LTX-109 presentation

Exploring the potential of innate immunity for developing antimicrobial drugs

Tromsø – 27th September 2013

Lytix Biopharma AS

Norwegian non-listed company – Founded 2003 – Locations in Tromsø and Oslo

Aim to develop novel therapeutics for areas of high unmet needs: – Infectious diseases – Oncology

Co-development or licensing at Proof-of-Concept

Tromsø

Oslo

Lytix Biopharma is a clinical-stage company

Antimicrobial resistance

Not only an international problem

1994 Project idea: Lars Vorland, Øystein Rekdal and John S. Mjøen Svendsen

1995/1996

Research funding: Alpharma/NFR

Lytix’ prehistorie

From PROSMAT report

Overview

Cationic antimicrobial peptides

Building the next generation peptidomimetic

LTX-109 – a novel antimicrobial drug in clinical development

Discovery of Cationic Antimicrobial Peptides (CAP`s)

Insects (cecropia moth) (Cecropin, 1981)

Human (LL-37, 1991)

Frogs (Magainin, 1987) Plants

More than 1000 CAPs characterized

Structures

+ +

+ +

+ + +

+ + + + +

Main properties antimicrobial peptides

Unique, clinically non-utilized mode of action – Rapid bacterial cell lysis

– Active against multi-resistant bacteria

– Resistance development difficult

– Synergy with other components of the innate immune system

Unusual antimicrobial spectrum – Varying degree, but usually broad

– Gram+, Gram-, fungi and yeasts

Magainin failure

Michael Zasloff (1987) 23 amino acids Relatively low activity Magainin Pharmaceutical

(1988) Treatment of diabetic

ulcers Failed in Phase III Lack of improvement over

wound care (placebo)

Developing antimicrobial peptide-based drugs

From biological activity to drug

0

100

200

300

400

500

MIC

(mic

rom

olar

)

Antimicrobial activity against E. coli

What is necessary?

Pharmacophore

E. coli: 3B + 2C S. aureus: 2B + 2C

Peptide sequence C B MIC E. coli MIC S. aureus

WRWRWR-NH2 4 3 10 7.5

RWRWRW-NH2 4 3 5 5

RRRWWW-NH2 4 3 5 5

RWWWRR-NH2 4 3 25 5

WWRRRW-NH2 4 3 25 10

WRWRW-NH2 3 3 15 10

RWRWR-NH2 4 2 200 25

WRWR-NH2 3 2 >200 200

WRRW-NH2 3 2 >200 200

RWWR-NH2 3 2 >200 100

WRW-NH2 2 2 >200 100

RWR-NH2 3 1 >200 >200 J. Med. Chem. 46 (2003) 1567

Pharmacophore framwork

Historical screening data

Stability

Binding mode I Binding mode II

From biological activity to drug - LTX-109

Lactoferrin B Pharmacophore LTX-109 (689 aa protein) (3 aa peptide)

LTX-109

Broad spectrum of activity

LTX-109 is capable of killing:

• Gram+ bacteria

• Gram- bacteria

• Fungi and yeasts

Extended screening - MRSA

Pathogen (N) Antimicrobial MIC mg/L

MIN 50% 90% MAX

Methicillin-resistant Staphylococcus

aureus (50)

LTX-109 ≤0.03 4 8 8

Amoxicillin 8 ≥32 ≥32 ≥32

Clindamycin 0.06 0.12 ≥16 ≥16

Erythromycin 0.25 32 32 32

Gentamicin ≤0.06 0.25 1 ≥64

Imipenem 0.06 4 ≥16 ≥16

Levofloxacin 0.12 16 ≥32 ≥32

Mupirocin ≤0.06 0.12 1 ≥32

Cefotaxime 8 ≥64 ≥64 ≥64

Tetracycline ≤0.12 0.25 1 32

Vancomycin 0.25 0.5 0.5 2

Extended screening - Pseudomonas

Pseudomonas aeruginosa (30)

LTX-109 8 8 16 16

Amoxicillin 16 ≥256 ≥256 ≥256

Cefuroxime ≥256 ≥256 ≥256 ≥256

Gentamicin 0.5 1 2 ≥128

Imipenem 0.5 2 ≥32 ≥33

Levofloxacin 0.25 0.5 4 16

Piperacillin-tazobactam

2 8 128 ≥256

Cefotaxime 8 32 ≥64 ≥64

Tetracycline 8 16 32 32

Pathogen (N) Antimicrobial MIC mg/L

MIN 50% 90% MAX

LTX-109 is rapidly bactericidal

Staphylococcus aureus Streptococcus pyogenes

Lack of resistance development

Lytixar™ kills S. aureus and S. pyogenes more effectively than Gold Standard drugs

Performed by:

Staphylococcus aureus Streptococcus pyrogenes

• Murine skin infection model (razor/tape-stripping) • Read-out is bacterial growth +9 hours after the first of 3 doses

Lytixar™ kills MRSA more effectively than Gold Standard drugs

Murine skin infection model (tape-stripping, ATCC 33591) Read-out is bacterial growth +9 hours after the first of 3 doses

27

LTX-109 kills P. aeruginosa biofilm

(Green indicate living cells and red indicate dead cells)

LTX-109 – Basic characteristics Novel mechanism of action

Rapid kill of bacteria

Broad spectrum of activity Bactericidal activity against G+ and G- bacteria, fungi and yeast

Low propensity for resistance development A first-in-class antibiotic compound; no/little cross-resistance

LTX-109 is currently being investigated in a clinical Phase 2

Phase 1 – healthy volunteers

Phase 1 / 2a – skin infections and nasal decolonisation

Ongoing Phase 2 study in impetigo

Contact information

Anders Fugelli, PhD Head of Business Development Lytix Biopharma AS Gaustadalleen 21 NO-0349 Oslo, Norway Mail: [email protected] Mobile: +47 924 81 432