Summary Basis of Decision for Holkira Pak

Clinical Pharmacology

Holkira Pak consists of a combination of three direct acting antiviral agents (DAA), along with possible co-administration of ribavirin. Given the combination of several agents, including the addition of ritonavir as a pharmacoenhancer for paritaprevir, this may in some cases increase the complexity of the drug's overall pharmacology and elicit the potential for drug-drug interactions through various enzymatic inhibition and induction pathways. Drug-drug interaction studies were conducted to evaluate mechanism-based interactions with concomitant medications used in special populations and commonly prescribed concomitant medications. A total of 24 drug-drug interaction studies were conducted with the combination DAA regimen; 22 drug-drug interactions studies evaluating 28 compounds and 31 regimens were conducted for the Holkira Pak regimen. In addition, the paritaprevir/ritonavir/dasabuvir regimen was evaluated in 2 additional drug-drug studies. These studies were conducted to evaluate mechanism-based interactions with concomitant medications used in special populations and commonly prescribed concomitant medications. Based on the results of these studies, labelling about drug combinations (including those that are contraindicated, should not be used or require dose adjustments), are captured in the Holkira Pak Product Monograph.

Significant transaminase elevations were also observed when Holkira Pak was co-administered with several drugs leading to early termination of drug interaction studies, and in patients receiving oral contraceptives in Phase III clinical studies. The mechanism of these transaminase elevations is not fully understood; thus there is a potential for other drugs when co-administered with Holkira Pak to cause clinically significant transaminase elevations. This identified safety issue has also been captured in the Holkira Pak Product Monograph.

The safety and efficacy of Holkira Pak have not been established in HCV-infected patients with moderate (Child-Pugh B) or severe hepatic impairment (Child-Pugh C). Therefore, Holkira Pak should not be used in these patients.

Holkira Pak can be administered in patients with mild, moderate or severe renal impairment. The safety of Holkira Pak however, has not been studied in patients on dialysis. In addition, for patients that require the addition of ribavirin, refer to the Ribavirin Product Monograph for information regarding use in patients with renal impairment.

The administration of Holkira Pak with food increased the exposure of paritaprevir, ombitasvir, ritonavir, and dasabuvir by up to 211%, 82%, 49%, and 30% respectively relative to the fasting state. The increase in exposure was similar regardless of meal type [for example (e.g.), high-fat versus moderate-fat] or calorie content (approximately 600 Kcal versus (vs.) approximately 1,000 Kcal).

Holkira Pak was associated with concentration-dependent QTc prolongation. At therapeutic plasma concentrations, the maximum mean difference from placebo in the QTc interval was reported to be <5 ms, with a 95% confidence interval (CI) upper limit of <10 ms. Caution should therefore be exercised when drugs that prolong QTc are co-administered with Holkira Pak.

For further details on the clinical pharmacology, please refer to the Holkira Pak Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Holkira Pak was evaluated in six randomized Phase III clinical studies, in over 2,300 patients with genotype 1 chronic hepatitis C (CHC). Of the six studies, three were conducted in treatment-naïve non-cirrhotic patients; two in treatment-experienced non-cirrhotic patients and one in patients with cirrhosis (Child-Pugh A).

For all six studies, the primary endpoint was based upon the sustained virological response (SVR) observed at Week 12 (SVR12). The SVR12 was defined as HCV RNA <lower limit of quantitation (LLOQ) in the SVR12 window (12 weeks after the last actual dose of active study drug) without any confirmed quantifiable (≥LLOQ) post-treatment value before or during that SVR window. Virologic failure during the Treatment Period was defined as confirmed HCV RNA ≥LLOQ after HCV RNA <LLOQ during treatment, confirmed increase from nadir in HCV RNA (2 consecutive HCV RNA measurements >1 log₁₀ IU/mL above nadir) at any time point during treatment or persistent HCV RNA ≥LLOQ during treatment with at least 6 weeks (≥36 days) of treatment). Relapse was defined as confirmed HCV RNA ≥LLOQ between end of treatment and 12 weeks after last actual dose of active study drug (up to and including the SVR12 assessment time point) for a subject with HCV RNA <LLOQ at Final Treatment Visit who completed treatment, among patients with available post-treatment HCV RNA data.

Across all six studies, the patient demographics and baseline characteristics were comparable between the treatment arms.

Treatment-Naïve Patients without Cirrhosis

The efficacy of Holkira Pak for use in treatment-naïve patients without cirrhosis was based on three Phase III studies, namely SAPPHIRE-I, PEARL-III, and PEARL-IV.

Study SAPPHIRE-1 (M11-646)

This was a multicenter, randomized, double-blind, placebo-controlled study conducted in 631 treatment-naïve adult patients infected with HCV genotype 1 (67.7% genotype 1a; 32.3% genotype 1b) without cirrhosis. Holkira Pak was administered for 12 weeks of treatment in combination with ribavirin (RBV). Patients randomized to the placebo arm received placebo for 12 weeks, after which they received open-label Holkira Pak in combination with RBV (Holkira Pak+RBV) for 12 weeks. Of the 631 patients enrolled, 473 patients were randomized to receive Holkira Pak+RBV and 158 patients were randomized to receive a placebo.

