Summary Basis of Decision for Galexos

Clinical Pharmacology

Simeprevir, the medicinal ingredient of Galexos, is a direct-acting antiviral agent against the hepatitis C virus (HCV). Simeprevir inhibits the HCV NS3/4A protease through a non-covalent, induced-fit binding into the active site of the NS3 protease.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. Simeprevir is mainly metabolized by the cytochrome 450 (CYP) enzyme, CYP3A, and it is a mild inhibitor of intestinal CYP3A, therefore co-administration of Galexos with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended.

A bridging study evaluated the absorption of the study drug with different formulations during different phases of the development program. The results of the pivotal comparative bioavailability study demonstrated that after intake with food, the rate and extent of absorption of the capsule formulation used in the Phase III studies was applicable to the capsule formulation used in the primary stability studies, and to the commercial capsule formulation. Based on the evaluation of this study, the food-effect statements stated in the Galexos Product Monograph are considered accurate.

Overall, the clinical pharmacological data support the use of Galexos for the specified indication. Appropriate warnings and precautions are in place in the approved Galexos Product Monograph to address the identified safety concerns.

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

Clinical Efficacy

The efficacy of Galexos as treatment for chronic hepatitis C in patients with HCV genotype 1 infection was evaluated in (a) treatment-naïve patients in two Phase III studies (C208 and C216) and a supporting Phase IIb study (C205); and in (b) treatment-experienced patients, that is, patients who relapsed after prior interferon-based therapy (Phase III study C3007), as well as patients who failed prior therapy with peginterferon alpha (PegIFN) and ribavirin (RBV) including prior relapsers, partial and null responders (Phase IIb study C206). Patients in these studies had compensated liver disease (including cirrhosis), hepatitis C virus ribonucleic acid (HCV RNA) of at least 10,000 IU/mL, and liver histopathology consistent with chronic hepatitis C.

In treatment-naïve and prior relapser patients, the overall duration of treatment with PegIFN and RBV (PR) in the Phase III studies was response-guided. In these patients, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA <25 IU/mL (detectable or undetectable) at Week 4 and undetectable HCV RNA at Week 12. Treatment stopping rules for HCV therapy were used to ensure that patients with inadequate on-treatment virologic response discontinued treatment in a timely manner.

Sustained virologic response (SVR) or virologic cure was defined as an HCV RNA <25 IU/mL (undetectable or detectable) 12 weeks after the planned end of treatment in the Phase III studies (SVR12), and an HCV RNA <25 IU/mL (undetectable or detectable) 24 weeks after the planned end of treatment in the Phase IIb study (SVR24).

Efficacy in Treatment-Naïve Patients

Efficacy of Galexos (simeprevir) in treatment-naïve chronic HCV genotype 1 infected patients was supported by results (pooled) from two ongoing double-blind, placebo-controlled Phase III studies (C208, QUEST-1 and C216, QUEST-2), as well as results from one Phase IIb study (C205).

In Studies C208 and C216, treatment-naïve genotype 1 HCV infected adult patients were randomized to receive Galexos 150 mg once a day (QD) or placebo in combination with PR. To evaluate overall treatment responses in relevant subgroups with higher precision, SVR data from these studies were pooled. In the population including both studies, 521 patients were in the Galexos/PR group and 264 patients were in the Placebo/PR group. Analysis of pooled data showed that SVR 12 weeks after planned end of treatment (SVR12) was achieved in 80.4% of patients in the Galexos/PR group compared with 49.9% of patients in the Placebo/PR group. The SVR12 rate was statistically significantly higher in the Galexos/PR group compared to the Placebo/PR group (p<0.001). The PR treatment duration in the Galexos/PR treatment group was guided by on-treatment response. Most (88%) of Galexos-treated patients met the protocol-defined RGT criteria for shortening duration of PR treatment to 24 weeks; of these, 88% achieved SVR12 (pooled analysis). In the group of patients who had HCV RNA <25 IU/mL undetectable at Week 4, 90% (or 362 of 404) achieved SVR12. In the group of patients who had HCV RNA <25 IU/mL detectable at Week 4, 67% (or 47 of 70) achieved SVR12. Most (98%) of the patients in the Galexos/PR group who met the protocol-defined RGT criteria completed treatment with PegIFN and/or RBV at Week 24.

