HCV Rx

One-A-Day: Deconstructing the Single-Tablet Regimen for HCV Genotype 1

The past year has been very important for the field of hepatitis C virus pharmacology, starting with the late-2013 approvals of the novel direct-acting antivirals simeprevir and sofosbuvir. Although these agents have significantly improved treatment tolerability and success, the October approval of the combination ledipasvir/sofosbuvir offers additional benefits for patients infected with HCV genotype 1, the most common genotype that also is the most difficult to treat.

Leah Molloy

Leah Molloy

Sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics) were each initially approved for HCV genotype 1 treatment, but only when combined with the traditional HCV drugs ribavirin and pegylated interferon-alfa, which are limited by their well-described and significant toxicities. Although the FDA has recently approved the use of sofosbuvir combined with simeprevir as a PEG-IFN-a and ribavirin-free treatment regimen, the fixed-dose combination tablet ledipasvir/sofosbuvir (Harvoni, Gilead) provides this with the added convenience of a once-daily, single-tablet regimen.

Clinical Pharmacology

Different areas of the HCV replication complex are each targeted by ledipasvir and sofosbuvir. The RNA-dependent RNA polymerase NS5B is inhibited by sofosbuvir, and ledipasvir is active against the NS5A protein also involved in viral replication.

Ledipasvir/sofosbuvir is available as a fixed-dose tablet containing 90-mg ledipasvir and 400-mg sofosbuvir to be taken once daily with or without food. In contrast to sofosbuvir, which is 60% to 65% bound to plasma proteins with a minimally bound metabolite, ledipasvir is more than 99.8% protein bound. Although sofosbuvir is metabolized in the liver by p-glycoprotein (P-gp) to form both active and inactive metabolites, ledipasvir undergoes very minimal metabolism and is primarily excreted as unchanged drug. Therefore, the drug-drug interaction profile of ledipasvir/sofosbuvir is no different from sofosbuvir alone, with which co-administration of P-gp inducers such as rifampin, St. John’s wort and phenytoin should be avoided. The elimination half-lives of ledipasvir and the primary sofosbuvir metabolite are 47 hours and 27 hours, respectively, lending the drugs well to a once-daily dosing regimen. Although ledipasvir is primarily eliminated via biliary excretion with minimal renal elimination, sofosbuvir is renally eliminated. Thus, ledipasvir/sofosbuvir, like sofosbuvir alone, should not be given to patients with impaired renal function (estimated glomerular filtration rate <30 mL/min/1.73m2)

Indications and Regimens

Ledipasvir/sofosbuvir is currently approved for the treatment of chronic HCV infection causes by genotype 1 only. The fixed-dose tablet of 90 mg/400 mg should be taken once daily for 12 weeks by treatment-naive patients with or without cirrhosis and patients who are treatment-experienced but without cirrhosis. Treatment duration should be extended to 24 weeks for patients who are both treatment-experienced and have cirrhosis. The working HCV treatment guidelines are maintained and updated online by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, and have been revised to incorporate ledipasvir/sofosbuvir.

Ledipasvir Sofosbuvir Table  

Clinical Study Data

Ledipasvir/sofosbuvir was approved on the basis of three phase 3 studies: ION-1, ION-2 and ION-3. All three studies included patients infected with HCV genotype 1 only. Each study was open-label with the same primary endpoint of sustained virologic response at 12 weeks after completion of therapy. In the ION-1 study, 865 treatment-naive patients were randomly assigned ledipasvir/sofosbuvir with or without ribavirin, each for either 12 or 24 weeks. Success rates were almost identical in each of the four groups and ranged between 97% and 99%, all higher than the 90% response rate noted in the NEUTRINO study of sofosbuvir + ribavirin + PEG-IFN-a for treatment-naive patients primary infected with HCV genotype 1. Although ION-1 was not powered to compare outcomes between patients with and without cirrhosis, 16% of included patients had cirrhosis, and they were evenly distributed between the four treatment arms.

