses of QT intervals using uncorrected data as well as the other QT corrections specified in the protocol were similar to those seen with QTcF, i.e., treatment with moxifloxacin led to increased QT/QTc interval length, while treatment with boceprevir did not.
- When QTcF was analyzed separately for men and women, the same conclusion was reached, i.e., boceprevir did not affect the QTc interval in either men or women.
- Categorical summaries of numbers of subjects with changes in QT interval of
<0, 0 to <30, 30 to <60, and ≥60 msec and/or with a QT interval >500 msec demonstrated no apparent effect by boceprevir at either 1,200 mg or 800 mg. - Other ECG parameters among subjects who received boceprevir also showed no clinically significant changes between baseline and post-dose timepoints.
3.3.2 Pharmacokinetics
Absorption
Boceprevir was rapidly absorbed with a time to maximum plasma concentration (Tmax) of approximately 2.0 hours and a plasma half-life (t1/2) of approximately 3.0 hours following single-dose administration with food to healthy subjects. Steady-state plasma exposure values increased in a less than dose-proportional manner. There was little difference between the exposure parameters with the 800 mg and 1,200 mg doses suggesting diminished absorption at higher doses.
Administration with food had a significant effect on the bioavailability of boceprevir increasing the AUC by 40-60% compared to the fasted state. The meal type and timing of the meal administration did not appear to affect the increase in exposure. In the Phase III clinical studies, boceprevir was administered with food. Therefore, the Victrelis™ Product Monograph states that Victrelis™ (boceprevir) must be taken with food (meal or snack).
Distribution
Boceprevir has a mean apparent volume of distribution of approximately 717 L (n = 71) at steady-state.
Boceprevir was not highly bound to human plasma proteins. The boceprevir protein binding was approximately 75% for human plasma.
Metabolism
Boceprevir is metabolized by two pathways: alpha keto reductase (AKR); and CYP450. When co-administered with diflunisal, an inhibitor of the AKR pathway, the minimum plasma concentration of boceprevir was increased approximately 31%, however, no effect was observed on the AUC. In another clinical pharmacology study, ibuprofen (another inhibitor of the AKR pathway) also had no effect. However, the co-administration with ketoconazole (400 mg twice a day), an inhibitor of CYP3A4, resulted in a 41% increase in the Cmax of boceprevir and a 131% increase in AUC.
Excretion
In a clinical study with radiolabelled boceprevir, a mean total of 88.2% of the radioactive dose was recovered in the urine and faeces 168 hours after a single oral administration of 800 mg. Radioactivity recovered in the urine and faeces accounted for 9.28% and 78.9% of the dose, respectively, with approximately 3% and 8% of the radiolabelled dose eliminated as boceprevir in the urine and faeces, respectively.
Special Populations
Race: In a small clinical pharmacology study in healthy subjects, African Americans appeared to have lower Cmax and AUC and shorter t1/2 compared to Caucasian subjects. However, the sample size was quite small (n = 6) and thus no conclusions can be made from this study. In another clinical pharmacology study in healthy subjects, the influence of race/ethnic origin on the PK of boceprevir was examined. Similar Cmax and AUC values were observed in Japanese and Caucasian subjects when boceprevir was administered with a meal.
Subjects with Renal Insufficiency: Study results demonstrated no significant increase in Cmax or AUC in subjects with end stage renal disease and dialysis did not affect the PK of boceprevir. The results of a Phase III Population Pharmacokinetic Study demonstrated that renal function (as measured by creatinine clearance) had no effect on the PK of boceprevir. No dose adjustment is required in patients with any degree of renal impairment.
Subjects with Various Degrees of Hepatic Impairment: There was a trend toward increased AUC and Cmax with mild and moderate liver impairment. In patients with severe hepatic impairment, the difference was statistically significant. From the results of this study and the Phase III Population Pharmacokinetic Study, data demonstrated that hepatic function (as measured by the liver enzymes) had no clinically significant effect on the PK of boceprevir, the active ingredient of Victrelis™. The sponsor has concluded that no dose adjustment is required for subjects with hepatic impairment. However, Victrelis™ should only be administered in combination with peginterferon alpha/ribavirin, and peginterferon alpha/ribavirin is contraindicated in patients with hepatic decompensation. Therefore, the Victrelis™ Product Monograph states that Victrelis™ is contraindicated in patients with hepatic decompensation.
3.3.3 Clinical Efficacy
The efficacy and safety of Victrelis™ was established in two Phase III, randomized, double blinded, placebo-controlled studies. SPRINT-2 was conducted with in previously untreated HCV, genotype 1-infected patients, and RESPOND-2 was conducted in previously treated HCV, genotype 1-infected patients (previous partial responders and relapsers) to the standard of care (peginterferon alpha + ribavirin).