Studies PEARL-III (M13-961) and PEARL-IV (M14-002)

These two studies were multicenter, randomized, double-blind, regimen-controlled studies conducted in 419 treatment-naïve adult patients with genotype 1b CHC infection without cirrhosis (PEARL-III) and 305 treatment-naïve adult patients with genotype 1a CHC infection without cirrhosis (PEARL-IV). Patients were randomized, in a 1:1 ratio (PEARL-III) or a 1:2 ratio (PEARL-IV), to receive Holkira Pak with or without RBV for 12 weeks.

Study Results: SAPPHIRE-I, PEARL-III, and PEARL-IV

The SVR 12rates among patients treated with Holkira Pak+RBV ranged from 96.2% to 99.5% across the three studies, SAPPHIRE-1, PEARL-III, and PEARL-IV. All treatment groups met the primary endpoint of achieving SVR at Week 12. Among patients treated with Holkira Pak without RBV, the SVR12 rates were similar in patients infected with genotype 1b virus as compared to rates observed with the Holkira Pak+RBV (99.0% and 99.5%, respectively).

Ten patients experienced virologic failure in the SAPPHIRE-I study; three patients with rebound and seven patients with relapse by post-treatment Week 12. There was no statistically significant association between baseline variants at signature resistance-associated amino acid positions and treatment outcome. Predominant variants in genotype 1a-infected patients at the time of failure were D168V and R155K in NS3, m²8T and Q30R in NS5A, and S556G in NS5B. The predominant variants in genotype 1b-infected patients at the time of failure were Y56H +D168V in NS3, Y93H in NS5A, and S556G in NS5B. Patients infected with genotype 1a virus (PEARL-IV study), experienced higher virologic failure when treated with the Holkira Pak as compared to those receiving Holkira Pak+RBV (16 and 2, respectively). Moreover, the presence of the variant Q80K at baseline in patients with virologic failure was higher than that among a matched set of patients who achieved SVR12 (68.8% and 19%, respectively). In the Holkira Pak+RBV arm, Q80K was present at baseline in one of the two virologic failures. All 18 patients had resistance associated variants in at least one target and 10 patients had resistance associated variants in all three targets. There was one virologic failure among patients infected with genotype 1b virus (PEARL-III study); the patient received Holkira Pak+RBV, had no resistance associated variants in NS3, one variant in NS5A at the time of failure and another variant in NS5B which was present at baseline and at the time of virologic failure.

Efficacy was independent of several baseline characteristics. The efficacy of Holkira Pak for patients of ≥65 years (8%) was comparable to that in patients younger than 65 years. Efficacy was not examined in pediatric patients, therefore its use is not recommended in this patient population.

Overall, the efficacy results presented in the current submission support an indication for treatment-naïve, non-cirrhotic patients infected with CHC genotype 1.

Treatment-Experienced Patients without Cirrhosis

The efficacy of Holkira Pak for use in treatment-experienced patients without cirrhosis was based on two Phase III studies, namely SAPPHIRE-II and PEARL-II.

Study SAPPHIRE-1I (M13-098)

This study was a multicenter, randomized, double-blind, placebo-controlled study conducted in 394 patients with genotype 1 CHC infection without cirrhosis who did not achieve SVR with prior treatment with pegylated interferon and ribavirin (pegIFN/RBV). This study included both HCV genotype 1a (58.4%) and genotype 1b (41.4%) patients. Patients were randomized to receive Holkira Pak+RBV or a placebo for 12 weeks in a 3:1 ratio. Patients randomized to the placebo arm received placebo for 12 weeks, after which they received Holkira Pak+RBV for 12 weeks.

Study PEARL-1I (M13-389)

This study was a multicenter, randomized, open-label study conducted in 179 adults with genotype 1b CHC infection without cirrhosis who did not achieve SVR with prior treatment with pegIFN/RBV. Patients were randomized, in a 1:1 ratio, to receive Holkira Pak±RBV for 12 weeks of treatment.

Study Results: SAPPHIRE-II and PEARL-II

In the SAPPHIRE-II study, results showed a total of 286/297 (96.3%) of patients achieved an SVR at Week 12, therefore the primary endpoint was met. No patient experienced on-treatment virologic failure and 7 (2.4%) patients experienced post-treatment relapse for a total of 2.4% virologic failures among all 297 intent-to-treat patients.

In the PEARL-II study, results showed a total of 85/88 (96.6%) of patients in the Holkira Pak+RBV arm and 91/91 (100%) of patients in the Holkira Pak arm achieved an SVR at Week 12 (SVR12). Therefore, the primary endpoint was met. No patient in either treatment group experienced on-treatment virologic failure or post-treatment relapse. Overall, these results suggest that the Holkira Pak treatment regimen without RBV provides optimal efficacy in HCV GT 1b infected previously treatment-experienced, non-cirrhotic patients.