Researchers for ION-2 randomly assigned 440 previously treated patients who had either failed to respond or experienced viral breakthrough or relapse with PEG-IFN and ribavirin-based therapy to the same treatment arms used in ION-1. Again, response rates were high, between 94% and 99%, but patients with cirrhosis (accounting for 20% of the study population, evenly distributed between treatment arms) who received 12 weeks of ledipasvir/sofosbuvir had worse outcomes than those without cirrhosis (86% vs. 95%). However, when treatment duration was extended to 24 weeks, outcomes among patients with cirrhosis were similar to those without. Additionally, the higher response rate of cirrhotic patients who received 24 weeks of treatment compared with 12 weeks of treatment was statistically significant, leading to the recommended prolonged duration of therapy for treatment-experienced patients with cirrhosis.

In the ION-3 study, a shorter duration of therapy was investigated among treatment-naive patients without cirrhosis. The 647 patients were randomly assigned ledipasvir/sofosbuvir for 8 or 12 weeks, or ledipasvir/sofosbuvir plus ribavirin for 8 weeks. Given the similar outcomes of SVR12 attainment rates ranging between 93% and 95% in each arm, the 8-week treatment course was deemed noninferior to the 12-week regimen, and no additional benefit was conferred by the use of ribavirin. Among patients with low baseline viral load (<6 million IU/mL), outcomes were very similar after 8 or 12 weeks of therapy (97% vs. 96%), prompting a note in the ledipasvir/sofosbuvir prescribing information that a shorter, 8-week course of therapy may be considered for treatment-naive patients without cirrhosis who have a pre-treatment HCV RNA less than 6 million IU/mL.

Cost and Acquisition

Not unlike its fellow novel HCV treatments that have gained widespread attention for high acquisition costs, ledipasvir/sofosbuvir is expensive, costing $1,125 per tablet. Although this is slightly higher than the famed $1,000 per pill cost of sofosbuvir, overall treatment costs could be expected to be slightly less, given the lack of required concomitant therapies as needed with sofosbuvir. As is also available for sofosbuvir, Gilead has developed Support Path (www.mysupportpath.com) for patient assistance. Patients ineligible for government reimbursement may qualify for discounted drug access with copays of as little as $5.

Future Applications

Ledipasvir/sofosbuvir is anticipated to play a major role in the future of HCV genotype 1 treatment, but phase 2 studies are ongoing to investigate the role of this treatment in genotypes 2, 3, 4, 5 and 6. Additionally, the pharmacokinetics, safety and tolerability of ledipasvir/sofosbuvir in children and adolescent patients is being evaluated in an actively recruiting phase 2 study.

In the quickly progressing era of novel HCV therapies, the approval of the first-ever one-tablet, once-daily drug is another important milestone in simplifying treatments and optimizing outcomes.

References:
AASLD/IDSA/IAS-USA. Recommendations for testing, managing and treating hepatitis C. Available at:  www.hcvguidelines.org. Accessed Dec. 30, 2014.
Afdhal N. N Engl J Med. 2014;370:1483-1493.
Afdhal N. N Engl J Med. 2014;370:1889-1898.
Gilead. Support path for Harvoni. Available at: www.mysupportpath.com. Accessed Nov. 30, 2014.
Gilead Sciences. A phase 2, multicenter, open-label study to investigate the efficacy and safety of sofosbuvir/ledipasvir fixed-dose combination in treatment-naive and treatment-experienced subjects with chronic genotype 4 or 5 HCV infection. National Library of Medicine (US). 2000. Available at: clinicaltrials.gov/ct2/show/NCT02081079. Accessed Nov. 30, 2014
Gilead Sciences. A phase 2, multicenter, open-label study to assess the efficacy and safety of sofosbuvir containing regimens for the treatment of chronic HCV infection. National Library of Medicine (US). 2000. Available at: clinicaltrials.gov/ct2/show/NCT01826981. Accessed Nov. 30, 2014
Gilead Sciences. A phase 2, open-label, multicenter, multi-cohort study to investigate the safety and efficacy of ledipasvir/sofosbuvir fixed-dose combination in adolescents and children with chronic HCV infection. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Accessed Nov. 30, 2014. Available at: clinicaltrials.gov/ct2/show/NCT02249182NLM.
Harvoni [package insert]. Foster City, GA: Gilead Sciences Inc; 2014.
Kowdely KV. N Engl J Med. 2014;370:1879-1888.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; 2014.
Schiff ER. Am J Manag Care. 2011;17 Suppl 4:S108-115.
Sovaldi [package insert]. Foster City, GA: Gilead Sciences Inc; 2014.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.

