Richard Bax Monday 4 th March 2013 London SUPERBUGS & SUPERDRUGS UPDATE ON CURRENT R&D AND THE REGULATORY ENVIRONMENT

Richard Bax Monday 4 th March 2013 London SUPERBUGS & SUPERDRUGS UPDATE ON CURRENT R&D AND THE REGULATORY ENVIRONMENT

The future of Antibiotics and Resistance World Economic Forum arguably the greatest risk to the human health comes in the form of antibiotic resistant bacteria Howell L ed Global Risks WEF 2013

Antibiotic Ages Most new classes developed between 1944-1975 Molecular roulette, medicinal chemistry and SARS 1975-1990 e.g. Betalactams, Quinolones Birth of modern pharmaceuticals outpaces antibiotics Slow down in new antibiotic development in spite of 1991-1999 increasing bacterial resistance Rise and fall of Omics Many governments and academics calling for new R&D of antibiotics Increased funding for developing World infections HIV, 2000- TB, Malaria etc. Launch of around 6 new products of which only linezolid and daptomycin are truly novel 2007?

Successful Therapies New Problems Challenge 1 Infectious disease morbidity and mortality was decreasing Progress was, in large part, due to antibiotics Due to the large growth in other markets and relative ease of discovering new compounds compared to antibacterials, some companies have halted antibiotic discovery and development. But new problems are emerging leading to increases in morbidity and mortality Demand for and use of antibiotics exceeds rationale role Proliferate use linked to increased bacterial resistance leads to pressures to reduce antibiotic use

More Rational, But less Intuitive Choices Have Led to More Complex Decisions - Challenge 2 Many antibiotic classes available with well defined but overlapping antimicrobial effectiveness Rationale prescribing difficult except to constantly reduce use Questionable link between use of antibiotics and improved patient outcome in some infections Most appropriate choice not clear, even in common infections Clinical and societal implications of bacterial resistance of concern but implications unclear

More Available Data, Less Useful Knowledge - Challenge 3 Increased regulatory demands for clinical trials, other data and multiple analysis, interpretation and reporting Large and growing research, clinical, and community database Omics Sensitivity/Resistance Patterns Prescribing Patterns Healthcare Utilization Demographics and Clinical Data But Market small compared to others Data Sources/Databases isolated Episodes of Care Unconnected Patients Outcomes not documented

Current Antibiotic Situation 4 Increasing concern on use and spread of bacterial resistance and lack of new antibiotics Fears of andromeda strain growing Many bacteria are promiscuous and have acquired resistance to multiple classes of antibiotics Many initiatives to combat antibacterial resistance in developed and developing World Significant reduction in antibiotic market especially in profitability Very few new and novel antibiotics discovered since the 1960 s. In spite of promises of riches in the 90 s, very few new and novel antibiotics in preclinical or clinical trials Will they come in time?

A unique medical situation Antibacterials have enormous benefits Use can lead to loss of benefits New class agents can restore the benefits Lack of incentives and success Antibiotics are running out Can the antibiotic era be sustained?

Antibiotics Perception of great value Increased expectations Mature large market with little actual demonstrable differentiation 1930s-1980s: Challenge of identifying and developing new antibiotics 1990s-more complex definition of most appropriate use 2000s-where are the new ones

The Situation. Regulatory View J. Woodcock 1 Pharma industry productivity down calls for regulatory change to support innovation but doctors, payers and public want more information about drugs and risk aversion Drug development is a progressive reduction in uncertainty about human responses to a candidate medicine Drug developers and investors are distressed at the magnitude and duration of the investment and the uncertainty of the result. Many state that these costs are unsustainable Evidence Vs Access Can 21 st Century Drug Regulation Refine the Tradeoffs? J. Woodcock nature Vol 91 No3 March 2012

