Update on Hepatitis C: Trials & Treatment

Transcription

1 Update on Hepatitis C: Trials & Treatment 2 nd Annual NYC Clinical Trials Training August 20, 2014 Tracy Swan Treatment Action Group

2 Overview Drug development: how did we get there? Treatment update: what do we have? Title of your presentation

3 How are drugs developed? What is a clinical trial? Phases of drug development Pre-clinical Phase I Phase II Phase III Phase IV Risks/benefits of participation, by phase

4 How are Drugs Developed? HCV: Drugable Targets First, researchers identify a target (in this case, part of the hepatitis C virus).

5 From Bench to Bedside Then, researchers pick chemical mixtures (called compounds) that seem likely to work against a target, and do more tests in the lab to find the best compound-- then improve it ( a process called lead optimization)

6 Drug Development

7 Preclinical Trials Begin in test tubes, then animals (at least 2 species) Safety: does the drug harm any organs? Does it cause cancer, what impact does it have on reproduction? Should anything be monitored when the drug goes into people?

8 a Clinical Trial is: An experiment in human beings to determine: SAFETY, EFFICACY, & ACTIVITY of a drug, an intervention, or a treatment for a certain condition or disease

9 Clinical Trials: Access to HCV Treatment? Clinical trials should never be substitute for access to health care, but but sometimes they are. Trials may offer something better than the current approved treatment (called standard of care) but not always The golden question If I decide not to join this trial, what are my options?

10 Informed Consent An important safeguard explains the purpose of the trial describes the known risks and benefits involved with participation in the trial describes your rights and responsibilities, and those of the institution conducting the trial explains what to do and whom to call in case something happens to you during the trial. A very long document that people don t always read

11 Phase I: First in People From Healthy Volunteers to Patients Safety, safety, safety Activity: Does it do anything? What is the response does it lower the amount of hepatitis C virus in the bloodstream? Efficacy: Does the produce a certain effect can it cure HCV? ADME: Absorption, distribution, metabolism, elimination

12 Phase I Trials Risks & Benefits RISKS The >you know about a drug, the <risky Drug resistance Toxicity--bad side effects that nobody expected BENEFITS <Risky many safeguards: Animals are given drugs for longer periods before people get them and you will take the drug for a short time Fialuridine animals got much higher doses, no liver toxicity in first 2 to 4 weeks, then at 13 weeks, life-threatening side effects due to cellular damage, even after people stopped it 5 of 15 people died You are helping science (altruism) You will get paid

13 Phase II: Prove it About 2/3 of drugs make it into Phase II Larger (>100 people) SVR or cure, is the primary endpoint >they last for 24 weeks or more (HCV trials are much faster now) Is it safe, does it work? What is the right dose? Strategy: how long should people be treated, how many drugs to combine?

14 Phase II Trials Risks & Benefits RISKS People usually take the drugs for a longer period of time in phase II You may get the wrong dose, treatment does not work HCV drug resistance You may not be eligible for other trials Unexpected side effects can even be fatal (BMS trial) very, very rare BENEFITS Access to high-quality care Access to new treatment that is otherwise not available You may be cured (BMS/Gilead trial) You are helping research

15 Phase III Usually called registration trials ; last step before approval Usually randomized and controlled Large, often international so that results apply to different groups of people Enroll hundreds to thousands of people Study the best ways to use a drug

16 Phase III Trials Risks & Benefits Risks Still risky---sometimes side effects are worse in sicker people (who are allowed into phase 3 trials) May get stuck in the control arm Benefits Safer: only 10% of drugs that make it into phase 3 usually fail Access to high-quality care Treatment may not work HCV drug resistance You may not be eligible for other trials Access to treatment that is otherwise not available Treatment may work; you may be cured You are helping research

17 Trials vs. Real World Efficacy (capacity to produce a certain effect) Effectiveness (a measure of the accuracy or success of a diagnostic or medicine when carried out in the real world ) Are cure rates the same in trials and the real world? Why?

