Drug Review: Daklinza for Chronic Hepatitis C Infection

Introduction^1-5

There are approximately 2.7 million Americans infected with the hepatitis C virus (HCV). Of these individuals, 75% to 85% will develop chronic HCV infection.

HCV infections are classified by viral genotype. Genotype 3 is one of the more difficult genotypes to treat due to its increased incidence of steatosis and more rapid progression to severe liver disease and hepatocellular carcinoma as compare with genotype 1.

Chronic HCV infection can lead to severe liver complications and even death if untreated. Since the discovery of HCV in 1989, research for treatment has blossomed and produced highly effective products that cure this infection.

Over the past 3 years, 6 drugs have been approved by the FDA for management of HCV. With an increased focus on oral agents, these advancements are allowing for shorter and more convenient treatment options than the historic 24-week, intravenous treatment regimen. One of the recently approved oral agents is Daklinza (daclatasvir).

Background^3,6

Daklinza, produced by the Bristol-Myers Squibb Company, was approved by the FDA on July 24, 2015. It is an oral, once-daily, 12-week treatment option for use in combination with sofosbuvir.

This regimen has been reviewed by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) and added to their recommendations for testing, managing, and treating hepatitis C, which were updated in August 2015.

Pharmacology/Pharmacokinetics/Pharmacodynamics⁷

Daclatasvir is considered a direct-acting antiviral agent for HCV genotype 3. This medication binds to the N-terminus of nonstructural protein 5A (NS5A), which is a large polyprotein translated from the HCV genome. The result of this binding is a structural distortion and impaired function of NS5A, which inhibits viral RNA replication and virion production.

This medication is taken orally and systemically absorbed with a steady-state volume of distribution of approximately 47 L. It is approximately 99% protein bound and metabolized by the cytochrome P450 enzyme, CYP3A4. Finally, its excretion is 88% fecal and 6.6% urinary, with an elimination half-life of 12 to 15 hours.

Strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, rifampin, St. John’s wort) are contraindicated with the use of daclatasvir as these medications reduce its efficacy. Strong inhibitors of CYP3A4 (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) will increase exposure to daclatasvir.

Daclatasvir is an inhibitor of P-glycoprotein transporter, organic anion transporting polypeptide 1B1 and 1B3, and breast cancer resistance protein; health care professionals should be aware that exposure to substrates of these protein transporters may be increased, which could result in adverse effects.

Daclatasvir was studied at 3 times the maximum recommended dose and no clinically significant QT interval prolongation was observed.

Dosing and Administration⁷

Daclatasvir is available as an oral, once-daily tablet. Daclatasvir is initiated at 60 mg by mouth once daily. Renal or hepatic dosing adjustments are not required, except if the patient is concurrently taking a strong CYP3A inhibitor, in which case the dose should be decreased to 30 mg daily, or a moderate-to-strong CYP3A inducer, in which case the dose should be increased to 90 mg daily.

Clinical Efficacy⁸

The efficacy of daclatasvir in combination with sofosbuvir was assessed in the open-label, 2-cohort phase 3 trial, ALLY-3. This study separated 152 chronic HCV genotype 3 patients into a treatment-naïve cohort (n = 101) and a treatment-experienced cohort (n = 51); all patients received daclatasvir 60 mg and sofosbuvir 400 mg once daily for 12 weeks, with follow-up for a subsequent 24 weeks.

Ninety-six percent of patients achieved sustained viral response, meaning undetectable HCV levels, for 12 weeks.

Medication Safety⁸

The safety of daclatasvir in combination with sofosbuvir was also assessed in ALLY-3. This regimen was well tolerated with no incidence of discontinuation of treatment.

The only serious adverse event reported was 1 event of gastrointestinal hemorrhage, which was considered not related to the study medications. The most common adverse effects are headache, fatigue, and nausea, which occurred in fewer than10% of the patients.

Availability and Cost^3,7,9,10

Daclatasvir is available as a 60-mg and 30-mg tablet. The 60-mg tablet is light green, pentagon-shaped, and imprinted with the letters “BMS.”

The 30-mg tablet is the same shape but slightly smaller and a darker shade of green with the same imprint. Cost of daclatasvir 60 mg once daily for 12 weeks is $63,000.

Bristol-Myers Squibb provides patient assistance financial programs; in order to receive patient support and financial assistance, patients and physicians may call (844) 44-CONNECT (844-442-6663). More information is available on their website.

