Is There Any Future for Inhibitors of Bacterial Cell Wall Biosynthesis?

Karen Bush

21 May 2013

21 May 2013 1

Disclosures (2012-2013)

Retiree: Johnson & Johnson , Pfizer (Wyeth), Bristol-Myers Squibb

Consultant or Scientific Advisory Board: Allecra,

AstraZeneca, Cempra, Cubist, Fedora, GlaxoSmithKline, Medivir, Merck,

Rempex, Shionogi, TB Alliance, Wockhardt

Research Support: AstraZeneca, Cubist, Forest

Points to be Covered

• Bacterial cell wall

• Current approved agents

• Agents in clinical development

• Future directions

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Comparison of the Cell Envelopes of Gram-Positive and Gram-Negative Bacteria

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b-lactamase

Peptidoglycan

Peptidoglycan

Gram-positive Gram-negative

Lipopolysaccharide Phospholipid

b-lactamase Porin Outer membrane

Cell wall Cell wall

Cytoplasmic membrane

Cytoplasmic membrane

Periplasmic space Penicillin-binding proteins

Penicillin-binding proteins

Approved Classes of Antimicrobial Agents that Target Cell Wall Biosynthesis

• Glycopeptides – Vancomycin, teicoplanin, telavancin

• Lipopeptides – Daptomycin

• Phosphonic acids – Fosfomycin (phosphonomycin)

• b-Lactams – Penicillins, cephalosporins, carbapenems, monobactams

• b-Lactamase inhibitors – Clavulanic acid, penicillanic acid sulfones

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Glycopeptides

Advantages – All

• Most important Gram-positive bacteria are in the spectrum

– Vancomycin • Familiar and widely used • Highly effective against many Gram-

positive bacteria • Inexpensive

– Teicoplanin • Active against VanB enterococci

– Telavancin • Active against VanB and some VanA

enterococci • Once-a-day dosing

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Vancomycin, teicoplanin, telavancin

Disadvantages

– All • Infusion site reactions

– Vancomycin • Questions about dosing and

monitoring drug levels • Nephrotoxicity

• 10-20% with normal dosing • 30-40% with high doses

• RESISTANCE in enterococci and staphylococci

– Telavancin • Genotoxicity • Nephrotoxicity, QTc prolongation

Elyasi . Eur. J. Clin. Pharmacol. 68:1243 (2012) Summarized in: Pucci & Bush. Clin. Micro. Rev. 2013

Lipopeptides -- Daptomycin

• Daptomycin mechanism of action – Cell wall? – Primary effect on cell membranes

– Redirects the localization of proteins involved in cell division and cell wall synthesis

– Dramatic cell wall and membrane defects

– Ultimately lead to cell death

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Pogliano, Pogliano & Silverman; J. Bacteriol. 194:4494 (2012)

Lipopeptides

Advantages

– Active against most Gram-positive bacteria • MRSA

• VRE (in vitro)

– Approved for right-sided infective endocarditis caused by S. aureus

– Once-a day dosing

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Daptomycin

Disadvantages

– Myopathy, neuropathy, elevated CPK

– Inactivated by lung surfactant – Cannot be used to treat

pneumonia

– Low, but increasing, resistance rates

Silverman et al. J. Infect. Dis. 191:2149 (2005); Bayer et al. Annals NYAS, 1277:139 (2013 )

Fosfomycin

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Disadvantages

– Rapid selection for resistance

– Frequently used in combination therapy with other agents

– Shortage of safety and efficacy data in controlled clinical trials

Advantages

– Inhibits MurA, a unique early step in cell wall synthesis – Analog of phosphoenol pyruvate,

a MurA substrate

– Broad spectrum activity against Gram-positive and Gram-negatives

– Oral treatment for UTI

Bergen et al. Curr. Opin. Infect. Dis. 25:626 (2012)

b-Lactams

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Advantages

– Inhibit last step in cell wall synthesis

– No mammalian homologs

– Broad spectrum activity against Gram-positive and Gram-negatives

– Medicinal chemistry well-established for drug optimization

– Safe, efficacious

– Can be inexpensive

Disadvantages

– Immunological responses

– Occasional toxicities

– Nephrotoxic cephalosporins

– CNS effects from carbapenems

– RESISTANCE – >1300 b-Lactamases

– RESISTANCE – altered PBPs

– RESISTANCE – porin defects

– RESISTANCE – efflux

– RESISTANCE – mobile elements with multiple resistance factors

b-Lactamase Inhibitors

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Advantages

– Restore activity of simple penicillins

– Avoid unnecessary use of carbapenems and expanded-spectrum cephalosporins

– Inactivators of key class A b-lactamases, not just inhibitors

– Safe, efficacious

– Oral and IV

Disadvantages

– Lack of broad spectrum activity against all serine b-lactamases

– No inhibitory activity against metallo-b-lactamases

– RESISTANCE – overproduction of susceptible b-lactamase

– RESISTANCE – b-lactamase variants with reduced affinity

– RESISTANCE – multiple enzymes per strain

Summarized in: Pucci & Bush. Clin. Micro. Rev. 2013

Investigational Agents in the Pipeline with Cell Wall Activity

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Phase 1 Phase 2 Phase 3

BAL30072 MK7655 + imipenem Dalbavancin

Avibactam + aztreonam

Avibactam + ceftaroline

Oritavancin

RPX7009 + biapenem CXA-201 (ceftolozane + tazobactam)

