7th International Workshop The Clinical Pharmacology of

Hepatitis Therapies

Hyatt Regency Hotel Cambridge, MA

June 27-28, 2012

Organizing Secretariat: Virology Education (virology-education.com)

The Past Year: What’s Been Happening in Viral Hepatitis?

• HBV (≈ 2 deaths/minute, globally*) • US prevalence of CHB being revised upwards by CDC, as many as 2.2 M • Lamivudine → generic in many countries (Lam and ADV generic in China) • New HBV antivirals needed, with different MOAs, to ↑durable response rate

• HCV (≈ 1 death/minute, globally*) • Advancing liver disease in 170-200 million people

• most CHC patients remain undiagnosed & untreated - in U.S., EU, and ROW • Endstage CHC emerging as a recognized public health crisis, N America & EU • First year of marketed HCV PI + pegIFN “triple” therapies

• AASLD 2011 & EASL 2012 • Rapid progress with IFN-sparing, multi-DAA oral therapies

• high SVR rates (>85%)with 12-24 weeks’ RX with several oral combination therapies • RBV used in some (most) oral DAA regimens, to ↓ viral breakthrough/relapse • At least 2 successful regimens have been IFN-free and RBV-free

• 1 regimen reported at EASL 2012 was IFN-free, RBV-free, and nuc-free

• CDC (May, 2012) • Provisional rec: HCV screening for all Baby Boomers (birth cohort 1945-1965) • If implemented effectively…

• could lead to substantial increase in HCV diagnosis (~ 800,000 newly-dx’d patients) • could avert premature mortality in 120,000 pts (or more, when SVR > 75%)

*Perz et al., J Hepatology 2006; 45: 529-538

The Globalization of Drug Development, and Implications for HBV and HCV Therapies

Nathaniel A. Brown, M.D. Chief Medical Officer

Presidio Pharmaceuticals, Inc.

7th International Workshop The Clinical Pharmacology of Hepatitis Therapies

Cambridge, MA June 27, 2012

100 Years of Increasing Life Expectancy In the United States

• 1900-1945 Improvements: sanitation/public health measures, infant mortality • 1945 - : medical & surgical advancements, including vaccines & pharmaceutics • 10-15 year increase in life expectancy during 1950-2007 “New drugs are no small part of this medical miracle.” —Mark McClellan, FDA

*

*SOURCE : CRS Report for Congress: Life Expectancy in the United States; Aug 16, 2006

↑ pharmaceutics →

Drug Development – The Old School

• Pre-1990s: mid-large Pharma invented most (90%) new drug candidates • Mid-large Pharma developed most new drugs, with internal staff

– Company’s therapeutic area choices envisioned as long-term franchises • Research divisions with long-term therapeutic area discovery focus • Clinical divisions with long-standing therapeutic development teams • Marketing teams with therapeutic area expertise

• Vendor support: consultants, few central laboratories, very few CROs

The New Way(s): The “Biotech Revolution”

• Advances in basic research methods, late 1970s - present → accelerated discovery of disease targets & drug candidates → advances in chemistry & structural biology

→ less need for large chemistry banks and random screening → increasing discovery by small groups (biotech, academia)

• Decreasing research productivity at Big Pharma (?) → increased in-licensing from small pharma/biotech → discovery alliances with academic research centers

• “Open Innovation” research model – esp., new targets • In past 25-30 years, increasing investor interest in small pharma/biotech • Increasing CRO/vendor support for projects at small pharma/biotech

→ new business model: small biotech discovery + Phase 1 to 2a POC → development de-risked for Pharma, with early clinical data

Increasing Globalization of Drug Development (1)

• Up to early 1990s, registration trials typically conducted regionally – North America, Western Europe, Japan – each with separate regulatory needs

– Foundations for ethical clinical research established by 1980s (Nuremburg Code → Declaration of Helsinki → Good Clinical Practice standards) • Human subject protection

– adequate risk-benefit, informed consent, ECs/IRBs, qualified investigators • Transparency in clinical research

– Protocol, EC/IRB oversight, verifiable data, complete data in dossiers

– Standards for development, registration dossiers, and product quality of new drugs varied by country

– Initial registration trials conducted in prioritized large pharmaceutic markets, with later “seeding trials” in secondary markets after initial approvals in NA/EU • Patients in small and developing nations waited many years for new medicines

• Occasionally, local abuses due to local corruption and lack of international standards

• Most clinical development programs are now globalized - Why? – “Lower costs”? “Greater access to [treatment-naive] patients for large trials”? – Yes (sometimes), but overall other drivers are more important....