Regulatory View J. Woodcock 2 Ways to refine the tradeoffs between evidence development and access is adaptive licensing Explicit acknowledgment that evidence development is a continuum regulatory approval in steps Market access and use would be restricted until knowledge and evidence development would continue in parallel with use/marketing, using evidence from RCT s and clinical practice

NEED ACCEPTANCE OF TRADEOFFS BY ALL STAKEHOLDERS. REGULATORY VIEW J. WOODCOCK 3 Current examples: HIV therapy, Flu vaccine, Cancer treatments, MDRTB, Orphan Drugs N.B if post marketing commitments are not fulfilled burden of proof shifts to the regulators Determining tolerance for drug safety is even more difficult

Regulatory View J. Woodcock 4 New drug regulatory paradigms will evolve during the new few decades. These need to be practical, feasible and address the needs of many stakeholders.

TATFAR Transatlantic taskforce on Antimicrobial Resistance 2011 2009 US EU SUMMIT Focus on appropriate use in medical and veterinary communities, prevention of healthcare and MDR infections Strategies for improving the pipeline

TATFAR 2 FDA/EMA intention to discuss ways to facilitate the use of the same clinical development program to satisfy regulatory submissions to both agencies Exchange information on possible approaches to drug development for bacterial disease where limited drugs are available

TATFAR REPORT 2011-3 These are multiple scientific, regulatory and economic factors that are believed to have contributed to the decline in development of new antibacterial drugs There is a need for new therapies (When?)

A & D are familiar, B & C are new Quantity of Clinical Efficacy Data Acceptance of smaller clinical datasets (often merged across body sites) in response to unmet medical need

New Pathway for Antibiotic Innovation PEW Charitable Trust Jan 21 st 2013 Exploratory drug development for limited population feasibility of a limited population pathway from implementation to use Regulatory, clinical trial design and reporting, patients providers, payers, business model, promotion and use questions to be addressed LPAD approval mechanism

Scenario: Hypothetical Drug C is a Drug 1 based on the Tier C Proposal PEW 2013 Typical Phase 3 study not feasible Small prospective studies and descriptive data focused on specific pathogen(s) e.g. narrow spectrum IV drug for MDR Ps aeruginosa Potential US Market 20,000 54,000 MDR out of 136,000 540,000 case total

Tier C Recommendations Small prospective, open-label randomised versus best comparators (HAP, VAP, CUTI, CSSTI). Numerically similar outcomes in patients with culture and Ps. at multiple infection sites showing a trend towards improvement (not statistical significance) Open label non comparative study for patients that cannot be enrolled into study and have limited RX option Observational study of inadvertent ineffective therapy for the target pathogen Phase I and special population studies micro data, animal safety data, and full PK/PD

APPROVAL FOR TIER C APPROVAL WILL USE A SMALL DATA SET How to assess benefit/risk? Increased need for PK/PD Quantitative RCT not possible Significant restrictive

Tier C Recommendations Analysis of about 300 patients with Drug C and (400 Safety) Label Caused by infections proven or strongly suspected to be caused by Drug C susceptible strains of Ps aeruginosa. As data is limited Drug C should only be used if other alternatives are known or suspected to be less suitable Projected Pricing: $15,000 - $30,000 / 10-20 day course

CHANGING SCENARIO 2003 2013 20 pharmas + numerous small companies in R+D Low perception of antibiotic value Antibiotic stewardship restricting antibiotic use Monotherapy seen as best Multiple antibiotics launched in known classes 2 big pharma and numerous small pharmas active Are of high and increasing medical need New antibiotics desperately needed Combination use Few new classes None for Gram negatives

New Interventions To Address Resistance Refilling antibiotic pipeline by aligning economic and regulatory approaches Government and non-profit grants Limited Population Drug Proposal (LPAD) Development of an reimbursement for rapid diagnostic and bio market tests to enable appropriate use Elimination of use of antibiotics to promote livestock growth Studies to define shortest effective courses Developing micro-attacking treatments with diminished potential to drive resistance Developing treatments attacking host targets other than microbial targets to avoid selection of resistance

