Summary Basis of Decision for Daklinza

Clinical Pharmacology

Daclatasvir, the medicinal ingredient in Daklinza, is a direct-acting antiviral agent (DAA) against the hepatitis C virus (HCV). Daclatasvir is a highly selective inhibitor of nonstructural protein (NS) 5A, a multifunctional protein that is an essential component of the HCV replication complex. Daclatasvir inhibits both viral ribonucleic acid (RNA) replication and virion assembly. In vitro and computer modeling data indicate that daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Overall, the broad experience and diverse subject populations in Phase I clinical studies together with patient data, resulted in a detailed characterization of the daclatasvir pharmacokinetics and pharmacodynamics profile, and enabled the identification of factors with the potential to influence daclatasvir pharmacokinetics/pharmacodynamics. The daclatasvir clinical pharmacology profile supports the proposed dose of 60 mg daily in combination with other agents for patients infected with chronic HCV.

The population pharmacokinetic analyses did not reveal significant gender and race exposure differences.

Daclatasvir reaches steady-state after approximately 4 days of once-daily dosing with a terminal half-life of 12-15 hrs.

Daclatasvir absolute bioavailability is approximately 67% and is not affected by administration of a light meal but is reduced following a high fat meal; the reduction in bioavailability following administration of a high fat meal is not expected to alter the antiviral activity of daclatasvir based on entity-relationship analysis.

Daklinza can be administered to patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment. The safety and efficacy of Daklinza have not been established in patients with decompensated cirrhosis. Daklinza can be administered to patients with any degree of renal impairment

QT Prolongation

The effect of daclatasvir 60 mg tablet and 180 mg tablet on the QTc interval was evaluated in a randomized, partially blinded, placebo-controlled, positive-controlled, 4-period, 4-treatment, single-dose, crossover study in 56 healthy subjects. Subjects were randomized to receive daclatasvir (60 mg or 180 mg) or matching placebo under blinded conditions; moxifloxacin 400 mg, the positive control, was administered as an open-label treatment. Neither 60 mg nor 180 mg of daclatasvir resulted in clinically relevant change in QTc prolongations

Daclatasvir 60 mg and 180 mg had no effect on heart rate, QRS or PR intervals.

Drug-Drug Interactions

Daclatasvir is a weak to moderate inhibitor of permeability glycoprotein (P-gp), organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, and breast cancer resistant protein (BCRP), thus it has the potential to increase the systemic exposure of concomitantly administered drugs that are substrates of transporters including P-gp, OATP1B1/B3 and BCRP. Daclatasvir is not expected to have clinical effects on the pharmacokinetics of substrates of OATP2B1, organic anion transporter (OAT) 1, OAT3, or organic cation transporter (OCT) 2.

Co-administration of a strong inhibitor of both P-gp and cytochrome P450 (CYP) 3A4 resulted in an approximately1.6-fold and 3-fold increase in maximum plasma concentration (Cmax) and area under the concentration curve (AUC), respectively.

The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the CYP3A4 enzyme system is low.

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

Clinical Efficacy

The efficacy and safety of Daklinza in combination with sofosbuvir, with or without ribavirin, in the treatment of infection with chronic HCV genotype 1, 2, or 3 were evaluated in one Phase II, open-label randomized study (AI444040) in 211 adults without cirrhosis. Among the 167 patients with HCV genotype 1 infection, 126 were treatment naive and 41 had failed prior therapy with a protease inhibitor (PI) (boceprevir or telaprevir)/pegylated interferon alfa/ribavirin regimen. All 44 patients with HCV genotype 2 or 3 infection were treatment naive. Eighty-two treatment-naive patients with HCV genotype 1 were treated for 12 weeks. All other patients in the study received 24 weeks of treatment. All patients were followed for 48 weeks post-treatment. In this study, sustained virologic response (SVR, virologic cure) was defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12.

Sustained virologic response at follow-up Week 12 (SVR12) was achieved by 99% of patients with HCV genotype 1, 96% of those with HCV genotype 2, and 89% of those with HCV genotype 3. Response was rapid (more than 97% of patients had HCV RNA <LLOQ at Week 4 for all genotypes) and sustained throughout the follow-up period. The response rates were consistently high in patients with HCV genotype 1 regardless of treatment duration (12 or 24 weeks). Treatment-naive patients with HCV genotype 1 who received 12 weeks of treatment had a similar response (SVR12 = 99%) as those treated for 24 weeks (SVR12 = 100%).

The SVR12 rates in HCV genotype 1-infected patients who had previously failed telaprevir/boceprevir-containing regimens were 100.0% with ribavirin and 100.0% without ribavirin, thereby indicating that the addition of ribavirin to the regimen did not lead to improved efficacy.

High SVR rates were observed across important baseline demographic and disease characteristics, including those historically predictive of poor outcome with other HCV treatment regimens: HCV genotype 1a subtype, HCV genotype 3, human interleukin-28B non-CC genotype, black race, cirrhosis, and high baseline HCV viral load.

Of the 211 patients treated with Daklinza + sofosbuvir, three patients (1.4%, two with genotype 3 and one with genotype 1a) met the protocol-defined criteria for virologic failure (one virologic breakthrough and two relapses).

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

Clinical Safety

The safety profile of Daklinza was primarily established in the Phase II study (AI444040) previously described in the Clinical Efficacy section. The combination of Daklinza + sofosbuvir was demonstrated to be safe and well-tolerated for 12 or 24 weeks of therapy.

Treatment adherence was high and low rates of dose interruption were observed in the study. Most study groups registering greater than 90% average therapy duration and greater than 90% average planned dose of therapy.

This regimen has a favorable safety profile with no deaths reported in this study, a low rate of serious adverse events (SAEs), and a low rate of adverse events (AEs) leading to discontinuation of study therapy. In general, AEs and laboratory abnormalities reported on-treatment were mild to moderate in severity, and did not indicate a distinct safety profile.

The major safety observation recorded in this study was the effect of ribavirin on rates of common AEs as well as on key hematologic parameters. Inclusion of ribavirin in the treatment regimen led to increased rates of AEs described in the ribavirin label, such as cough, anemia, rash, insomnia, anxiety, and dyspnea.

There was no benefit to adding ribavirin to the Daklinza + sofosbuvir regimen. Ribavirin did not increase efficacy but it contributed to the safety burden of the regimen by contributing ribavirin-associated AEs.

Daklinza has the potential to be a good substitute for ribavirin and/or interferon therapy, when given in combination with sofosbuvir.

Overall, the all-oral treatment regimen of daclatasvir + sofosbuvir is suitable across multiple patient populations and genotypes, including genotype 1, 2, and 3. The addition of ribavirin was associated with multiple adverse events as well as hematologic issues and poses a risk to the use of this regimen. This regimen of daclatasvir + sofosbuvir provides an interferon- and ribavirin-sparing alternative for multiple patient populations with wide genotypic coverage.

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