The Frontier of Research Advocacy: Hepatitis C Drug Development

1. The Frontier of Research Advocacy: Hepatitis C Drug Development HIV Research Catalyst Forum Michael Carden, SUNY Downstate/Cornell Tracy Swan, Treatment Action Group

2. Overview • HCV & HIV/HCV: US Epi--who has it? • Natural history of HCV and HIV/HCV-what happens to people with HCV and HIV/HCV? • Current standard of care for hepatitis C: how well does it work, what are the side effects? • The future of HCV treatment--what’s next? • Activist checklist--what do you think?

3. True or False? • One phase II HCV treatment trial excluded African Americans • People who are using drugs are usually eligible to participate in HCV clinical trials of new drugs, as long as they show up for study visits • People with cirrhosis (serious liver scarring) are excluded from HCV clinical trials until the drugs are approved • All pre-approval HCV treatment trials have excluded HIV/HCV coinfected people

4. HCV in the US 1.8% of the US population (4 to 5 million people) has been infected with HCV, and ~3.3 million people are chronically infected ~300,000 people In the US are HIV/HCV coinfected Armstrong et al; Ann Intern Med 2006; Edlin; AASLD 2005; Sulkowski et a; JAMA 2002

5. HCV Prevalence (US) General population 1.6% White: 1.5% African American: 3% African American Males, 50-59 years of age: 13.6% Veterans(esp. Vietnam) : ~20% HIV + people: 25-30% Homeless people: ~40% Current & former IDU: up to 90% People who received pre-1987 clotting factor: up to 95%

6. Why is HCV a Problem? HCV enters the bloodstream, & infects liver cells HCV becomes chronic (lifelong) in 55-85% of people who get it The hepatitis C virus does not not damage the liver; scarring is caused when the immune system responds to the virus by walling off infected liver cells 15 to 50 years later, serious liver scarring (cirrhosis), develops in 20- 30% of people with chronic HCV

7. Range of HCV Outcomes,Over Decades • No symptoms, no liver damage • Symptoms (fatigue & depression) & some liver damage • Fat in the liver (steatosis) • Liver scarring (fibrosis) • Serious liver scarring, making it difficult for the liver to function, called cirrhosis (20-30%) • Liver cancer (1% to 5% of people with cirrhosis per year) • Liver failure (3% to 4% of people with cirrhosis per year)

8. HCV Progression: Cofactors • HIV coinfection • Age >40 at time of infection • Insulin resistance, obesity, steatosis • Aging/duration of HCV infection • Chronic HBV infection • Male

9. HCV & Alcohol Alcohol accelerates HCV progression, especially >50 grams/day Safe amount? Cutting down or quitting may be more important than HCV treatment for some people Many physicians won’t treat drinkers, biased by data from old studies

10. Goal of HCV Treatment Is……to get rid of the virus, permanently, an outcome called SVR SVR (sustained virological response), meaning that no HCV is detected in the blood 6 months after HCV treatment completion) SVR is durable (>10 years), and reduces liver-related Illness and death, regardless of HIV status Barreiro et al; Antiviral Ther 2006; Lau et al; Hepatology 1998; Maylin et al; Gastroenterology 2008; Vedt et al; Ann Intern Med 2007; Yu et al; Antivir The 2006

11. How Does HCV Treatment Work? HCV treatment works in 2 ways: By killing infected cells (immunologic effect) By blocking viral replication, to protect uninfected cells from HCV (anti-viral effect)

12. Get Down, & Stay Down! Successful HCV treatment rapidly—& completely —suppresses the virus, & keeps it suppressed throughout the course of treatment (12-72 weeks)

13. HCV: Current SOC Drugs: Pegylated interferon & ribavirin Duration: 12 to 72 weeks Efficacy: ~50%, depends on several factors Side effects: NASTY! Pegasys pegylated interferon alfa 2a flat dosing Hoffman La Roche Peg Intron pegylated interferon alfa 2b dosed by weight Schering Plough / Merck Ribavirin dosed by weight generic

14. Interferon (IFN) Interferon is a synthetic version of a chemical messenger made by the human body; it stimulates the immune system & fights viruses Pegylated Interferon (PEG-IFN) is the standard of care Pegylation means thata small molecule has been attached to interferon to keep it in the body longer & make it more effective Pegylatedinterferon is injected 1 X per week; old-school interferon was injected 3 X per week (sometimes even 1 X per day)

15. Side Effects of IFN Flu-like (fever, aches, nausea, appetite loss, weakness, & fatigue) Lab Abnormalities (anemia, neutropenia, thrombocytopenia) Neuropsychiatric (suicidal ideation/suicide (rare), depression, insomnia, anxiety, irritability, mood swings, mania, psychosis) Other (hair loss, optic nerve damage)

16. Ribavirin (RBV) • Pill or capsule, taken 2 X a day • Same family (NRTI) as some HIV drugs but it does not work against HIV • RBV dosing is based on weight • There are interactions between RBV and some HIV drugs

