ltx-109 presentation
TRANSCRIPT
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
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
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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