Dr. Flic Gabbay Senior Partner TranScrip Partners LLP HOW DO WE GET THE ANTIBIOTICS WE NEED? Opportunities and challenges posed and lessons learned from recent submissions 24th Annual EuroMeeting 26-28 March 2012 Copenhagen, Denmark Dr. Flic Gabbay Senior Partner TranScrip Partners LLP

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How do we get the antibiotics we need? Why do we need new antibiotics? What is prohibiting the development of new antibiotics? discovery funding regulatory hurdles successful launch and stewardship

Why do we need new antibiotics?

Crisis in Treatment of Bacterial Infection Infectious Diseases Society of America US senate, GAIN act ECDC and EMA Focus of World Health Day 2011; April 7th

Why do we not hear more about antibiotic resistance? If it was important the media would tell us about it wouldn’t they? Superbugs – MRSA is getting under control C.difficile is still worrying but being addressed Other diseases are perceived to be much more important AIDs, malaria, coronary heart disease and cancer So why are all these organisations worried?

Incidence of disease (millions) based on WHO 2004 Diarrhoea 0-4y children – 5% mortality European figures LRTI CAP – up to 5% mortality HAP – up to 20% mortality COPD and AECB, ranked 4th in deaths in US not measurable by incidence alone a US alone, b JAMA 2007, c CDC annual, d 10 countries only 2010 EU Kock et al, e ECDC annual

We have been through a period of believing antibiotics are not needed for respiratory infections Many serious respiratory infections are perceived to be caused by viruses alone, however….. there is an increasing recognition of the interplay between viral infections and bacterial infection both needing to be treated (e.g. exacerbations of COPD and asthma) Resistance to antibiotics is perceived by some to be controlled by antibiotic stewardship alone… it has now been shown this is not possible for established resistance

Incidence of disease (millions) based on WHO 2004 MRSA – up to 20% mortality Healthcare associated infection – up to 5% mortality a US alone, b JAMA 2007, c CDC annual, d 10 countries only 2010 EU Kock et al, e ECDC annual

MRSA and E.coli resistance Data: 1293 hospitals in 31 countries in Europe MRSA: 5,503 excess deaths associated with resistance E.Coli: 2712 excess deaths associated with resistance Trends estimate that 97,000 resistant bloodstream infections and 17,000 associated deaths could occur in 2015. ‘…. despite anticipated gains in the control of MRSA, the persistently increasing number of infections caused by third-generation cephalosporin-resistant Gram-negative pathogens is likely to outweigh this achievement ….‘ de Kraker MEA, Davey PG, Grundmann H, BURDEN study group (2011)

And it is not just MRSA and E.coli it includes pneumococcus In the US S.pneumonia has >40% resistance to macrolides, 15% to penicillin and 30% to quinolones

So everyone now agrees we need new antibiotics… What is prohibiting the development of new antibiotics?

New classes of antibiotics in last 50y

Lack of antibiotics in R&D 2009 analyses by IDSA & ECDC/EMA Only 15-16 antibiotics in clinical development Only 8 have activity against key G-ve bacteria Of these, NONE has activity against bacteria resistant to all currently available drugs 2011 show only 10 compounds in clinical development against G-ves and no trials running in HAP/VAP and still NONE has activity against bacteria resistant to all currently available drugs

Why is pharma not researching more new antibiotics? Challenges to find novel targets Return on investment for pharma companies is less attractive than other therapeutic areas due to the “acute” nature of the disease and the current risk and cost of a regulatory programme Even if products are generated from discovery in small or big pharma it is hard to convince companies to fund drugs beyond Phase I

The Antibacterial-Target Tree Rifampicin Fidaxomycin Fluoroquinolones RNA POLYMERASE D NA GYRASE Nitrofurantoin CELL WALL Vancomycin Penicillins Cephalosporins Carbapenems PROTEIN SYNTHESIS 30S ribosome Aminoglycosides Tetracyclines FOLATE SYNTHESIS Trimethoprim Sulphonamides Metronidazole DNA SYNTHESIS 50S ribosome CYTOPLASMIC MEMBRANES Oxazolidinones Macrolides Chloramphenical Lincosamides Polymixins Daptomycin tRNA SYNTHETASE Mupirocin White and Fairhead 2012 White and Fairhead 2012

Novel targets… Novel versions of existing mechanisms Except non specific bacterial DNA inhibition (SASP) which is universally effective but the vector is bacteria specific Faster diagnostics - to allow narrower spectrum antibiotics Control of mobile genetic elements resistance (inhibition of plasmids) Human Microbiome Vaccines, therapeutic vaccines Immunological approaches

