Harvoni® ledipasvir/sofosbuvir Manufacturer: Gilead Sciences FDA Approval Date: 10/10/2014

Harvoni® - ledipasvir/sofosbuvir Clinical Application Indication: Treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. Place in therapy: One pill a day for convenient dosing and increased compliance Less adverse effects than the current treatment options for genotype 1

Harvoni® - ledipasvir/sofosbuvir Clinical Application Contraindications: None Warnings and Precautions: P-gp inducers may reduce therapeutic effect of Harvoni. The use of Harvoni with other products containing sofosbuvir (Sovaldi) is not recommended.

Harvoni® - ledipasvir/sofosbuvir Clinical Application Pregnancy: Category B Lactation: It is not known whether Harvoni can be found in human breast milk.

Harvoni® - ledipasvir/sofosbuvir Drug Facts Pharmacology: Ledipasvir – inhibits the HCV NS5A protein necessary for viral replication Sofosbuvir – prodrug converted to its active form (GS-461203), which inhibits NS5B RNA-dependent RNA polymerase and acts as a chain terminator

Harvoni® - ledipasvir/sofosbuvir Drug Facts Pharmacokinetics: A Cmax 4-4.5 hours Well absorbed D >99.8% protein bound M Slow oxidative metabolism via an unknown mechanism E 87% feces, 1% urine T1/2 47 hours

Harvoni® - ledipasvir/sofosbuvir Drug Interactions Drug Interactions – Object Drugs:  digoxin  tenofovir  simeprevir  rosuvastatin

Harvoni® - ledipasvir/sofosbuvir Drug Interactions Drug Interactions – Precipitant Drugs: Acid reducing agents  solubility of ledipasvir Anticonvulsants  Harvoni Antimycobacterials  Harvoni HCV products  ledipasvir St. Johns wort  Harvoni

Harvoni® - ledipasvir/sofosbuvir Adverse Effects 8 weeks 12 weeks 24 weeks Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% Insomnia 5%

Harvoni® - ledipasvir/sofosbuvir Monitoring Parameters Efficacy Monitoring: Signs of clinical improvement HCV RNA (viral load) at weeks 4 and 12 Toxicity Monitoring: CBC, basic chemistry panel, liver enzyme levels, bilirubin levels at weeks 1-2, 4, and then monthly during treatment

Harvoni® - ledipasvir/sofosbuvir Prescription Information Dosing: One tablet (90mg ledipasvir/400mg sofosbuvir) taken orally once daily with or without food Treatment-naïve with or without cirrhosis: 12 weeks Treatment-experienced without cirrhosis: 12 weeks Treatment-experienced with cirrhosis: 24 weeks

Harvoni® - ledipasvir/sofosbuvir Prescription Information Duration of Treatment Estimated Cost 8 Weeks $63,000 12 Weeks $94,500 24 Weeks $189,000 *Estimated cost based on Wholesaler Acquisition Cost of $1125 per pill

Harvoni® - ledipasvir/sofosbuvir Literature Review ION-1 Design: open-label, randomized, phase 3 trial 99 sites in the United States and Europe Interventions Fixed-dose combinations of ledipasvir/sofosbuvir +/- ribavirin for 12 or 24 weeks in treatment-naïve patients with genotype 1 HCV Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni® - ledipasvir/sofosbuvir Literature Review ION-1 Primary Endpoint: SVR at 12 weeks after the end of treatment Assessed in all patients who were randomized and received treatment Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni® - ledipasvir/sofosbuvir Literature Review ION-1 Inclusion Criteria: Chronic HCV Genotype I (n=865) 18 years or older No prior HCV treatment Patients with cirrhosis accepted (up to 20% of patients) Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni® - ledipasvir/sofosbuvir Literature Review ION-1 12 week treatment 24 week treatment Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni® - ledipasvir/sofosbuvir Literature Review ION-1 *Subgroup results do not include patients who withdrew consent or were lost to follow-up 12 week treatment 24 week treatment Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni® - ledipasvir/sofosbuvir Literature Review ION-1 Conclusions: “Once daily ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.” Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni® - ledipasvir/sofosbuvir Summary Harvoni® is indicated for the treatment of chronic hepatitis C genotype 1 infection in adults The use of Harvoni® with P-gp inducers is not recommended Harvoni® has a convenient dosing schedule which may increase compliance

Harvoni® - ledipasvir/sofosbuvir References Harvoni package insert. Gilead. October 2014. http://www.gilead.com/~/media/Files/pdfs/medici nes/liver-disease/harvoni/harvoni_pi.pdf http://www.harvoni.com/ November 2014. UPDATE 2 - US FDA approves Gilead’s $94,500 hepatitis C drug. Reuters. October 2014. (http://www.reuters.com/article/2014/10/10/gilead- fda-hepatitis-idUSL2N0S51WN20141010) Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-98.