Both studies were conducted with peginterferon alpha 2b. The use of Victrelis™ in combination with peginterferon alpha/ribavirin was proposed and accepted in the indication with the additional explanation that the clinical studies were performed with peginterferon alfa 2b.
The efficacy of Victrelis™ as a treatment for CHC genotype 1 infection was assessed in approximately 1,500 adult patients who were previously untreated (SPRINT-2) or who had failed previous therapy (RESPOND-2), in Phase III clinical studies. Both Phase III studies were similar with a control arm [peginterferon alfa 2b/ribavirin (PegIFNα2b/RBV-48) for 48 weeks] and two treatment arms with Victrelis™: BOC-RGT; and BOC/PegIFNα2b/RBV-48. The BOC-RGT arms used Response Guided Therapy (RGT) where the duration of treatment depended on the study population and HCV-RNA response at Treatment Week (TW) 8 and TW24 for SPRINT-2 and TW8 for RESPOND-2. In the other Victrelis™ arm (BOC/PegIFNα2b/RBV-48), the treatment duration was fixed at 48 weeks. The RGT arm assessed the possibility of a shortened duration of therapy for a specified population compared to the fixed duration of therapy (48 weeks). The primary efficacy endpoint for both Phase III studies was the sustained virologic response (SVR) which is defined as undetectable HCV-RNA (hepatitis C virus ribonucleic acid particles) in the blood 24 weeks after completion of therapy.
The addition of Victrelis™ to PegIFN alpha-2b/RBV demonstrated significant improvement in SVR rates in both previously untreated patients (SPRINT-2) and previous treatment failures (RESPOND-2).
- In previously untreated patients, the SVR rates were 63% and 66%, respectively, in patients who received Victrelis™ in the RGT and BOC/PegIFNα2b/RBV-48 arms, compared to 38% in the control arm.
- In patients with previous treatment failures, the SVR rates were 59% and 66% in patients who received Victrelis™ in the RGT and BOC/PegIFNα2b/RBV-48 arms, respectively, compared to 21% in the control arm.
In addition, the rates of relapse (undetectable HCV-RNA at end of treatment but detectable during follow-up), discontinuation, and treatment failure were much lower in the treatment arms containing Victrelis™ when compared to the control arm.
In general, African-American patients have shown a reduced responsiveness to interferon and represent a subgroup with a high unmet need for new CHC therapy. The design of the SPRINT-2 study included a separate cohort to ensure an adequate number of patients were enrolled in order to examine the effect of Victrelis™ in this population. The addition of Victrelis™ to the PegIFN alpha-2b/RBV backbone therapy significantly increased SVR rates in previously untreated African-American patients. When analyzed by the individual cohorts, the SVR rates for Caucasian patients reached 67-68% compared to 40% in the control arm and the SVR rates for African-American patients, although numerically lower, was still significantly greater than the control arm [42-53% versus (vs.) 23%]. Relapse rates were also lower in both Victrelis™ arms compared to the control arm (9% vs. 22%).
The duration of therapy with Victrelis™ in the RGT arm differed for the previously untreated patients and the patients with previous treatment failures, i.e., 24 weeks and 32 weeks respectively, (24/32). After the 4-week lead-in with PegIFNα2b/RBV, the duration of the total treatment was 28 weeks and 36 weeks, for the previously untreated patients and the patients with previous treatment failures, respectively, (28/36). One of the objectives of the RGT arms was to determine if patients with undetectable HCV RNA at TW8 through TW24 (early responders) would have similar SVR rates when exposure to Victrelis™ was almost halved, i.e., 24/32 weeks in RGT compared to 44 weeks in the BOC/PegIFNα2b/RBV-48 arm. SVR rates were identical between similar subgroups of patients who received a total treatment of 28/36 weeks; or 48 weeks of treatment when analyzed per protocol for patients who had persistently undetectable HCV-RNA from TW8-TW24. Thus for the early responders, the RGT arm offered the benefit of a shorter treatment duration with a corresponding lower drug exposure.
In late responders, patients who had detectable HCV-RNA at TW8 (undetectable at TW24) also received a total of 24 weeks (previously untreated patients) or 32 weeks (patients with previous treatment failures) of Victrelis™ treatment, but PegIFNα2b/RBV treatment continued until TW48. Overall, there was no additional improvement in SVR rates attained in late responders who continued triple therapy for 44 weeks. However, subgroup analyses indicated that certain subgroups, “historical” null responders and patients with cirrhosis, may benefit from longer Victrelis™ and PegIFNα2b/RBV therapy. Consequently, the dosing instructions have identified that these two populations should receive triple therapy for 44 weeks following a 4-week lead-in with PegIFNα2b/RBV.