Study C205 was conducted in treatment-naïve genotype 1 HCV infected adult subjects without cirrhosis. This study evaluated two doses of simeprevir, 75 mg once a day (QD) and 150 mg QD of simeprevir, administered for 12 or 24 weeks, in combination with 24- or 48-week response-guided treatment with PR. The observed SVR rates 24 weeks after planned end of treatment (SVR24) in the simeprevir 150 mg/PR group were higher than in the Placebo/PR group. Of the patients who met the protocol-defined response-guided therapy (RGT) criteria and completed treatment with PR at Week 24, 93.4% of patients who received simeprevir 150 mg for 12 weeks and 95.6% of patients who received simeprevir 150 mg for 24 weeks achieved SVR24. The viral relapse rate was lower in the simeprevir 150 mg dose groups (7.8% and 7.6% in the 12 and 24 week simeprevir-treatment groups, respectively) compared with the 75 mg dose groups (10.3% and 18.7% in the 12 and 24 week simeprevir-treatment groups, respectively) and placebo (14.3%). A trend for lower viral relapse was observed when patients were dosed with 150 mg, especially in patients with HCV genotype 1a. Relapse was not observed after 24 weeks after the end of treatment.

Overall, in treatment-naïve patients, the results demonstrated that Galexos (simeprevir) 150 mg QD administered for 12 weeks in combination with PR followed by an additional 12 or 36 weeks of PR therapy as determined by protocol-defined response-guided therapy (RGT) for a total treatment duration of 24 weeks or 48 weeks, respectively, was superior to 48 weeks of treatment with PR alone (control) in patients with chronic HCV genotype 1 infection.

Efficacy in Treatment-Experienced Patients

The efficacy analysis of Galexos (simeprevir) in treatment-experienced patients was based on one Phase III study (HPC3007) and one Phase IIb study (C206).

The Phase III Study HPC3007 (PROMISE) evaluated the once-daily dose of 150 mg Galexos administered for a duration of 12 weeks in genotype 1 HCV-infected adult patients who relapsed after previous IFN-based therapy. In this study, 393 patients were randomized to receive Galexos 150 mg QD or placebo, in combination with PR. A total of 79.6% of the patients in the Galexos/PR group achieved SVR12, compared to 36.6% in the Placebo/PR group. The SVR12 rate was statistically significantly higher in the Galexos/PR group compared to the Placebo/PR group (p<0.001). The PR treatment duration in the Galexos/PR treatment group was guided by on-treatment response. The majority (93%) of Galexos-treated patients met the RGT criteria of whom 83% achieved SVR12. In the group of patients who had HCV RNA <25 IU/mL undetectable at Week 4, 87% (or 173 of 200) achieved SVR12. In the group of patients who had HCV RNA <25 IU/mL detectable at Week 4, 60% (or 28 of 47) achieved SVR12. Most (97%) of the patients in the Galexos/PR group who met the protocol-defined RGT criteria completed treatment with PegIFN and/or RBV at Week 24.

Study C206 (ASPIRE), a Phase IIb study, was conducted in 396 treatment-experienced HCV genotype 1 infected patients and evaluated two doses (100 mg QD and 150 mg QD) of Galexos. In the group that was treated with Galexos 150 mg for 12 weeks in combination with PR for 48 weeks, SVR12 rates were 66.7% for the overall population, 76.9% for prior relapsers, 65.2% for prior partial responders, and 52.9% for prior null responders.

In treatment-experienced patients (Prior Relapsers and Prior Non-responders), Galexos (simeprevir) 150 mg QD administered for 12 weeks in combination with PR followed by additional PR therapy was superior to PR alone (control). For Prior relapsers, the additional PR therapy was 12 or 36 weeks of PR based on RGT, for a total treatment duration of 24 weeks or 48 weeks, respectively. For Prior Non-responders (partial responders and null responders), the additional PR therapy was 36 weeks of PR, for a total treatment duration of 48 weeks, irrespective of the treatment Week-4 response (not based on RGT).

In treatment-experienced and treatment-naïve patients the presence of Q80K polymorphism at baseline reduced SVR12 response. SVR rates were higher in Q80K patients who achieved rapid virologic response (RVR: undetectable HCV RNA at treatment Week 4) compared to those not achieving RVR.

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

Clinical Safety

The safety profile of Galexos in combination with PegIFN and RBV (PR) was established using pooled safety data from the Phase III studies C208, C216 and HPC3007 (described in the Clinical Efficacy section). During the first 12-week phase, at least 1 adverse event (AE) was reported in the majority of Galexos-treated patients (95.3%) and patients treated with placebo (94.7%). The most frequent AEs (in >25% of Galexos-treated patients) were fatigue (35.6%), headache (33.2%), and influenza-like illness (26.0%), all of which are common adverse drug reactions of PR treatment. Pruritus was the only AE with a notable (>5%) higher incidence in Galexos-treated patients than in patients on placebo. Most AEs were Grade 1 or 2. Grade 3 AEs were reported in 20.0% of Galexos-treated patients and in 21.9% of patients on placebo. Grade 4 AEs were reported in 2.9% and in 2.8%, respectively. All Grade 3 or 4 AEs were reported in <5.0% of patients, with the exception of neutropenia which was reported in 9.2% of Galexos-treated patients and in 8.6% of patients on placebo. Serious AEs were reported in 2.0% of Galexos-treated patients and in 2.5% of patients on placebo. There were no deaths during the first 12-week phase, but 3 Galexos-treated patients died after completion of Galexos treatment. None of the deaths were considered Galexos-related.