But they all need to pass the regulatory hurdles

Regulatory submissions submitted or reviewed since 2006 in EU or US IV/IM or IV/oral 2006 daptomycin 2008 telavancin oritavancin iclaprim doripenem 2009 ceftobiprole 2010 ceftaroline Oral/topical/inhaled 2006 garenoxacin faropenem gemifloxacin 2007 retapamulin 2009 Inhaled aztreonam cethromycin 2010 fidaxomicin

Key points US and EU registration Approvals: 7/14 (50%) total antibiotics 1/5 (20%) oral antibiotics* 4/7 ( 57%) parenteral antibiotics 2/2 (100%) approvals for topical/inhaled antibiotics *fidaxomicin was gained both EU and FDA approval for C.difficile

Indications 2006 daptomycin P 6 faropenem O garenoxacin gemifloxacin Date of submission or review 2006 Comp skin HAP VAP CAP Endo cUTI AI SITL/ ERY Decol AECB Sinus itis decol daptomycin P 6 faropenem O garenoxacin gemifloxacin 2008 telavancin PO oritavancin iclaprim doripenem 2007 retapamulin 2009 ceftobiprole inhaled aztreonam cethromycin 2010 ceftaroline fidaxomicin Oral/topical IV/parenteral

Key issues – changing environment Most antibiotics attempted registration in US first Until 2006 most antibiotics were submitted for multiple indications but since 2007 maximum indications has been 3 Daptomycin was the first antibiotic to submitted for a single specific indication (cSSTI) Three of the 5* successful antibiotic submissions in last 5 years were for cSSTI Doripenem achieved, HAP, cAIS, cUTI Telavancin got cSSTI in US and NP in Europe *excluding topical and inhaled

Why did the antibiotics fail? Was this bad navigation?

Oral antibiotics Change in regulatory attitude Non inferiority changed to superiority over placebo AECB, sinusitis etc Few investigators will do these studies Most products didn’t reach EMA This has paralysed development of new oral antibiotics Safety issues garenoxacin – rare but unexplained hypotension gemifloxacin – rash in 0.8% subjects

IV Antibiotics registration failure Four submissions failed in complicated SSTI telavancin (EU) (based on benefit-risk) oritavancin (lack of evidence of outcome (MRSA)) iclaprim (study designs inadequate) ceftobiprole (GCP issues) One failed in HAP telavancin (FDA) based on failure to meet new endpoint guidance of 28 day mortality

So why are companies and agencies so far adrift on benefit risk decisions at end of Phase III

Detailed FDA Recent Guidance since 2006 Note cUTI issued Feb 2012

EU guidance “Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections” 15 December 2011 CPMP/EWP/558/95 rev 2 Committee for Medicinal Products for Human Use (CHMP) More generic and flexible… Is this the way to go?

Current FDA guidance Predominantly requires two large studies per indication based on non inferiority guidance introduced in the early1990s Non inferiority was ironically introduced to reduce the size of studies! Indications have been subdivided to such an extent that no company can afford to register a drug for more than two or three indications making the return on investment limited.

Successful launch and stewardship Companies are concerned that restrictions on cost and use of antibiotics will struggle to cover the cost of the substantial drug development programmes Thus it will be difficult to get large pharmas to register and launch antibiotics

In summary The need for new antibiotics is critical Governments and charity money are available in recognition of this but mainly pre-clinical The lack of funding for Phase II/III will kill off novel compounds in Phase I Regulatory guidance has been mainly US based and has driven large expensive studies based on principles put in place 20y ago can we think differently?

Finally WHO quote: “Antibiotic resistance is becoming a public health emergency of yet unknown proportions” We could revert to infection mortality not seen since pre 1950s – we must find ways of developing and registering new antibiotics… IDSA quote

Just as a reminder that antibiotics do make a difference.. 1 IDSA Position Paper ’08 Clin Infect Dis 47 (S3): S249-65; 2IDSA/ACCP/ATS/SCCM Position Paper ’10 Clin Infect Dis In Press; 3Kerr AJ. Subacute Bacterial Endocarditis. Springfield IL: Charles C. Thomas, 1955 & Lancet 1935 226:383-4; 4 Lancet ’38 231:733-4 & Waring et al. ’48 Am J Med 5:402-18; 5 Spellberg et al. ’09 Clin Infect Dis 49:383-91 & Madsen ’73 Infection 1:76081

Thank you