A new antivirulence approach A new antivirulence approach against pathogenic bacteriaagainst pathogenic bacteria

May 2005Sonia Escaich - President & CSO

Corporate overviewCorporate overviewCorporate overviewCorporate overview

• Biopharmaceutical company specialized in antibacterial drug discovery for prevention of severe infections especially nosocomial

• Portfolio of intellectual property

• Virulence validated targets – Preclinical development of inhibitors small molecules

• Experienced management and R&D team - Prestigious academic partnerships - 3 R&D grants (ANVAR, Genhomme,

BioSecurity)

• 20 Employees:– 1 CEO/CSO, 1 director MedChem, 9 biologists/biochemists, 7

medicinal chemists (8 Ph.D,10 RAs)– 2 G&As

• Incorporated mid-2001 - Located at Biocitech Parc, Paris (France)

• EUR 10.2M (USD 13M) raised since 2002 - Investors: BioAm, Axa PE, Auriga, Credit Agricole PE.

MUTABILIS’ research objectivesMUTABILIS’ research objectivesMUTABILIS’ research objectivesMUTABILIS’ research objectives

Discovery of innovative anti-virulence treatments for nosocomial infections

– Therapeutic molecules : Inhibition of virulence factors.

– Therapeutic vaccines and antibodies

Background: Medical need for new Background: Medical need for new anti-infective therapiesanti-infective therapiesBackground: Medical need for new Background: Medical need for new anti-infective therapiesanti-infective therapies

• Nosocomial infections (NI) occur in 2-10% of hospitalized patients (ICU, Surgery, internal medicine…)

• Three types of pathogens: Gram+ bacteria: 45%. Gram- bacteria: 35%. Others: 20%.

• Complications of nosocomial infections generate extensive hospitalization, and intensive care costs. Severe infections and sepsis can be lethal (30% cases)

• The increasing number of invasive procedures and the emergence of antibiotic resistance are causing a real public health problem

• Antibiotics-based treatments result in the destruction of commensal bacteria and drug resistance

• Newer antibiotics are kept as last resort therapy

• Nosocomial infections (NI) occur in 2-10% of hospitalized patients (ICU, Surgery, internal medicine…)

• Three types of pathogens: Gram+ bacteria: 45%. Gram- bacteria: 35%. Others: 20%.

• Complications of nosocomial infections generate extensive hospitalization, and intensive care costs. Severe infections and sepsis can be lethal (30% cases)

• The increasing number of invasive procedures and the emergence of antibiotic resistance are causing a real public health problem

• Antibiotics-based treatments result in the destruction of commensal bacteria and drug resistance

• Newer antibiotics are kept as last resort therapy

Pathogenic bacteria use a range of Pathogenic bacteria use a range of virulence factors to establish infectionvirulence factors to establish infectionPathogenic bacteria use a range of Pathogenic bacteria use a range of virulence factors to establish infectionvirulence factors to establish infection

Pathogenic bacteriaSpecific

ImmunityInnate

Immunity

Colonization

Invasion

Shield to immune system

Toxins

Virulence mechanismsHost defenses

Environment adaptation

MUTABILIS’MUTABILIS’ approach to virulenceapproach to virulenceMUTABILIS’MUTABILIS’ approach to virulenceapproach to virulence

Gut

Blood

Systemic infection

Selective inhibition of the virulence factors required for systemic dissemination in the host.

• Drug approach:

– Selective inhibition of pathogenic bacteria by targeting virulence factors necessary for bacterial spreading in blood

– Virulence inhibitors do not perturb development of commensal bacteria

– Diminished risk of developing resistant mutants because of lower selective pressure

This lead to the discovery of new classes of antibacterial molecules that are not classical antibiotics

• Vaccine approach: Inhibition of specific pathogens in a bacterial species

Preventive vaccine/passive immunity for nosocomial infections

Scientific strategy:Scientific strategy:Scientific strategy:Scientific strategy:

THERAPEUTIC APPROACH: THERAPEUTIC APPROACH: AntibioticsAntibiotics versus virulence versus virulence inhibitors inhibitors THERAPEUTIC APPROACH: THERAPEUTIC APPROACH: AntibioticsAntibiotics versus virulence versus virulence inhibitors inhibitors

• Common ground in both approaches:

– Infections are treated through eradication of bacteria in the blood.

• Advantages of virulence inhibitors:

– Virulence inhibitors do not perturb development of commensal bacteria.– Diminished risk of developing resistant mutants because of lower selective

pressure.

Anti-virulence product profile opens Anti-virulence product profile opens preventive therapypreventive therapyAnti-virulence product profile opens Anti-virulence product profile opens preventive therapypreventive therapy

• Product profile: – Anti-infective agent (not an antibiotic) which eradicates bacteria from the blood

and leaves the commensal flora untouched.

• Product characteristics:– No induction of bacterial resistance.– No cross resistance with existing antibiotics. – Large gram- spectrum.– Large gram+ spectrum.– Gram- and gram+ combination.

• Product positioning:– Preventive therapy: compound will be used on its own.

Virulence inhibition: Virulence inhibition: planplanVirulence inhibition: Virulence inhibition: planplan

• Mutagenesis of every coding sequence in the genome of a model bacteria.

• Identification of pathogen genes which are essential for producing systemic infection.

• Validation of these genes as therapeutic targets in experimental models of infection.

• Drug development based on molecules which inhibit these targets.

Drug discoveryDrug discoveryDrug discoveryDrug discovery

Objective: Discovery of new class of antibacterial molecules for selective inhibition of pathogenic bacteria

Discovery process:Discovery process:•Target identification (complete Tn mutagenesis of pathogenic Gram+ and Gram- pathogenic bacteria) and validation (KO mutants phenotype, protein function, consevation…)

•Rational drug design, virtual screening, hit identification

Anti-virulence product profile Anti-virulence product profile opens preventive therapy markets.opens preventive therapy markets.Anti-virulence product profile Anti-virulence product profile opens preventive therapy markets.opens preventive therapy markets.

Healthy individuals Patients at risk of infections Infected patients

VACCINATION ANTIVIRULENCE ANTIBIOTICS

Specific to the risk of infection

•Haemophilus•Meningococcus•Pneumococcus•E. Coli•Streptococcus B

Broad spectrum therapy

•Transplantees (kidney, bone marrow, liver, etc.)•Intensive care patients•Cancer patients undergoing treatment•Kidney failure•Corticoid treatment

Pathogenic strainsPrevention

MUTABILIS targets: conserved, required for virulence and systemic infection but not for commensalism.

MUTABILIS developed assays needed for pharmacological studies.

Efficacy prediction through animal model: targets functions are conserved in animal species and man.

MUTABILIS using rational approaches did identify inhibitors molecules.

Conclusions: virulence projectsConclusions: virulence projects Conclusions: virulence projectsConclusions: virulence projects

Research area of interest:Research area of interest:Research area of interest:Research area of interest:

• Comparative genomics + physiopathology of infectious diseases Interactions bacteria/host Metabolic pathways common to pathogenic

bacteriaconserved targets

• Bacterial membranes and pharmacology : why some drugs get through or not?