Avibactam + ceftazidime

Summarized in: Pucci & Bush. Clin. Micro. Rev. 2013

Older Glycopeptides in Late Clinical Development

Dalbavancin

– Vicuron to Pfizer

– Potent anti-staph and VSE activity

– Abandoned by Pfizer after approvable letter by the FDA requesting additional trials

– Durata finished trials & is ready to file an NDA this year

– Once weekly dosing (t1/2 = 258 h or 11 d)

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Oritavancin

– Lilly to InterMune to Targanta to The Medicines Company

– Anti-staph and VRE (VanA)

– Approvable letter by FDA requesting additional trials

– Phase 3 trials for ABSSSI completed

– Single dose may be effective (t1/2 = 393 h or 16 d)

O

O O

O

O

NH

Cl Cl

OH

HN

O

O

OH

OH

OHN

O OH

HN

NH

O

NH

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OH2N

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HN

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From Pucci & Bush. Clin. Micro. Rev. 2013

CXA-201 (Cubist) Ceftolozane + Tazobactam

• Ceftolozane (FR264205) – the novel component of the combination

– Potent anti-pseudomonal activity

– MIC90 = 1 mg/ml against P. aeruginosa resistant to ceftazidime, imipenem and/or ciprofloxacin

• Vulnerable to hydrolysis by AmpC, serine carbapenemases (KPC) and ESBLs

• Addition of 4 mg/ml tazobactam resulted in lower ceftolozane MICs

– 8 mg/ml for 76% of ESBL-producing isolates

– CTX-M-14 and CTX-M-15 producing strains (most prevalent ESBLs)

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Juan et al. AAC 54:846 (2010)

Attributes of Non-b-Lactam b-Lactamase Inhibitors

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Avibactam MK-7655 RPX7009

Structure Novel bicyclic non-b-lactam

Novel bicyclic non-b-lactam

Boronic acid analog

Spectrum Ser-carbapenemases (KPCs)

AmpC ESBLs Some OXAs

Ser-carbapenemases (KPCs)

AmpC ESBLs

Ser-carbapenemases (KPCs)

AmpC ESBLs

Partner and targeted organisms

Ceftazidime (Pseudomonas)

Ceftaroline (MRSA) Aztreonam (MBLs)

Imipenem (Pseudomonas)

Biapenem (Pseudomonas)

Avibactam (AstraZeneca) MK-7655 (Merck) RPX7009 (Rempex)

Summarized in Pucci & Bush. Clin. Micro. Rev. 2013

Siderophore Monocyclic b-Lactams

• BAL30072 (Basilea)

– Monosulfactam with iron chelating dihydropyridone side chain

– Activity against many Pseudomonas and Acinetobacter

• MC-1 (Pfizer)

– Similar structural side chain in a monocarbam with activity against non-fermentative bacteria

• Both

– Low resistance selection in contrast to earlier siderophore-substituted b-lactams

– Stable to hydrolysis by metallo-b-lactamases

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Page et al. AAC 54:2291 (2010) Flanagan et al. ACS Med CChem Lett 2011, 2:385

Why Have Previous Cell Wall Active Agents Failed to be Developed?

• RESISTANCE develops ahead of clinical development

• PK/PD considerations

– Underdosing to lower costs and side effects

• Competition from agents that still are active against resistant pathogens

• Risk averse management styles in large Pharma

– “No risk. High benefit.”

– Outside compounds are always better than compounds developed by our own scientists

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Undeveloped Investigational Cell Wall Inhibitors

• Oral carbapenems and penems (many companies)

– Tebipenem in Japan

– Stable against ESBLS, but no anti-pseudomonal activity

– PK in humans unfavorable compared to once-a-day quinolones

– Cost-of-goods issues

– Merck carbapenem patents closed the area to many companies

• Anti-MRSA b-lactams (many companies)

– Limited spectrum of activity due to b-lactamase liabilities

– Nephrotoxicity

• Mur pathway (many companies)

– “Easy” to find enzyme inhibitors, difficult to find agents that work in vivo

• FtsZ inhibitors (Prolysis/Abgentis)

– Novel target – ring formation -- initiation of cell division

– In vivo activity, but poor drug-like properties

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Future for Cell Wall Active Agents

• Narrow spectrum b-lactams used in combinations

– Agents that target Acinetobacter, Pseudomonas

• Drug-like inhibitors of essential targets like FtsZ

• Agents with less frequent dosing intervals to minimize length of hospitalization

• b-Lactam or b-lactam-like molecules still viable

• Monobactam combinations for metallo-b-lactamase-producing organisms

• Triple b-lactamase inhibitor combinations

– Broad spectrum agent + Serine b-lactamase inhibitor + Metallo- b-lactamase inhibitor

• b-lactamase inhibitors with antibacterial activity

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Other Combinations of Cell Wall-Active Agents

• Tedizolid and Daptomycin

– May 13, 2013

– Trius Therapeutics received a notice of allowance from the USPTO for a

patent application

– Use of tedizolid phosphate (protein synthesis inhibitor) in combination

with daptomycin

– Claims that sub-therapeutic doses of tedizolid prevent bacterial

resistance development when daptomycin is used long term

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http://triusrx.com/

Conclusions

• Cell wall active agents have been highly successful

– No corresponding mammalian targets

– Safe and efficacious

• Resistance has been a major factor in their decreasing use

• The future lies in combinations

– b-lactamase inhibitors

– Unusual combinations of cell wall active agents

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THANK YOU !

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