The past year has been very important for the field of hepatitis C virus pharmacology, starting with the late-2013 approvals of the novel direct-acting antivirals simeprevir and sofosbuvir. Although these agents have significantly improved treatment tolerability and success, the October approval of the combination ledipasvir/sofosbuvir offers additional benefits for patients infected with HCV genotype 1, the most common genotype that also is the most difficult to treat.

Leah Molloy

Leah Molloy

Sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics) were each initially approved for HCV genotype 1 treatment, but only when combined with the traditional HCV drugs ribavirin and pegylated interferon-alfa, which are limited by their well-described and significant toxicities. Although the FDA has recently approved the use of sofosbuvir combined with simeprevir as a PEG-IFN-a and ribavirin-free treatment regimen, the fixed-dose combination tablet ledipasvir/sofosbuvir (Harvoni, Gilead) provides this with the added convenience of a once-daily, single-tablet regimen.

Clinical Pharmacology

Different areas of the HCV replication complex are each targeted by ledipasvir and sofosbuvir. The RNA-dependent RNA polymerase NS5B is inhibited by sofosbuvir, and ledipasvir is active against the NS5A protein also involved in viral replication.

Ledipasvir/sofosbuvir is available as a fixed-dose tablet containing 90-mg ledipasvir and 400-mg sofosbuvir to be taken once daily with or without food. In contrast to sofosbuvir, which is 60% to 65% bound to plasma proteins with a minimally bound metabolite, ledipasvir is more than 99.8% protein bound. Although sofosbuvir is metabolized in the liver by p-glycoprotein (P-gp) to form both active and inactive metabolites, ledipasvir undergoes very minimal metabolism and is primarily excreted as unchanged drug. Therefore, the drug-drug interaction profile of ledipasvir/sofosbuvir is no different from sofosbuvir alone, with which co-administration of P-gp inducers such as rifampin, St. John’s wort and phenytoin should be avoided. The elimination half-lives of ledipasvir and the primary sofosbuvir metabolite are 47 hours and 27 hours, respectively, lending the drugs well to a once-daily dosing regimen. Although ledipasvir is primarily eliminated via biliary excretion with minimal renal elimination, sofosbuvir is renally eliminated. Thus, ledipasvir/sofosbuvir, like sofosbuvir alone, should not be given to patients with impaired renal function (estimated glomerular filtration rate <30 mL/min/1.73m2)

Indications and Regimens

Ledipasvir/sofosbuvir is currently approved for the treatment of chronic HCV infection causes by genotype 1 only. The fixed-dose tablet of 90 mg/400 mg should be taken once daily for 12 weeks by treatment-naive patients with or without cirrhosis and patients who are treatment-experienced but without cirrhosis. Treatment duration should be extended to 24 weeks for patients who are both treatment-experienced and have cirrhosis. The working HCV treatment guidelines are maintained and updated online by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, and have been revised to incorporate ledipasvir/sofosbuvir.

Ledipasvir Sofosbuvir Table  

Clinical Study Data

Ledipasvir/sofosbuvir was approved on the basis of three phase 3 studies: ION-1, ION-2 and ION-3. All three studies included patients infected with HCV genotype 1 only. Each study was open-label with the same primary endpoint of sustained virologic response at 12 weeks after completion of therapy. In the ION-1 study, 865 treatment-naive patients were randomly assigned ledipasvir/sofosbuvir with or without ribavirin, each for either 12 or 24 weeks. Success rates were almost identical in each of the four groups and ranged between 97% and 99%, all higher than the 90% response rate noted in the NEUTRINO study of sofosbuvir + ribavirin + PEG-IFN-a for treatment-naive patients primary infected with HCV genotype 1. Although ION-1 was not powered to compare outcomes between patients with and without cirrhosis, 16% of included patients had cirrhosis, and they were evenly distributed between the four treatment arms.

