1 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 submissions24th AnnualEuroMeeting26-28 March 2012Copenhagen, DenmarkDr. Flic GabbaySenior PartnerTranScrip Partners LLP
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3 How do we get the antibiotics we need? Why do we need new antibiotics?What is prohibiting the development of new antibiotics?discoveryfundingregulatory hurdlessuccessful launch and stewardship
7 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 controlC.difficile is still worrying but being addressedOther diseases are perceived to be much more importantAIDs, malaria, coronary heart disease and cancerSo why are all these organisations worried?
8 Incidence of disease (millions) based on WHO 2004 Diarrhoea 0-4y children – 5% mortality European figuresLRTICAP – up to 5% mortalityHAP – up to 20% mortalityCOPD and AECB, ranked 4th in deaths in US not measurable by incidence alonea US alone, b JAMA 2007, c CDC annual, d 10 countries only 2010 EU Kock et al, e ECDC annual
9 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
10 Incidence of disease (millions) based on WHO 2004 MRSA – up to 20% mortalityHealthcare associated infection – up to 5% mortalitya US alone, b JAMA 2007, c CDC annual, d 10 countries only 2010 EU Kock et al, e ECDC annual
11 MRSA and E.coli resistance Data: 1293 hospitals in 31 countries in EuropeMRSA: 5,503 excess deaths associated with resistanceE.Coli: excess deaths associated with resistanceTrends 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)
12 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
13 So everyone now agrees we need new antibiotics… What is prohibiting the development of new antibiotics?
15 Lack of antibiotics in R&D 2009 analyses by IDSA & ECDC/EMAOnly antibiotics in clinical developmentOnly 8 have activity against key G-ve bacteriaOf these, NONE has activity against bacteria resistant to all currently available drugs2011show only 10 compounds in clinical development against G-vesand no trials running in HAP/VAP and still NONE has activity against bacteria resistant to all currently available drugs
16 Why is pharma not researching more new antibiotics? Challenges to find novel targetsReturn 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 programmeEven if products are generated from discovery in small or big pharma it is hard to convince companies to fund drugs beyond Phase I
17 The Antibacterial-Target Tree RifampicinFidaxomycinFluoroquinolonesRNA POLYMERASEDNA GYRASENitrofurantoinCELL WALLVancomycinPenicillinsCephalosporinsCarbapenemsPROTEIN SYNTHESIS30S ribosomeAminoglycosidesTetracyclinesFOLATE SYNTHESISTrimethoprimSulphonamidesMetronidazoleDNA SYNTHESIS50S ribosomeCYTOPLASMICMEMBRANESOxazolidinonesMacrolidesChloramphenicalLincosamidesPolymixinsDaptomycintRNA SYNTHETASEMupirocinWhite and Fairhead 2012White and Fairhead 2012
18 Novel targets… Novel versions of existing mechanisms Except non specific bacterial DNA inhibition (SASP) which is universally effective but the vector is bacteria specificFaster diagnostics - to allow narrower spectrum antibioticsControl of mobile genetic elements resistance (inhibition of plasmids)Human MicrobiomeVaccines, therapeutic vaccinesImmunological approaches
19 But they all need to pass the regulatory hurdles
20 Regulatory submissions submitted or reviewed since 2006 in EU or US IV/IM or IV/oral2006daptomycin2008telavancinoritavanciniclaprimdoripenem2009ceftobiprole2010ceftarolineOral/topical/inhaled2006garenoxacinfaropenemgemifloxacin2007retapamulin2009Inhaled aztreonamcethromycin2010fidaxomicin
21 Key points US and EU registration Approvals:7/14 (50%) total antibiotics1/5 (20%) oral antibiotics*4/7 ( 57%) parenteral antibiotics2/2 (100%) approvals for topical/inhaled antibiotics*fidaxomicin was gained both EU and FDA approval for C.difficile
22 Indications 2006 daptomycin P 6 faropenem O garenoxacin gemifloxacin Date of submission or review2006CompskinHAPVAPCAPEndocUTIAISITL/ERYDecolAECBSinusitisdecoldaptomycinP6faropenemOgarenoxacingemifloxacin2008telavancinPOoritavanciniclaprimdoripenem2007retapamulin2009ceftobiproleinhaled aztreonamcethromycin2010ceftarolinefidaxomicinOral/topicalIV/parenteral
23 Key issues – changing environment Most antibiotics attempted registration in US firstUntil 2006 most antibiotics were submitted for multiple indications but since 2007 maximum indications has been 3Daptomycin 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 cSSTIDoripenem achieved, HAP, cAIS, cUTITelavancin got cSSTI in US and NP in Europe*excluding topical and inhaled
24 Why did the antibiotics fail? Was this bad navigation?
25 Oral antibiotics Change in regulatory attitude Non inferiority changed to superiority over placebo AECB, sinusitis etcFew investigators will do these studiesMost products didn’t reach EMAThis has paralysed development of new oral antibioticsSafety issuesgarenoxacin – rare but unexplained hypotensiongemifloxacin – rash in 0.8% subjects
26 IV Antibiotics registration failure Four submissions failed in complicated SSTItelavancin (EU) (based on benefit-risk)oritavancin (lack of evidence of outcome (MRSA))iclaprim (study designs inadequate)ceftobiprole (GCP issues)One failed in HAPtelavancin (FDA) based on failure to meet new endpoint guidance of 28 day mortality
27 So why are companies and agencies so far adrift on benefit risk decisions at end of Phase III
28 Detailed FDA Recent Guidance since 2006 Note cUTI issued Feb 2012
29 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?
30 Current FDA guidancePredominantly requires two large studies per indication based on non inferiority guidance introduced in the early1990sNon 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.
31 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 programmesThus it will be difficult to get large pharmas to register and launch antibiotics
32 In summary The need for new antibiotics is critical Governments and charity money are available in recognition of this but mainly pre-clinicalThe lack of funding for Phase II/III will kill off novel compounds in Phase IRegulatory guidance has been mainly US based and has driven large expensive studies based on principles put in place 20y agocan we think differently?
33 FinallyWHO 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
34 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 :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: & Madsen ’73 Infection 1:76081