Guideline Implementation⁶

Daclatasvir-containing treatment regimens have been incorporated into the HCV guidelines produced by AASLD and IDSA for treatment of HCV genotypes 1, 2, and 3 for both treatment-naive patients and patients who have failed other therapies, as shown in the table below.

The guidelines also provide updated information regarding dose adjustments of daclatasvir when administered with HIV/AIDS medications.

Table: Hepatitis C Treatment Guidelines of the American Association for the Study of Liver Disease and the Infectious Disease Society of America for Regimens Containing Daclatasvir

Genotype

Treatment-naive Therapy Options Containing Daclatasvir for Treatment-Naïve Patients

Therapy Options Containing Daclatasvir for Patients in Whom Prior Therapy Has Failed

1a

Daily daclatasvir 60 mg and sofosbuvir 400 mg with or without weight-dosed ribavirin for 12 weeks

Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients who failed PEG-interferon and ribavirin treatment

• Daily daclatasvir 60 mg and sofosbuvir 400 mg for 24 weeks with or without weight-dosed ribavirin in patients with complicated cirrhosis who failed PEG-interferon and ribavirin therapy or HCV protease inhibitor plus PEG-interferon and ribavirin treatment
• Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis who failed HCV protese inhibitor plus PEG-interferon and ribavirin treatment

1b

Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis

Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis who failed PEG-interferon and ribavirin treatment

Daily daclatasvir 60 mg and sofosbuvir 400 mg with or without weight-dosed ribavirin for 24 weeks in patients with cirrhosis

2

Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients who cannot tolerate ribavirin

Daily daclatasvir 60 mg and sofosbuvir 400 mg with or without weight-dosed ribavirin for 24 weeks in patients who failed sofosbuvir and ribavirin treatment and who are not eligible to receive interferon

3

Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis

• Daily daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis who failed PEG-interferon and ribavirin treatment
• Daily daclatasvir 60 mg and sofosbuvir 400 mg for 24 weeks in patients with cirrhosis who failed PEG-interferon and ribavirin treatment and are not eligible to receive interferon
• Daily daclatasvir 60 mg and sogosbuvir 400 mg for 24 weeks with weight-dosed ribavirin in patients who failed sofosbuvir plus ribavirin treatment and are not eligible to receive interferon

Daily daclatasvir 60 mg and sofosbuvir 400 mg with our without weight-dosed ribavirin for 24 weeks in patients with cirrhosis

HCV = hepatitis C virus; PEG = pegylated.

References:

• Hepatitis C FAQs for health professionals. Centers for Disease Control and Prevention website. www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1. Updated October 14, 2015. Accessed September 29, 2015.
• Hepatitis C: 25 years of discovery. Centers for Disease Control and Prevention website. www.cdc.gov/knowmorehepatitis/timeline.htm. Updated August 22, 2014. Accessed October 1, 2015.
• FDA Approves Daklinza (daclatasvir) for the treatment of patients with chronic hepatitis C genotype 3 [news release]. Princeton, NJ: Bristol-Myers Squibb Company; July 24, 2015. http://news.bms.com/press-release/fda-approves-daklinza-daclatasvir-treatment-patients-chronic-hepatitis-c-genotype-3. Accessed September 28, 2015.
• Ampuero J, Romero-Gomez M, Reddy KR. Review article: HCV genotype 3—the new treatment challenge.Aliment Pharmacol Ther. 2014;39(7):686-698.
• Hepatitis B and C. Food and Drug Administration website. www.fda.gov/ForPatients/Illness/HepatitisBC/ucm20041759.htm. Updated October 6, 2015. Accessed October 7, 2015.
• American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org/full-report-view Updated August 7, 2015.
• Daklinza (daclatasvir) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; July 2015.
• Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61(4):1127-1135. doi: 10.1002/hep.27726.
• Daclatasvir (Daklinza). University of Washington. 2015. www.hepatitisc.uw.edu/page/treatment/drugs/daclatasvir. Accessed October 1, 2015.
• Hepatitis Treatment News: FDA OK’s BMS Daklinza (Daclatasvir) to Treat Hep C Genotype 3. Hepmag.com. 2015. Available at: http://www.hepmag.com/articles/Daklinza_Sovaldi_daclatasvir_2501_27556.shtml. Accessed November 9, 2015.