HOW DO WE GET THE ANTIBIOTICS WE NEED?Opportunities and challenges posed and lessons learned from recent submissions

Dr. Flic GabbaySenior Partner

TranScrip Partners LLP

24th AnnualEuroMeeting

26-28 March 2012Copenhagen, Denmark

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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

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Why do we need new antibiotics?

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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

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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?

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Incidence of disease (millions) based on WHO 2004

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Diarrhoea0-4y children – 5% mortalityEuropean figures

a US alone, b JAMA 2007, c CDC annual, d 10 countries only 2010 EU Kock et al, e ECDC annual

LRTICAP – up to 5% mortalityHAP – up to 20% mortality

COPD and AECB, ranked 4th in deaths in US not measurable by incidence alone

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

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Incidence of disease (millions) based on WHO 2004

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a US alone, b JAMA 2007, c CDC annual, d 10 countries only 2010 EU Kock et al, e ECDC annual

MRSA – up to 20% mortality

Healthcare associated infection – up to 5% mortality

MRSA and E.coli resistance

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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

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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?

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New classes of antibiotics in last 50y

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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

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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

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The Antibacterial-Target Tree

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White and Fairhead 2012

RifampicinFidaxomycin

Fluoroquinolones

RNA POLYMERASE

DNA GYRASE Nitrofurantoin

CELL WALL

VancomycinPenicillinsCephalosporinsCarbapenems

PROTEIN SYNTHESIS30S ribosome

Aminoglycosides Tetracyclines

FOLATE SYNTHESISTrimethoprimSulphonamides

Metronidazole DNA SYNTHESIS

PROTEIN SYNTHESIS

50S ribosome

CYTOPLASMIC

MEMBRANES

OxazolidinonesMacrolides

ChloramphenicalLincosamides

Polymixins

Daptomycin

tRNA SYNTHETASEMupirocin

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 - allows narrower spectrum antibiotics• Control of mobile genetic elements resistance (inhibition

of plasmids) • Human Microbiome• Vaccines, therapeutic vaccines• Immunological approaches

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But they all need to pass the regulatory hurdles

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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

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Oral/topical/inhaled

2006• garenoxacin• faropenem• gemifloxacin2007• retapamulin2009• Inhaled aztreonam• cethromycin2010•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

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Indications

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O = submitted and failed

P =registered

6 =studied

Date of submission or review

2006Comp skin HAP VAP CAP Endo cUTI AI

SITL/ ERY Decol AECB

Sinusitis decol

daptomycin P 6 Pfaropenem O O O Ogarenoxacin O O O O O Ogemifloxacin O O O2008telavancin PO PO POoritavancin Oiclaprim Odoripenem P P P2007retapamulin P 6 62009ceftobiprole O 6 6 6inhaled aztreonam Pcethromycin O2010ceftaroline P P

fidaxomicin P

Oral/topicalIV/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

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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

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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

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

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Detailed FDA Recent Guidance since 2006

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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?

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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.

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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

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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?

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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…

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IDSA quote

Just as a reminder that antibiotics do make a difference…

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DiseaseDeath Pre-Antibiotics

Death With Antibiotics

Change in Death

Community Pneumonia 1

~35% ~10% -25%

Hospital Pneumonia 2 ~60% ~30% -30%

Heart Valve Infection 3 ~100% ~25% -75%

Brain Infection 4 >80% ˂23% -60%

Skin Infection 5 11% ˂0.5% -10%

-3%By comparison...treatment of myocardial infarction

with aspirin or streptokinase 6

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

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