Increasing Globalization of Drug Development (2) Key factors driving globalization of drug development

• Increasing international trade (incl. medicines): global economic expansion • Expansion of international IP protection (Paris & PCT/WIPO, WTO, etc)

– Trade in patented/copyrighted products requires protection of those products • Shifts in global pharmaceutic markets

– N America, EU, and Japan increasingly constrained, single-digit growth – Emerging markets: double-digit annual growth in pharmaceutic markets – Large Pharma have prioritized products for developing/emerging markets

• International Committee on Harmonization (ICH) – since 1990 – International harmonization of regulatory requirements for drug development

• Vast global expansion of CROs & specialty vendors, since late 1980s – Multinational/global clinical CROs, regional & local CROs, specialty CROs

• Operational support of Phase 1-4 trials

– Multi-national contract labs – standardized lab testing for multi-center trials • Improvements in information technology & communication modes

The International Committee on Harmonization (ICH) • 1980s: Multi-state regulatory harmonization begun by European Commission (EC)

• 1990 - 1st meeting of the International Committee on Harmonization, in Brussels The ICH Mission: make recommendations toward greater harmonization in the interpretation

and application of technical guidelines and requirements for pharmaceutical product registration, to reduce duplication of testing during the development of new human medicines

• ICH initial signatories: U.S.(FDA), EC (EMA/EU), Japan

• ICH processes include regulatory agency and Industry representation

• ICH guidelines support ethical, rigorous drug development internationally, and better-standardized safety monitoring pre- and post-approval

• Tri-partite ICH Guidelines on safety, quality, and efficacy topics

• Pharmaceutic product quality standards

• Preclinical and clinical development standards

• MEDRA adverse event coding system (Medical Dictionary for Regulatory Activities)

• Facilitates/standardizes international adverse event recording and analysis

• Common Technical Document (CTD) format – standard format for study reports, etc

• Facilitates near-simultaneous multi-national registration dossiers

• Hardcopy still required for most registration dossiers (eCTD NDAs –FDA)

Global Expansion of Contract Research Organizations (CROs) & Specialty Vendors

• Q: What do non-clinical CROs do? • A: just about any service needed by a discovery organization:

• specialized biologic assessments and special assay development • chemical development, analytic development • manufacturing scale-up, formulation development, etc • pre-clinical pharmacology & toxicology

• Q: What do clinical CROs do? • A: operational support for clinical development activities (Phase 1-4 trials)

• assist with regulatory submissions and documentation • help establish investigator network, contracting & budgeting • trial initiation, data monitoring & QA, and close-out activities at clinical sites • interface for sponsor at clinical sites, re: issues arising

•Vastly increased availability of CRO support and specialty vendors • Key contributor to the new `business model’ for small pharma/biotech • Small discovery organizations could not move promising new therapeutics through pre-clinical and early clinical development without CRO support • If necessary, small companies can do global drug development, to product registration, with CRO support

Facilitation of Globalized Trial Programs By Improvements in Information Technology And Communication Modes

• The IT/communication revolution • Better-and-better computers (hardware and software)

• Word processing, spreadsheets, graphics, numerous Apps, etc • Continued `miniaturization’ → improved mobility

• Improved telephone and video communications • Mobile phones & hand-held devices; satellites, wireless - national & international

• Pre-1990 clinical trials: • Data capture (case record forms): paper → data transcription from paper • Communication among people (sponsor staff, investigators, patients)

• Telephone, snail mail, courier; personal travel • Hardcopy regulatory submissions (ca. 100,000 pages, manually duplicated)

• Today’s clinical trials • Electronic data capture (& `direct’ transmission into database, after QA) • Electronic integration of multi-trial databases, for integrated analyses • Electronic regulatory submissions, with facilitating linkages • Communication among people: cell phones, e-mail, videoconferencing, etc

Continuing Globalization of Clinical Trial Programs: Locations of Phase 1-3 Clinical Trial Sites