18 Phase IV (post-marketing) Sometimes regulators or sponsors want information in certain groups of people who were under-represented, or ineligible (children, the elderly, women, people from certain ethnic/racial groups, people with other medical conditions) Look at different doses and durations, to see if there is a better way to use a medicine

19 Phase IV Trials Risks and Benefits Risks Nothing is 100% safe Treatment may not work as well for a certain group of people Treatment may not work Drug resistance The standard of care may change to something better while you are in the trial (ex. HCV trials with a 3 rd drug) You may not be eligible for other trials Benefits Much more is known about safety, efficacy, dosing, side effects Access to highquality care Access to treatment Helping research

20 Trial Participation PHASE I: high-risk (toxicity, risk of incorrect dose/resistance) PHASE II: if you can take a risk, it might be a good idea, speaks to access issues PHASE III: safer entry point; more is known about the drug

21 HCV Drug Development Preclinical 3.5 to 6.5 years Lab & animals??????? 5,000; 5 enter clinical trials Phase I 1 to 1.5 years Humans: safety, activity, dose/pk; small & shortterm (days); healthy volunteers before people with HCV $100,000 to $1,000,000 Phase II 1-2 years Safety, dose, efficacy: >100 people; 8 to 24 weeks of treatment plus weeks of follow up $10 to $100 million Less than 1/3 make it past phase II Phase III 1-2 years Safety; efficacy, 100s to >1000 people; 8 to 24 weeks of treatment plus 12 to 24 weeks of follow up $10 to $500 million Only 1 drug approved Phase IV 2-3 years Diverse populations; treatment strategies? Adapted from: Drug Development Process. International Society for Pharmaceutical Engineering. Addie D. Andeson.

22 OVERVIEW New terms HCV in the US Trial participation When to treat Curing HCV: from interferon to DAAs DAAs Cure rates, by HCV genotype What s here now, and what s coming Treat now, or wait? What matters most?

23 Short for.. SVR: sustained virologic response, means No hepatitis C virus was found in a person's bloodstream AFTER treatment SVR-12 and SVR-24 = cure SVR-4, SVR-6 and SVR-8 = someone was in a hurry not a cure yet.. DAAs: direct-acting antivirals, oral drugs used to treat hepatitis C DDI: drug-drug interaction

24 NHANES: HCV in the US Total US population: almost 317,000,000 HCV rate, White: 1.3% HCV rate, African Americans: 2.2 % HCV rate, Latinos/as: 1% A closer look: HCV in the Bronx 14.8% Latino 5.5% Latina Ditah, et al; J Helatol 2013; Kuniholm, et al; JID 2014; US Census Bureau May 20, 2014

25 Trial Participation: Why it Matters IDEAL & the IL28B genotype African Americans > likely to have TT less likely to clear HCV less likely to be cured with interferon Long term studies Hispanics more likely to get sicker, die from untreated HCV

26 When to Treat HCV

27 HCV Treatment: Cure Rates Penn State, GI report.available at:

28 CURING HCV: Interferon Era SVR: less risk of illness & death (liver-related, AIDS-related, all-cause) Less likely for: People with HCV genotype 1 People who have cirrhosis People who are HIV-positive People who are treatment-experienced Older people (>40) African Americans? Latinos/Latinas

29 DIRECT-ACTING ANTIVIRALS (DAAs) DAAs work like HIV meds do they stop HCV from reproducing 4 families, blocking different steps in the HCV life cycle need to hit in >1 spot Until 2011, nobody knew if DAAs would be enough to cure HCV

30 DAA TARGETS PROTEASE, NUCLEOSIDE/TIDE, NS5A, NON-NUCLEOSIDES Asselah T et al. Liver International 2012

31 As of December FDA approved DAAs The first interferon-free treatment (for certain types of HCV) was approved DAAs that can be used together Trials in people with HIV, people with cirrhosis, pre and post transplant are now ongoing More DAAs are coming in 2014 and 2015

32 FDA prescribing information; Jacobson et al; EASL 2013; Lawitz et al; DDW 2013; Manns et al; EASL Genotype 1, Option 1 OLYSIO + PEG-IFN/RBV 24 or 48 weeks Cure rate: ~80% (less in some treatment experienced people) Not recommended for: People who can t use interferon G1a and Q80K People treated with an HCV protease inhibitor (incivek or victrelis) People with advanced cirrhosis Use with some HIV meds

33 Genotype 1, Option 2 SOVALDI + PEG-IFN and RBV for 12 weeks Cure rate: 90% 89% in HIV/HCV 80% with cirrhosis 74% in treatment-experienced Not recommended for: people who can t use interferon, people with advanced cirrhosis Lawitz, et al; NEJM 2013; Sulkowski, et al; AASLD 2013; Pol et al; EASL 2014

