Epclusa® sofosbuvir/velpatasvir Manufacturer: Gilead Sciences, Inc FDA Approval Date: June 28, 2016 Kelsy Combs, PharmD

Epclusa® - sofosbuvir/velpatasvir Objectives At the end of this presentation participants will be able to: Appropriately recommend Epclusa® - (sofosbuvir/velpatasvir) Effectively educate patients on the purpose, proper use and potential adverse effects of Epclusa® - (sofosbuvir/velpatasvir)

Epclusa® - sofosbuvir/velpatasvir Clinical Application Indications: Treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 Without cirrhosis or with compensated cirrhosis (Child-Pugh A) With decompensated cirrhosis (Child-Pugh B or C) in combination with ribavirin (RBV) Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Clinical Application Place in therapy: An option for 1st line treatment of any genotype HCV infection without cirrhosis, with compensated cirrhosis, or decompensated cirrhosis Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Clinical Application Contraindications (Ribavirin): Hemoglobinapathy Pregnancy Warnings: (and Black Box warnings) Ribavirin may cause hemolytic anemia which can worsen cardiac disease Precautions: Bradycardia in patients taking amiodarone Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Clinical Application Pregnancy: RBV - Contraindicated in pregnant women and men whose female partners are pregnant Sofosbuvir/velpatasvir – No human data Lactation: Unknown if excreted in human breast milk Excreted in milk of treated rats Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Drug Facts Pharmacology: Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor RNA chain terminator Velpatasvir prevents viral replication via inhibition of NS5A protein Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Drug Facts Pharmacokinetics:   Sofosbuvir Velpatasvir A Tmax 0.5-1h 3 h Effect of high fat meal (relative to fasting) 78% 21% D % Bound 61-65 >99.5 Blood to plasma ratio 0.7 0.52-0.67 M Metabolism Active Metabolite GS-461203; Inactive Metabolite GS-331007 CYP2B6 CYP2C8 CYP3A4 E % Urine 80 0.4 % Fecal 14 94 T1/2 (h) SOF: 0.5; GS-331007: 25 15 Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Drug Interactions Drug Interactions – Object Drugs: May increase the concentration of: Topotecan Digoxin Tenofovir Rosuvastatin Atorvastatin Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Drug Interactions Drug Interactions – Precipitant Drugs: Antacids, H2RA, PPI and efavirenz may decrease the concentration of velpatasvir Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifampin, tipranavir/ritonavir and St. Johns wort may decrease sofosbuvir/velpatasvir Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Adverse Effects Common Adverse Effects: (sofosbuvir/velpatasvir%) [placebo%] Headache (29) [28] Fatigue (20) [20] Nasopharyngitis (13) [10] Nausea (12) [11] Diarrhea (8) [7] Asthenia (7) [8] Feld, J.J, et al. N Engl J Med 2015; 373:2599-607.

Epclusa® - sofosbuvir/velpatasvir Monitoring Parameters Efficacy Monitoring: Reduction in HCV RNA viral load Toxicity Monitoring: RBV – Hemoglobin At baseline, weeks 2 and 4 Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Prescription Information Dosing: Patients w/o cirrhosis and with compensated cirrhosis (Child-Pugh A) sofosbuvir 400 mg/velpatasvir 100 mg once daily for 12 weeks Patients with decompensated cirrhosis sofosbuvir 400 mg/velpatasvir 100 mg once daily + Ribavirin for 12 weeks Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Prescription Information Dosing: Patients w/o cirrhosis and with compensated cirrhosis (Child-Pugh A) sofosbuvir 400 mg/velpatasvir 100 mg PO once daily for 12 weeks Patients with decompensated cirrhosis Cost: – $29904 / 28 tablets Source – UpToDate 9/26/16 Epclusa [package insert].