(Most phase 2 & 3 trial programs for NCEs are now globalized)

Median Number of Countries Hosting Phase 1-3 Trials For New Drugs

Phase 1 trials: 2002: 2 countries 2010: 2 countries Phase 2 Trials: 2002: 11 countries 2010: 18 countries Phase 3 Trials: 2002: 19 countries 2010: 34 countries

• Increasing ROW sites in Phase 2 & 3, esp. Asia, Eastern Europe, South America

Ethical Issues in International Trials (more common in local non-GCP trials) • Need to avoid “human guinea pig” situations • Need to assure high-quality, verifiable data – esp. registration data for new medicines

Recommendations:

• Should be a local need for, and potential access to, better therapy for the disease • Sponsor commits to launching the product in territories where trials are conducted

• In each country/territor y involved in a trial program, local healthcare infrastructure (including regulatory bodies) , clinical research capabilities, and sponsor resourcing should be sufficient to assure GCP adherence throughout the trial program and drug registration process

• Consistent Sponsor standards (ICH/GCP-compliant) for all sites & territories • Data independently verifiable by sponsor’s monitors and regulatory agencies

• New medicinal products (from NCEs) should be available locally only after review of product registration data and product quality by fully-staffed, experienced regulatory agencies

• CPPs to assure safety & quality in countries that are not CPP-qualified (WHO) (CPP = Certificate of Pharmaceutic Product)

• Continued regulatory and pharmaceutic industry progress is needed, toward international collaborative assessment of post-launch safety of marketed products

• Local and international professional societies can play a role in recommending regional priorities for new drug development in their territories

Assuring Ethics and Scientific Rigor in International Drug Development

Globalization of Drug Development: Implications for Hepatitis B and C

Global Diseases Need Globalized

Drug Development Strategies

Implications for Hepatitis B Therapies

Lessons Learned, Global Development of HBV Antivirals:

HBV nucleos(t)ides & Peg-IFNs

HBsAg Prevalence ≥8% - High

2-7% - Intermediate <2% - Low

Geographic Distribution of Chronic Hepatitis B 350-400 million HBV carriers, 15-40% will die of HBV (≥ 2 deaths/min)

Source: CDC

8 HBV Genotypes (A-H): differing natural histories and responsiveness to IFN Rx

Lessons Learned: Global HBV Drug Development • Development of new HBV medicines must include endemic regions

• esp., China & SE Asia (8-10% prevalence of chronic HBV infection) • China has ~100-120 million HBV carriers (1/4 to 1/3 of world total)

• ca. 300-400,000 HBV-related deaths/year in China • `universal’ HBV vaccination improving, but won’t help present HBV carriers

• HBV registration trials accrue much faster in Asia/China, with expert clinicians

• Clinical experts in many countries contributed to Phase 1-4 international GCP trials with HBV nucleos(t)ides and pegIFNs, since 1992

• N & S America, western & eastern Europe, China, Asia, Japan, Russia, India, etc • Satisfactory data inspections at leading sites in China & east Asia, elsewhere

• IP protection for proprietary medicines still an issue in some endemic regions • For agents patented after 1993, China now offers full GATT/WTO protection • Improving prospects for IP protection in India (~ 40 million HBV carriers) • Most countries with endemic HBV are now WIPO IP treaty adherents (Paris, PCT)

• A wide global network of GCP-experienced clinical investigators is available for future trials of new HBV (and HCV) medicines

Hepatitis C: Geographically Diverse Viral and Human Factors

Can Influence Treatment Response

Global Prevalence of HCV Infection*

*Lancet Inf 2005; 5: 558-567

• Global prevalence is 2-3%: 170-200 million people (3 to 5 million U.S.) • >90% of HCV infections are outside of N America and Europe • >360,000 HCV deaths/yr (≈ 1 per minute), mortality increasing • High-prevalence countries have higher rates of new HCV infections

• contaminated blood products and medical sharps still a problem, globally

*N. Zein, Clin Microbiol Rev 2000; 13(2): 223-235

Global Prevalence of HCV Genotypes*

• globally, 40-60% of HCV infections are g1a or g1b, the rest are g2-g7 • g1a > g1b in N America, g1b>g1a in EU and ROW • g1 and g4 are less responsive to IFN • g3 increasing in Europe & N America • g4 prevalence – 10% of Egyptians with chronic hepatitis C