34 Genotype 1: Option 3 Olysio and Sovaldi (phase 3 open) 12 weeks Cure rate: 93% (includes null responders, and people with cirrhosis) Not recommended for: People who were treated with an HCV protease inhibitor (incivek or victrelis) People with advanced cirrhosis Use with some HIV meds Lawitz et al; EASL 2014; Sulkowski et al; EASL 2014

35 HCV G1: Option 4 Sovaldi + RBV 24 weeks Cure rate: 78% (real-life population) 75%- 85% in HIV/HCV Limitation: RBV Molina, et al; IAC 2014; Osinusi et al; JAMA 2013Sulkowski, et al: JAMA 2014

36 Coming in 2014 AbbVie 3D + or - RBV, 12 weeks Cure rate: 90% to 99% (experienced too) In cirrhosis, 90% (12 W) to 97% (24 W) Trial in HIV: 93% (12 W) or 97% (24W) Limitations: RBV, DDIs, few re-treatment options, < effective for null responders with G1a and cirrhosis Total studied (phase 3): 2,319* African American: 6% (134) Female: 43% (994) Hispanic: 6% (137) Asian: <2% (42) Other: <1% (12) From: PEARL 2, 3 and 4; SAPPHIRE 1 and 2; TURQUOISE- 2 Andreone et al; DDW 2014; Feld et al; NEJ 2014; Ferenci et al; NEJM 2014; Kowdley et al; NEJM 2014; Lawitz et al; AASLD 2013; Poordad et al; NEJM 2014; Sulkowski, et al; IAC 2014

37 Coming in 2014 Sovaldi/ledipasvir FDC, 8 or 12 weeks Cure rate: 93% to 99% (experienced too) In HIV/HCV 100% (SVR-4) In cirrhosis, 86% (12W) to 99% (24 W) Limitations: possible drug-drug interactions Total studied (phase 3)* : 1,952 African American: 15% (308) Female : 39% (777) Hispanic: 9% (181) Asian :<1% (12) Other<: 2% (31) *From ION-2. 3 and 3 Afhdal, et al; NEJM 2014; Afhdal et al; NEJM 2014; Kowdley et al; NEJM 2014

38 Coming in 2014 Sovaldi + daclatasvir 12 weeks Cure rate: 100% Trials in HIV/HCV, cirrhosis Limitations:? Sulkowski et al; NEJM 2014

39 Getting Ready for a Cure Find out: What your insurance covers What shape your liver is in Your genotype, and (maybe) subtype, or pick a regimen that works for 1a and 1b If you are HIV+, -can you, and are you willing to switch your HIV meds?

40 HCV G3: Option 1 Sovaldi + RBV 24 weeks Cure rate: 92% In treatment-experienced: 87% In cirrhosis, no experience: 92% In cirrhosis, treatment-experienced 60% In HIV/HCV (12 W) 67% Limitations: RBV Sulkowski et al; AASLD 2013; Zeuzem et al; NEJM 2014

41 HCV G3: Option 2 Sovaldi + PEG-IFN/ RBV 12 weeks Cure rate: 92% In treatment-experienced: 87% In cirrhosis, no experience: 92% In cirrhosis, treatment-experienced 60% In HIV/HCV (12 W) 67% Limitations: PEG-IFN, can t be used in advanced cirrhosis Jacobson et al; NEJM 2013l; Lawitz et al; NEJM 2013; Lawitz et al; AASLD 2013;

42 HCV G3: Option 2 Sovaldi + PEG-IFN/ RBV 12 weeks Cure rate: 92% In treatment-experienced: 87% In cirrhosis, no experience: 92% In cirrhosis, treatment-experienced 60% In HIV/HCV (12 W) 67% Limitations: PEG-IFN, can t be used in advanced cirrhosis Jacobson et al; NEJM 2013l; Lawitz et al; NEJM 2013; Lawitz et al; AASLD 2013;

43 HCV G3: Coming in 2014 Sovaldi + daclatasvir 12 weeks Cure rate: 88% Trials in HIV/HCV, people with cirrhosis Limitations:? Sulkowski et al; NEJM 2014

44 HCV G4: Option 2 Sovaldi + RBV,24 weeks Cure rate: 100% 93% (experienced) Limitations: RBV Ruane et al; AASLD 2013