Epclusa® - sofosbuvir/velpatasvir Literature Review Sofosbuvir and Velpatasvir for HCV genotype 2 and 3 Infection (ASTRAL-2 and ASTRAL-3) Design Randomized, open-label, phase 3 trial Assigned 1:1 ratio to: Sofosbuvir 400 mg/velpatasvir 100 mg once daily x 12 weeks OR Sofosbuvir 400 mg + Ribavirin for 12 weeks (genotype 2) or 24 weeks (genotype 3) Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review Inclusion Criteria ASTRAL 2 – HCV genotype 2 ASTRAL 3 – HCV genotype 3 ≥ 18 YO 6 month history of HCV Treatment naive or previous treatment with interferon based regimen With or without compensated cirrhosis Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review Primary Endpoint Sustained virologic response at 12 weeks HCV RNA level <15 IU/mL After the end of treatment Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review Patient Characteristics HCV Genotype 2 HCV Genotype 3 Mean age (yr) 57 50 Male sex (%) 60 62 White (%) 87 88 HCV RNA Mean (log10 IU/mL) 6.5 6.2 Compensated Cirrhosis (%) 14 29 Previous HCV Tx 26 Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review Efficacy HCV Genotype 2 HCV Genotype 3 HCV RNA <15 IU/mL (End of Tx) Sofosbuvir/Velpatasvir x 12 wks (N=134) Sofosbuvir/Ribavirin x 12 wks (N=132) (N=277) Sofosbuvir/Ribavirin x 24 wks (N=275) At 4 wk 133 (99) 127 (96) 268 (97) 225 (82) At 12 wk 124 (94) 264 (95) 221 (80) Absolute Difference 5.2% (95% CI 0.2-10.3) p=0.02 14.8% (95% CI 9.6-20.0) p<0.001 Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review SVR12 According to Cirrhosis Status and Previous Treatment in Genotype 3 Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review Adverse Effects HCV Genotype 2 HCV Genotype 3 Sofosbuvir/Velpatasvir x 12 wks Sofosbuvir/Ribavirin x 12 wks Sofosbuvir/Ribavirin x 24 wks Any ADE N (%) 92 (69) 101 (77) 245 (88) 260 (95) Fatigue N (%) 20 (15) 47 (36) 71 (26) 105 (38) Headache N (%) 24 (18) 29 (22) 90 (32) 89 (32) Hgb < 10 g/dL N (%) 0 (0) 6 (5) 10 (4) Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Literature Review Conclusions Sofosbuvir/velpatasvir has superior efficacy in rates of SVR12 in patients with HCV genotype 2 or 3 including those: with or without previous treatment with or without compensated cirrhosis Sofosbuvir/velpatasvir has lower rates of adverse drug events than sofosbuvir/ribavirin Foster, G.R., et al. N Engl J Med 2015; 373:2608-17.

Epclusa® - sofosbuvir/velpatasvir Summary Epclusa® is indicated for once daily treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 Dosing is sofosbuvir 400 mg / velpatasvir 100 mg by mouth daily for 12 weeks for patients without cirrhosis and patients with compensated cirrhosis. Ribavirin is added for 12 weeks for patients with decompensated cirrhosis. Ribavirin may cause hemolytic anemia. Monitor hemoglobin (at baseline, weeks 2 & 4, then periodically) in patients with decompensated cirrhosis coadministered ribavirin.

Epclusa® - sofosbuvir/velpatasvir References https://www.epclusainfo.com/ Epclusa (sofosbuvir and velpatasvir) [prescribing information]. Foster City, CA: Gilead Sciences Inc; June 2016. Feld, J.J, et al. Sofosbuvir and velpatasvir for hcv genotype 1, 2, 3, 4, 5, and 6 infection. N Engl J Med 2015; 373:2599- 607. Foster, G.R., et al. Sofosbuvir and velpatasvir for hcv genotype 2 and 3 infection. N Engl J Med 2015; 373:2608-17. Curry, M.P., et al. Sofosbuvir and velpatasvir for hcv in patients with decompensated cirrhosis. N Engl J Med 2015; 373:2618-28.