Results from the RGT arm demonstrated that frequent virologic testing between TW8 and TW24 is not needed for making a treatment duration decision and that the decision on treatment duration or futility can be based on HCV-RNA testing at TW8 and TW24.
In the RESPOND-2 study (patients who failed previous therapy), patients who were referred to as "historical" Null Responders (defined by a <2.0 log10 decline in HCV-RNA at TW12) were excluded. However, the results of the Phase III studies included a post-hoc analysis of a similar population; patients who were poorly interferon responsive at TW4 (<1.0 log10 decline in HCV RNA). This post-hoc analysis demonstrated that the addition of Victrelis™ to PegIFN alpha-2b/RBV provided considerable improvements in SVR compared to PegIFN alpha-2b/RBV alone in this modified definition of Null Responders (SVR rates: 28-38% vs. 0-4%, respectively). A strong correlation was demonstrated between patients who are poorly interferon responsive and "historical" Null Responders; consequently, similar improvements would be expected for "historical" Null Responders. Because of the demonstrated correlation and significant medical need for alternate therapies in this hard-to-treat population, the indication states that Victrelis™ is for all patients who have previously failed treatment with peginterferon and ribavirin.
3.3.4 Clinical Safety
The safety profile of Victrelis™ in combination with PegIFNα2b/RBV was assessed in 2,095 patients with CHC. Overall, Victrelis™ in combination with PegIFNα2b/RBV was well-tolerated when used in previously untreated and previous treatment failure patients treated for up to 48 weeks, in the Phase III studies. The most common adverse events were generally consistent with those frequently reported with PegIFNα2b/RBV. In the key clinical studies, adverse reactions reported at an incidence >35% and considered by investigators to be causally related to the combination of Victrelis™ with PegIFNα2b/RBV in adult patients were fatigue, anaemia, nausea, headache and dysgeusia (alteration of taste).
The most notable adverse reaction was anaemia. Decreases in haemoglobin content with concomitant increased reporting of anaemia are a well-documented side effect of peginterferon alpha + ribavirin therapy. Although Victrelis™ alone has not been shown to cause anaemia, the addition of Victrelis™ to the standard of care therapy (PegIFNα2b/RBV) increased the proportion of patients reporting anaemia from 29% in the control arm to 49% in the Victrelis™-containing arms and caused an incremental decrease (approximately 1 g/dL) in haemogloblin concentrations compared to PegIFNα2b/RBV alone. Anaemia appeared to be part of an overall bone marrow suppressive effect as shown by the increased frequency of neutropaenia and thrombocytopaenia in Victrelis™-treated patients when compared to controls. The management of anaemia was accomplished by ribavirin dose reduction, discontinuation of RBV therapy, in some cases blood transfusion, and by using erythropoietin at defined reduced levels of haemoglobin. Although not approved for the treatment of anaemia associated with Hepatitis C, the use of erythropoiesis stimulating agents was permitted for management of anaemia, at the investigator's discretion, with or without RBV dose reduction in the Phase II and Phase III clinical studies.
Dysgeusia (alteration of taste) was reported at a considerably higher frequency in Victrelis™-treated patients compared with patients receiving PegIFN alpha-2b/RBV alone (35% compared to 16% in previously untreated patients and 44% compared to 11% in previous treatment failure patients). The majority of these adverse reactions were of mild severity and did not interfere with treatment.
Due to the fact that Victrelis™ must be co-administered with peginterferon alpha + ribavirin, the contraindications and warnings associated with peginterferon alpha and ribavirin also apply to the use of Victrelis™, for example (e.g.), Victrelis™ is contraindicated in pregnant women and men whose female partners are pregnant because of the known teratogenic effects associated with ribavirin.
The use of Victrelis™ in the BOC-RGT arm reduced the extent of drug exposure to the patient and theoretically the likelihood of causing unwanted reactions. In the patients with previous treatment failures, fewer subjects (10%) in the BOC-RGT arm reported serious adverse events (SAEs) and study drug discontinuations due to adverse events (AEs) (8%) compared with the 48-week BOC/PegIFNα2b/RBV-48 arm (14% and 12%, respectively), but in both cases, more frequently in the Victrelis™-containing arms than in the control arm (5% SAEs and 3% discontinuations).