17. RBV Side Effects Anemia: major, sometimes treatment-limiting side effect Cardiac events Shortness of breath, coughing Itchy skin/rash May also cause depression, irritability

18. HCV Treatment Efficacy(how well does it work?) Data from clinical trials; 24- 48 weeks of PEG-IFN + RBV (all treatment naïve; by genotype and HIV status) (Carrat et al; JAMA 2004; Chung et al: NEJM 2004; Fried et al; NEJM 2002; Manns et al; Lancet 2001; Laguno et al; AIDS 2004; Torriani et al; NEJM 2004)

19. HCV Treatment in African Americans & Latino/as SVR, SVR, SVR, Study African American Latino/a White * plus an HCV protease inhibitor

20. Pretreatment Genetics (IL-28b CC vs. TT) Hepatitis C genotype (2,3,4,1) & subtype (1b vs 1a) Race (Asian> White > Latino/a> AA) HCV RNA<400,000 HIV status (not CD4 count or HIV RNA) Liver damage/steatosis BMI Insulin resistance, diabetes On Treatment Support Endurance Aggressive side effects management WBD of ribavirin Early response to TX Adequate TX duration Adherence (80/80/80) HCV TX Response: Prognostic Factors

21. Population-Specific Issues Treatment Naïve VS. Treatment Experienced • More than one type of experience: null response, non-response, viral breakthrough, relapse • Response to retreatment better for some treatment experienced groups (relapsers>breakthrough >non-responder>null responder) What was original treatment regimen, duration, dose, & how were side effects managed? (Shiffman; Hepatology 2002)

22. The Candidates • HCV protease inhibitors • HCV polymerase inhibitors • NS5a inhibitors • Cyclophilin inhibitors • Entry inhibitors • MicroRNA • Nitazoxanide • Immunomodulators • Novel Interferons • Monoclonal Antibodies • Therapeutic Vaccines • Milk Thistle • Anti-fibrotic Agents

23. The Big Question(s) Will antiviral therapy cure HCV without an immune-based therapy? Will it work for everyone? If so, how long will it take? -may differ by population & individual factors What are the least risky, most efficient ways to answer these questions?

24. 2010 Landscape HCV clinical trials in HIV/HCV coinfected (TX naïve) people a single HCV antiviral + SOC HCV clinical trials in HCV monoinfected (TX naïve & TX experienced) people with 2 oral antivirals, with or without SOC HCV clinical trials (phase 1, 2 and 3) in monoinfected (TX naïve & TX experienced) people people add a single antiviral to SOC

25. HCV Trial Design Issues Drug-drug interactions (especially for HIV+ people) Overlapping safety issues (ANEMIA, RASH) Confusing dosing (tid + bid) Design of trials and control arms as SOC continues to evolve, especially for treatment experienced people Will/should stopping rules change? What role will genetics have?

26. HCV Replication & Mutation • Hepatitis C makes billions of copies each day, called virions • These virions are not identical; some have changes in the genetic structure of the virus, called mutations • Mutations in viral enzymes occur randomly • Some mutations make it harder for the virus to reproduce; others can stop drugs from working • HCV mutations that cause resistance to the new antiviral drugs are present in many people who have never taken them

27. HCV Replication

28. Drug Resistance the ability of an organism to grow in the presence of a drug that would normally kill it or limit its growth; drug resistance can develop or emerge within days With HCV, no one knows how long resistance mutations will last, and if they will compromise future TX options

29. Drug Levels & Resistance

30. HCV Protease Inhibitors Resistance: cross-resistance is a problem, resistance emerges / develops within days & can still be found years later; long-term consequences unclear Activity may be genotype-specific More side effects (rash, GI) and cost! All of the HCV protease inhibitors may cause anemia Different treatment strategies/ durations for each drug, makes comparison difficult

31. In the Clinic Phase III • Boceprevir (Merck/Schering-Plough) 3X day • Telaprevir (Vertex/Tibotec) 3X day, possibly 2X day *studied with low-dose ritonavir

32. HCV Polymerase InhibitorsToxicity has been an issue Nucleoside/nucleotide: Active against all HCV genotypes, high genetic barrier/ resistance less likely Non-nucleosides: Genotype-specific, resistance-prone

33. NS5a Inhibitors: Potent,PROMISING A-832 and BMS 790052 are in Phase II

34. Combination Trials Roche/Genentech INFORM-3 (HCV protease + HCV polymerase)Delayed, dosing issues BMS: pairing BMS-650032 (a protease inhibitor) with 790052 ( an NS5a inhibitor) in null responders: OpenVertex: pairing telaprevir (a protease inhibitor) with VX 222 (a polymerase inhibitor) Open soon

35. HCV TX Trials in HIV/HCV Coinfected People • Two HCV protease inhibitors trials in HIV/HCV coinfected people open in US/Europe (boceprevir and telaprevir) • Nitazoxanide in US only

36. What do You Think? CRAPPYVIR: Big study planned No women No methadone / buprenorphine use Drug testing No HIV+ people No psych meds or history of depression, etc Trial in HIV+ NO ARVs Must have >500 CD4 cells No cirrhosis