Treatment-Naïve and Treatment-Experienced Patients with Cirrhosis

Study TURQUOISE-1I (M13-099)

This study was a multicenter, randomized, open-label study conducted exclusively in 380 genotype 1-infected patients with cirrhosis (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. Holkira Pak+RBV were administered for either 12 or 24 weeks of treatment.

TURQUOISE-II Study Results

Treatment with a 12- and 24-week regimen of Holkira Pak+RBV resulted in SVR12 rates of 91.8% and 95.9% respectively. While the difference in SVR12 rate was not statistically significant, HCV GT1a-infected null responders had a higher SVR12 rate with 24 weeks versus 12 weeks of treatment (92.9% versus 80.0%, respectively) suggesting that GT-1a-infected prior null responder patients with cirrhosis may benefit from 24 weeks of treatment.

Efficacy Conclusion

In summary, high SVR12 rates were observed when Holkira Pak without RBV was administered for 12 weeks in non-cirrhotic GT-1b patients and with RBV for 12 weeks in cirrhotic patients. Similar high SVR12 rates were observed with Holkira Pak+RBV for 12 weeks in non-cirrhotic patients with genotype 1a infection. A longer duration of treatment (24 weeks) has shown better results in HCV-GT1a infected patients with compensated cirrhosis. A long term sustainability of the virologic suppression achieved with Holkira Pak with or without RBV is not known at this time.

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

Clinical Safety

The overall safety profile of Holkira Pak was primarily established based on pooled data from Phase III clinical studies (previously described in the Clinical Efficacy section) in addition to several supportive Phase II studies. A total of 2,632 patients who received Holkira Pak (with or without RBV) were included in the data set.

The median number of days of treatment across all treatment groups was 84 days. Both Holkira Pak and Holkira Pak+RBV regimens were well tolerated. The majority of patients in each study experienced at least one adverse event, mainly mild in severity. The most common (≥10.0% of patients) treatment-emergent adverse events in the Holkira Pak+RBV treatment group were headache, fatigue, nausea, pruritus, insomnia, asthenia, diarrhea, and rash. Incidence of anemia, asthenia, insomnia, rash, dry skin and indirect bilirubinaemia is higher in patients receiving Holkira Pak+RBV. All of these side effects are known to be associated with ribavirin use.

Serious adverse events were reported in approximately 2% of patients receiving Holkira Pak+RBV and 1.4% receiving Holkira Pak alone. There were three deaths [non-small cell lung cancer and mediastinal mass in one patient (both events treatment emergent), coronary artery stenosis and arteriosclerosis in one patient (both events non-treatment emergent), severe hypotension and lactic acidosis in one subject who subsequently received a liver transplant (all events non-treatment emergent), none of which was related to study drug.

Discontinuations due to an adverse event were reported for approximately 1% for patients. The most common reasons for discontinuation of study drug were virologic failure (0% Holkira Pak+RBV, 1.2% Holkira Pak alone) and adverse event (0.5% Holkira Pak+RBV, 0.4% Holkira Pak alone).

During clinical studies with Holkira Pak with or without RBV, transient, asymptomatic elevations of alanine transaminase (ALT) to greater than five times the upper limit of normal (ULN) occurred. Grade 2 ALT elevations were reported in 2.2%, with approximately 1% reporting at least Grade 3 elevation. Alanine increases appear to be associated with concomitant systemic estrogen use. Alanine transaminase elevations typically occurred during the first 4 weeks of treatment and declined within approximately two weeks of onset with continued dosing of Holkira Pak with or without RBV. Increases in ALT were not associated with simultaneous increases in bilirubin levels. Cirrhosis was not a risk factor for elevated ALT. No specific monitoring of liver chemistries is required for the majority of patients.

Ethinyl estradiol-containing medications should be discontinued prior to starting therapy with Holkira Pak. Alternative contraceptive agents or methods of contraception [for example (e.g,) progestin only contraception or non-hormonal methods] are recommended during Holkira Pak therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with Holkira Pak. Patients using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens (1%). However, due to the limited number of subjects taking these other estrogens [patient number (n) = 87], caution is warranted for co-administration with Holkira Pak.

Transient elevations in bilirubin (predominantly indirect) were observed in patients receiving Holkira Pak with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations was lower among patients who did not receive ribavirin.

Holkira Pak was associated with concentration-dependent QTc prolongation. At therapeutic plasma concentrations, the maximum mean difference from placebo in the QTc interval was reported to be <5 ms, with a 95% confidence interval (CI) upper limit of <10 ms. In a double-blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects, a single dose of paritaprevir/ritonavir/ombitasvir 200/150/25 mg co administered with dasabuvir 250 mg resulted in statistically significant QTcF prolongation from 3-8 hours post-dosing, with a maximum mean difference from placebo of 3.6 msec (90% CI 1.8, 5.4) at 5 hours. A single dose of paritaprevir/ritonavir/ombitasvir 350/150/50 mg co-administered with dasabuvir 500 mg resulted in statistically significant QTcF prolongation from 3-8 hours post-dosing, with a maximum mean difference from placebo of 5.9 msec (90% CI 4.1, 7.7) at 5 hours. These combination treatments had no noteworthy effect on the QRS duration, the PR interval, or heart rate.

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