SOFOSBUVIRUS FDA approved molecule for hepatitis C

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Layout of presentation

Introduction of Hepatitis C

Current Common Therapy for Hepatitis C

Mechanism of action of Sofosbuvir

Data of effect of sofosbuvir in HCV infected patients

Safety of sofosbuvir

Advantage of sofosbuvir

Introduction- Hepatitis C

• Hepatitis C is a viral disease that causes the inflammationof the liver which can ultimately lead to a diminishedliver function or liver failure.

• Mostly it is asymptomatic disease until the appearanceof liver damage.

• Approximately 130 to 170 million people experiencechronic HCV infection, which has a global prevalence of2%-3%[1,2].

• In 2002, worldwide, 27% of 783000 deaths from cirrhosisand 25% of 619000 deaths from hepatocellularcarcinoma were attributed to HCV infection[3].

1. Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. JHepatol. 2014;61:S45-S57. [PubMed] [DOI]2. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29 Suppl 1:74-81. [PubMed] [DOI]3. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis andprimary liver cancer worldwide. J Hepatol. 2006;45:529-538.

Current Common Therapy for Hepatitis C

• Interferon (injectable), Ribavirin (oral) and Protease Inhibitor(telaprevir, boceprevir, simeprevir, faldaprevir and vaniprevir)

• Limitation of Current Therapies:▫ High toxicity▫ Low efficacy : Treatment with peginterferon plus ribavirin induces only

about 50% of patients infected with HCV genotype 1 at high viral loadsto achieve sustained virologic response (SVR)

▫ Longer time for recovery▫ For PI, patients who are ineligible for or intolerant to treatment with

peginterferon plus ribavirin are contra-indicated from receiving theabove treatment

▫ Injectable therapy based▫ Higher cost of treatment

Kanda T, Imazeki F, Yokosuka O. New antiviral therapies for chronic hepatitis C. Hepatol Int. 2010;4:548-561.

Mechanism of Action of Sofosbuvir

• Sofosbuvir, an oral tablet is a direct acting antiviral agentand the first-in-class nucleotide analog inhibitor thatwas approved by FDA on December 6, 2013 for thetreatment of adults with chronic hepatitis C infection.3

• It works to inhibit HCV NS5B RNA dependent RNApolymerase which is considered to be an essentialcomponent of viral replication. 4,5&6

• It undergoes a metabolism to form the active uridineanalog triphosphate (GS-461203) that is combined intoHCV RNA by NS5B polymerase. 4,5&6

3. Tucker M. FDA approve game changer hepatitis C drug sofosbuvir. Medscape Medical News. 2013. Available at http://www.medscape.com/viewarticle/817371MPR.4. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl JMed. 2013;368:34-44. [PubMed] [DOI]5. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J BiolChem. 2010;285:34337-34347. [PubMed] [DOI]6. Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Niu C, Zennou V, Keilman M, Zhu Y, Lan S, Otto MJ. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis Cvirus. Antimicrob Agents Chemother. 2012;56:3359-3368.0

Mechanism of Action of Sofosbuvir

Place in Therapy

• Sofosbuvir delivers an enhanced SVR versus existingtreatment options in patients with variousgenotypes.

• It is the first FDA-approved all oral, interferon-freeregimen for patients diagnosed with genotype 2 and3 chronic hepatitis C.

Recommended regimens and treatment duration for sofosbuvir combination therapy in HCV

Sofosbuvir- Indication• It is available as a 400-mg once-daily tablet with or

without food.• It can be taken in combination with ribavirin or in

combination with pegylated interferon and ribavirin forthe treatment of chronic hepatitis C.5

• The treatment regimen and duration of treatment isgenerally based on the HCV genotype (genotype 1-4) andor clinical scenarios.

• There is no dosage adjustment needed for those with aCrCl >30 ml/min, no studies for those with CrCl <30, orthose with decompensated cirrhosis. 5,6

5. Solvadi. Highlights of prescribing information. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf Accessed March 20, 2014.6. Rx List. Sovaldi. 20143 Available at http://www.rxlist.com/sovaldi-drug.htm Accessed March 20, 2014

Data of sofosbuvir on HCV infected

patient

Safety of Sofosbuvir

• Sofosbuvir also possess a noteworthy safety profileand high tolerability.

• In phase 3 trials of sofosbuvir, the frequency of seriousadverse events ranged from 1% to 8% and the rate oftreatment discontinuation because of adverse eventsrange from 0% to 4.4%.

1. Liu X, Wang Y, Zhang G, Li N, Zhu Q, Chang H, Han Q, Lv Y, Liu Z. Efficacy and safety of sofosbuvir-based therapy for the treatment of chronic hepatitis C in treatment-naïve and treatment-experienced patients. Int J Antimicrob Agents. 2014;44:145-151. [PubMed] [DOI] 2. Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, Nakane K, Enomoto H, Ikeda F, Yanase M. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Lancet Infect Dis. 2015;15:645-653.

Sofosbuvir- Advantages• High Cure Rate (around 90%)• All-Oral (no injections)• Faster Treatment (within months)• No known resistance (as in the case with interferon)• In clinical trials, sofosbuvir plus RBV, with or without

PegIFN, has demonstrated SVR rates in excess of 80% formost cirrhotic patients and greater than or equal to90% in the majority of treatment naïve patients.

• Based on these data, the AASLD/IDSA guidancerecommended sofosbuvir for the treatment of HCVpatients

• Less adverse effects• Cheaper treatment as compare to current options

Prepared by: Med-Advise TeamDr. Kalpesh Jain (MBBS; MD Pharmacology), Dr. Niral Patel (MBBS; MD Pharmacology),

Dr. Dilip Patel (MBBS; MD Medicine), Ms. Mauli Patel(B Pharm, MBA)