It s all about Benefit-Risk High unmet need for new MDR therapies justifies accepting more uncertainty regarding efficacy and safety in product development. Without this, we ll see a continuing increase in unmet need These greater levels of uncertainty can be managed & described Efficacy Increased utilization of pre-clinical and early clinical data At least some controlled data in the clinical trials Safety Usual preclinical assessments Safety data from all trials to identify AEs in the 0.5-1.0% range SmPC to focus on situations where both potential benefit and tolerance of unexpected safety events are greater

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WHAT DOES SMALL PHARMA NEED? Streamline clinical trials Money and expertise to manufacture Need a new paradigm for market failures appropriate price and patient population Need a clear regulatory strategy with high L.O.S Compelling value of sales Develop and communicate robust development plans for investors Robust phase 2 study along with appropriate PK/PD will predict success High value activities throughout development (i.e. POC)

Severe Threat at the moment i.e. how sick you look Serious Threat to life in the future

What does regulators need? Clear explanations of why bottlenecks Public perception of value of regulatory activities Challenge led rather than technology led Rapid diagnostic When do we know when are successful? Clear evidence of efficacy and estimation of harms. Benefit/Risk New diagnostic to reduce empiric use

Many More Questions than Answers Pricing and Cost Reimbursement Global availability Manufacture/Supply Off label use When to prescribe What pathogen where? Can rapid diagnostic help when? Does use on label mean it is appropriate? AB stewardship New marketing through scientific liaisons? Labelling should not detail the practice of medicine After labelling what are the post marketing commitments Who will police use?

Many More Questions than Answers Currently patients with multi drug resistant pathogens are complicated and difficult to treat. Most products take over 10 years to research and develop What do we do now?

The Future of Antibiotics and Resistance Antibiotics naturally selects for pre existing resistant populations of bacteria After billions of years of evolution microbes have most likely invented antibiotics against every biochemical target that can be attacked These antibiotic resistances already exist and are widely disseminated in the nature and to drugs not yet invented Innovation will arise from therapies that do not drive resistance eg Mab's, sequestration of iron These therapies must not increase the host response to the microbe itself Incremental tweaking of old processes of research is unlikely to deal with the problem in the future Brad Spellberg. N Engl J Med Jan 2013

ANTIBIOTIC MARKET SNAPSHOT: IN EXCHANGE FOR HIGHER PRICES, MORE VALUE

Whitley Park May `98 RCT s Strengths Weaknesses Concept Scientifically accepted Over emphasis on outcome as truth EBM inhibits development of alternatives Equivalence Is equivalence needed? Conduct Capable of rigour Costly, complex, difficult practically Long and Short term Short term only Interpretation Internally valid Externally less valid Poorly predictive for individual prescribing decision

Whitley Park May `98 RCT s (Cont d) Application Strengths Weaknesses Industry Good for registration and No demonstration of superiority marketing Physicians Microbiologists Society Efficacy and safety known Mean results only extrapolation to real versus standard patients difficult antibiotics Confirmation of S No confirmation of I or R category category Some benefits and costs No long term epidemiology clarified Development of No data on spread of sensitive/resistant resistance in few and organisms selected patients True costs and outcomes seldom determined

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Bacterial Infections High medical need Changing field $30 billion value Lack of new products or in late development New antibiotics would be launched into a generic market Opportunity for personalised healthcare and impact of diagnostic pathogen specific treatments Shift in the regulatory area to early introductions for products to meet high medical need

Richard Bax 35 years in Infection Trained at Northwick Park in ID Antibiotics Developed/Launched:Cefuroxime, ceftazidime, cefotaxime, cefamandole, moxalactam, cephalexin, cefaclor, cefotetan, meropenem, augmentin BD, Bactrogan, daptomycin Worked on 4 out of the last 5 antibiotics submitted to EMA as a consultant Other antivirals, antifungals and orphan drugs.