Researchers for ION-2 randomly assigned 440 previously treated patients who had either failed to respond or experienced viral breakthrough or relapse with PEG-IFN and ribavirin-based therapy to the same treatment arms used in ION-1. Again, response rates were high, between 94% and 99%, but patients with cirrhosis (accounting for 20% of the study population, evenly distributed between treatment arms) who received 12 weeks of ledipasvir/sofosbuvir had worse outcomes than those without cirrhosis (86% vs. 95%). However, when treatment duration was extended to 24 weeks, outcomes among patients with cirrhosis were similar to those without. Additionally, the higher response rate of cirrhotic patients who received 24 weeks of treatment compared with 12 weeks of treatment was statistically significant, leading to the recommended prolonged duration of therapy for treatment-experienced patients with cirrhosis.

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In the ION-3 study, a shorter duration of therapy was investigated among treatment-naive patients without cirrhosis. The 647 patients were randomly assigned ledipasvir/sofosbuvir for 8 or 12 weeks, or ledipasvir/sofosbuvir plus ribavirin for 8 weeks. Given the similar outcomes of SVR12 attainment rates ranging between 93% and 95% in each arm, the 8-week treatment course was deemed noninferior to the 12-week regimen, and no additional benefit was conferred by the use of ribavirin. Among patients with low baseline viral load (<6 million IU/mL), outcomes were very similar after 8 or 12 weeks of therapy (97% vs. 96%), prompting a note in the ledipasvir/sofosbuvir prescribing information that a shorter, 8-week course of therapy may be considered for treatment-naive patients without cirrhosis who have a pre-treatment HCV RNA less than 6 million IU/mL.

Cost and Acquisition

Not unlike its fellow novel HCV treatments that have gained widespread attention for high acquisition costs, ledipasvir/sofosbuvir is expensive, costing $1,125 per tablet. Although this is slightly higher than the famed $1,000 per pill cost of sofosbuvir, overall treatment costs could be expected to be slightly less, given the lack of required concomitant therapies as needed with sofosbuvir. As is also available for sofosbuvir, Gilead has developed Support Path (www.mysupportpath.com) for patient assistance. Patients ineligible for government reimbursement may qualify for discounted drug access with copays of as little as $5.

Future Applications

Ledipasvir/sofosbuvir is anticipated to play a major role in the future of HCV genotype 1 treatment, but phase 2 studies are ongoing to investigate the role of this treatment in genotypes 2, 3, 4, 5 and 6. Additionally, the pharmacokinetics, safety and tolerability of ledipasvir/sofosbuvir in children and adolescent patients is being evaluated in an actively recruiting phase 2 study.

In the quickly progressing era of novel HCV therapies, the approval of the first-ever one-tablet, once-daily drug is another important milestone in simplifying treatments and optimizing outcomes.

References:
AASLD/IDSA/IAS-USA. Recommendations for testing, managing and treating hepatitis C. Available at:  www.hcvguidelines.org. Accessed Dec. 30, 2014.
Afdhal N. N Engl J Med. 2014;370:1483-1493.
Afdhal N. N Engl J Med. 2014;370:1889-1898.
Gilead. Support path for Harvoni. Available at: www.mysupportpath.com. Accessed Nov. 30, 2014.
Gilead Sciences. A phase 2, multicenter, open-label study to investigate the efficacy and safety of sofosbuvir/ledipasvir fixed-dose combination in treatment-naive and treatment-experienced subjects with chronic genotype 4 or 5 HCV infection. National Library of Medicine (US). 2000. Available at: clinicaltrials.gov/ct2/show/NCT02081079. Accessed Nov. 30, 2014
Gilead Sciences. A phase 2, multicenter, open-label study to assess the efficacy and safety of sofosbuvir containing regimens for the treatment of chronic HCV infection. National Library of Medicine (US). 2000. Available at: clinicaltrials.gov/ct2/show/NCT01826981. Accessed Nov. 30, 2014
Gilead Sciences. A phase 2, open-label, multicenter, multi-cohort study to investigate the safety and efficacy of ledipasvir/sofosbuvir fixed-dose combination in adolescents and children with chronic HCV infection. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. Accessed Nov. 30, 2014. Available at: clinicaltrials.gov/ct2/show/NCT02249182NLM.
Harvoni [package insert]. Foster City, GA: Gilead Sciences Inc; 2014.
Kowdely KV. N Engl J Med. 2014;370:1879-1888.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; 2014.
Schiff ER. Am J Manag Care. 2011;17 Suppl 4:S108-115.
Sovaldi [package insert]. Foster City, GA: Gilead Sciences Inc; 2014.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.