D. Thomas, Nature 2009: 461 : 798-801

Global Variation in IL-28B Human Genotypes

• C allotype favorably influences responses to IFN-containing therapies and cyclophillin antagonists • Influence on treatment responses to IFN-free potent DAA regimens is presently unknown

we are here

Liver Transplant (cumulative)

HCC

Decompensated Cirrhosis

Vertex Milliman HCV Review 2009

Temporal Profile of U.S. HCV Morbidity/Mortality (Global Morbidity/Mortality: Higher and Longer)

• Potential for 150-250,000 HCV-related U.S. deaths, in next 15 years, if nothing done • Lifetime global HCV deaths, current patients: ≈ 0.2 x 170-200 million = 34-40 million

• Many new HCV drugs reaching clinical stage, clinical development typically 6-9 yrs • Need to quickly leverage experienced clinical centers worldwide, to develop effective and safe new HCV combination therapies ASAP

• Phase 1-3 registration programs typically require thousands of patients

Optimal reductions in HCV mortality will require: • Greater patient identification - broad screening programs • Treatment access for most patients • Treatment regimens with ≥ 80% SVR rates

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Reducing HCV Mortality in the Unites States (and Elsewhere): Major Improvements Needed in Diagnosis and Treatment

SVR

G Davis, 5th International Workshop on Clinical Pharmacology of Hepatitis Therapies; Gastroenterology 2010

Global Drug Development Strategies for Hepatitis C To meet the challenge of increasing HCV morbidity/mortality

• Can’t wait for `perfect’ HCV combination therapies, HCV morbidity rising • PegIFN/RBV is 80% curative for HCV-g2-g3, so HCV-g1 infection has been the main priority for HCV DAA therapies

• predominant HCV genotype in N America , EU, Japan, Asia, but only ≈ 40-60% globally • most g1 patients don’t respond to pegIFN/RBV • most current clinical-stage DAAs (esp., HCV PIs and non-nuc HCV pol inhibitors) are optimized for g1 activity and targeted to development in g1 patients

• 2 classes of DAAs are pan-genotypic, when optimized: nucs and 5A inhibitors • Recently, several `pan-genotypic’ (or broadly active) HCV PIs and non-nucs have progressed to late preclinical/early clinical development • Cyclophillin antagonists are also potentially `pan genotypic’

• Pan-genotypic HCV therapies potentially advantageous as global HBV therapies, but the clock is ticking (1 death/minute) - so “do the do-able”, to begin to ameliorate HCV mortality

• Prioritization of new HCV therapies: SVR ≥ 80%, safe/well-tolerated (IFN and RBV-free) • Pan-genotypic therapies can be prioritized but may be slower to develop

• fewer clinical-stage pan-genotypic drugs are currently available • global development will greatly facilitate assessment of pan-genotypic therapies

• Amount of data needed (per HCV genotype), for a pan-genotypic claim? • g1-targeted therapies in development can save many lives this decade • g2-g3 patients can be treated with pegIFN/RBV, or in trials, until better Rx arrives

Globalization of Clinical Trials: Conclusions • The globalization of drug development over the past 25-30 years has been driven by intertwined forces:

• expanding international trade (the Global Economy) • with correllative expansion of international IP protection

• shifts in pharmaceutic market growth, favoring emerging countries • facilitation of multi-national drug development by ICH guidances • increased availability of CRO support

• Increasing statistical rigor in Phase 2 & 3 trials, active-controlled trial designs, and ICH requirement for sufficient safety data (e.g.minimum 1500 patients, for product registration → large Phase 2 and 3 trial populations needed

• larger numbers of (Rx-naïve) patients available with multi-national site networks • expanding availability of clinicians experienced in multi-national GCP trials

• Hepatitis B and Hepatitis C are globally common serious diseases, in urgent need of better therapies to reduce global mortality (≈ 1 million deaths/yr) • New HBV and HCV therapies need global clinical development strategies

• To fully elucidate efficacy & safety in diverse patient populations • viral genotype variation (HBV and HCV), IL28B and other ethnic factors

• For more efficient (time & resource) multi-national product registration