Adverse events of special interest included increased levels of blood bilirubin, rash (any type), pruritus, photosensitivity reactions, anemia, and neutropenia. The incidence in Galexos-treated patients was higher than in patients on placebo for increased bilirubin[7.9% versus (vs.) 2.8%], rash of any type (23.2% vs. 16.9%), pruritus (22.0% vs. 14.9%), and photosensitivity reactions (3.3% vs. 0.5%). For anemia and neutropenia, the incidence rates were similar in both treatment groups, and the lack of any relevant difference was corroborated by the absence of differences in corresponding laboratory values. Grade 3 or 4 AEs were infrequent in both treatment groups (<5% of patients), with the exception of neutropenia. No clear pattern regarding the incidence and prevalence over time could be established for photosensitivity reactions. For the other events, the highest incidence occurred during the first 4 weeks of treatment, except for anemiawhere the highest incidence occurred from Weeks 5 to 8. In both treatment groups, the incidence and prevalence of increased blood bilirubinwas low, with the highest incidence and prevalence seen during the first 4 weeks of treatment, followed by a decline. During the first 12-week phase, the incidence of hyperbilirubinemia (any grade) was higher in Galexos-treated patients (49.5%) than in patients on placebo (26.1%). Grade 3 or 4 hyperbilirubinemia was infrequent (<5% of patients) in both treatment groups and tended to occur more often in patients with a METAVIR score F4 (cirrhosis). Rashwas reported at a higher incidence in female patients; increased bilirubin levelsand anemiawere reported at a higher incidence in patients with a METAVIR score F4. These results are in line with the higher incidence of related laboratory abnormalities. However, a more pronounced difference between Galexos-treated patients and patients on placebo was seen only for the laboratory abnormality hyperbilirubinemia in patients with METAVIR score F4, but not for hemoglobin.

Regarding the adverse drug reaction (ADR) profile, at least 1 Galexos ADR was reported in 44.7% of Galexos-treated patients and in 31.2% of patients on placebo, during the first 12-week phase. Adverse drug reactions reported in Galexos-treated patients and patients on placebo were pruritus(21.9% vs. 14.6%), rash(21.8% vs. 16.6%), increased blood bilirubin (7.4% vs. 2.8%), photosensitivity reaction (4.7% vs. 0.8%), and constipation (2.6% vs. 2.5%). Most ADRs were Grade 1 or 2 in severity. The incidence of Grade 3 or 4 ADRs (2.8% in Galexos-treated patients and 0.5% in patients on placebo), serious ADRs (0.3% vs. 0.0%), and ADRs leading to Galexos or placebo discontinuation (0.9% vs. 0.3%) was low. Apart from the bilirubin parameters, a slight difference between the Galexos and placebo group was seen for mean alkaline phosphatase (ALP) blood levels. Elevations of ALP were Grade 1 in most cases and were quickly reversible after completion of Galexos treatment. During the first 12-week phase, the most frequent laboratory abnormalities (in >25% of Galexos-treated patients) (any grade) were decreased neutrophils (75.9% in Galexos-treated patients and 77.2% in patients on placebo) and hyperbilirubinemia. Apart from hyperbilirubinemia, no difference between treatment groups was observed in incidences of Grade 3 or 4 laboratory abnormalities for any of the hematology and other biochemistry parameters.

Mean changes from baseline in vital signs and electrocardiogram parameters were generally small and not considered clinically relevant. There were no QTcF values above 480 ms and no QTcF increases vs. baseline of >60 ms in either treatment group.

Fatigue, depressive symptoms, functioning, and quality of life assessed by patient-reported outcomes showed that the addition of Galexos did not increase tolerability problems commonly associated with PR.

The safety concerns of anemia and severe rash, associated with the currently marketed direct acting antiviral drugs are not associated with Galexos.

Development of drug resistance is considered a potential risk related to the use of Galexos. In most patients (91.4%) with failure and sequencing information available, emerging mutations were detected, mainly R155K in patients with HCV genotype 1a (with and without Q80K) and mainly D168V in patients with HCV genotype 1b. The long-term clinical impact of the emergence or persistence of virus containing simeprevir-resistance-associated substitutions is unknown.

The introduction of treatment stopping rules should reduce potential evolution for simeprevir-resistant variants. All simeprevir-resistant associated mutations studied remained susceptible to representative HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, and NS5A inhibitors in vitro.

Overall, treatment with Galexos was generally safe and well-tolerated. The adverse drug reaction profile of Galexos, based on thorough review of clinical safety data, reflects the safety and tolerability of the product. The safety data from the Phase III placebo-controlled studies support the use of Galexos 150 mg QD in combination with PR for the treatment of chronic hepatitis C in adults with compensated liver disease (including cirrhosis).

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