In previously untreated patients, the proportion of study drug discontinuations due to AEs was also less in the BOC-RGT arm (12%) compared with the 48-week BOC/PegIFNα2b/RBV-48 arm (16%). SAEs were reported by a similar proportion of patients in the BOC-RGT and BOC/PegIFNα2b/RBV-48 arms (11% and 12%, respectively). There were similar proportions of patients with treatment-emergent AEs; treatment-related, treatment emergent AEs; and dose modifications due to AEs in the BOC-RGT arms compared with the BOC-PR 48-week arms in both studies. Dose modifications due to AEs occurred with greater frequency in both Victrelis™-containing arms compared to the control arm in both studies. While RGT therapy did not reduce the overall incidence of AEs, this may be related to the fact that most of the AEs were reported within the first 28 weeks of treatment. RGT should be beneficial with respect to the AE of anaemia because once therapy was discontinued the haemoglobin began to return to baseline values.
A number of safety signals have been detected with Victrelis™ treatment in patients with previous treatment failures, and have therefore been listed in the Victrelis™ Product Monograph. Examples of these signals included the psychiatric SAEs that were found to be slightly higher in the Victrelis™ arms (2-3%) when compared to the control arm (0%), the more common appearance of rash/skin eruptions in the Victrelis™ arms (22-25%) relative to the control arm (9%), and the slightly greater reduced levels of neutrophils and platelets in the Victrelis™ arms when compared to the control arm. The addition of Victrelis™ to PegIFNα2b/RBV did not show added cardiovascular risks.
In the previously untreated population, similar adverse events of interest, cardiac/vascular, psychiatric and rash were not increased with the addition of Victrelis™ to PegIFNα2b/RBV. On the other hand, similar to the previous treatment failure population, neutropaenia and thrombocytopaenia were reported in a slightly greater proportion of patients administered Victrelis™ in combination with PegIFNα2b/RBV compared to PegIFNα2b/RBV alone.
The three-time daily adherence to treatment may result in missed doses with potential negative consequences of reduced product efficacy and the potential development of drug resistance mutations. To safeguard against non-compliance to medication, labelling warnings have been introduced in the Victrelis™ Product Monograph.
Re-treatment of HCV patients may pose a risk of failure or resistance to HCV patients due to the persistence of some resistance associated variants (T54S and R155K) after 2.5 years of study.
A Risk Management Plan was provided and was modified in collaboration with Health Canada.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review Status was granted for the evaluation of Victrelis™ as it appeared to provide substantial evidence of increased clinical efficacy such that the overall benefit/risk profile was improved over existing therapies.
The pivotal Phase III studies demonstrated that the Victrelis™ regimens were safe, tolerable, and produced significantly higher SVR rates when compared to the current standard of care therapy (Peginterferon alpha + ribavirin) for patients with CHC genotype 1 infection who were previously untreated or who had previous treatment failures.
Victrelis™ presents a substantial advancement in the treatment of CHC, genotype 1 infection (including hard-to-treat subpopulations such as African-American patients, patients with high viral load and patients with poor interferon responsiveness) when compared to the current standard of care. In addition, Response-Guided Therapy appeared to be a successful therapeutic approach for the treatment of most HCV infected patients.
The safety profile of Victrelis™ in combination with the standard of care therapy was similar to the standard of care therapy administered alone. The major risk of the standard of care therapy was anaemia. The addition of Victrelis™ to the standard of care therapy resulted in moderate increases of anaemia above the levels of the standard of care therapy alone. However, management of anaemia was accomplished by RBV dose reduction and discontinuation, transfusion, and in many cases use of erythropoietin. The clinical studies did not reveal specific toxicities which were attributable to Victrelis™ which could have limited its clinical use.
Overall, the studies demonstrated that Victrelis™ was well-tolerated and associated with a manageable safety profile. Based on the safety and efficacy profile, the benefits of Victrelis™ in combination with standard of care therapy (Peginterferon alpha + ribavirin) seem to outweigh the risks. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Victrelis™ Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Victrelis™ is favourable in the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alpha/ribavirin, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: VictrelisTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2010-11-10 |
| Request for priority status | |
| Filed | 2010-11-08 |
| Approval issued by Dr. Jacques Bouchard, Director of Bureau of Gastroenterology Infection and Viral Diseases | 2010-12-20 |
| Submission filed: | 2010-12-22 |
| Screening | |
| Screening Acceptance Letter issued | 2011-02-01 |
| Review | |
| Quality Evaluation complete: | 2011-07-06 |
| Clinical Evaluation complete: | 2011-07-26 |
| Labelling Review complete: | 2011-07-26 |
| Notice of Compliance issued by Director General: | 2011-07-29 |