ANTIBACTERIAL POLYMYXIN B ANALOGS
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Transcript of ANTIBACTERIAL POLYMYXIN B ANALOGS
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Barcelona, 14 de marzo de 2012
Antibacterial Polymyxin B analogs
Francesc Rabanal Anglada
A project of:
Managed by:
Content
1. The Research Group 2. The Product
a) Target indications b) Innovative mechanisms of action c) Differential features facing the market d) Current status of development e) IPR protection f) Pitfalls & Risks to be considered
3. Partnering Opportunities
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Research Group - Team and collaborators
Dr. Francesc Rabanal (PI) (Dept. Organic Chemistry, UB) Design and Synthesis
Dr. Yolanda Cajal (Dept. Physical Chemistry, UB)
Biophysical Studies MoA
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Antimicrobial activity evaluation (Dept. Microbiology, UB) Dr. Ángeles Manresa Antimicrobial activity in MDR bacteria (UB, CRESIB, CEK, Hospital Clínic) Dr. Jordi Vila In vivo studies (CERETOX/ UTOX-UB, Parc Científic de Barcelona) Dr. Miquel Borràs
The Product. Target Indication
Need of new antibiotics ▫ Infectious diseases Second cause of death in the world (third in the
developed world) ▫ Inadequate use of antibiotics Increase in resistant bacteria
Antibiotics loose effectiveness ▫ Reduced pipeline of new antibiotics
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
AntiMicrobial Peptides (AMP) - Innovative mechanism of action • New antibiotics with novel MoA • AMPs: act on bacterial membrane (no enzymes) lower risk of resistance (or reversible resistance)
Zasloff, Nature, 2002
Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
...facing de market
• Need of new antibiotics • Remergence of Polymyxin
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Objectives and differential features • Design and synthesis new antibiotics: lipopeptides based on the
structure of polymyxin/colistin
• Looking for... Activity in resistant and multi-resistant bacteria Lower toxicity Broader spectrum of activity Chemical synthesis designed for optimal scale up
Target IDTarget
ValidationLead
Optimization Pre-Clinical
Drug Discovery Animal Test
Clinical Trials Commercialization
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Objectives and differential features
Design & Synthesis Of New Compounds
In vitro Efficacy
(MIC)
MoA SAR
In vitro TOX
IN VIVO EFFICACY
IN VIVO TOX. (LD50)
Design
Synthesis
In vitro Efficacy
MoA
NH2
HNO
NH
NH2
O
HN
ONH
OH2N
NHO
NH
O
SS
NH
ONH2
HN
O
OH
NH
O
NH2
HN
O
ONH2
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Polymyxin B
Design Rational…
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Polymyxin B
Design Rational…
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Polymyxin B
Design Rational…
Analogs Design
Designed lipopeptide
NH2
HNO
NH
NH2
O
HN
ONH
OH2N
NHO
NH
O
HN
O NH
ONH2
HN
O
OH
NH
O
NH2
HN
O
HO
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Polymyxin
NH2
HNO
NH
NH2
O
HN
ONH
OH2N
NHO
NH
O
SS
NH
ONH2
HN
O
OH
NH
O
NH2
HN
O
ONH2
Nº Peptide sequenceGram+ Gram-
S. aureus P. aeruginosa E. coli
pxb CH3-octanoyl-Dab-Thr-Dab-Dab-Dab-Phe-Leu-Dab-Dab-Thr >32 2 1
0 nonanoyl-Dab-Thr-Dab-Cys-Dab-Phe-Leu-Dab-Dab-Cys >32 8 4
1 nonanoyl-Arg-Thr-Dab-Cys-Dab-Phe-Leu-Arg-Dab-Cys 32 16 8
2 nonanoyl-Arg-Thr-Arg-Cys-Dab-Phe-Leu-Arg-Dab-Cys 8 8 4
3 nonanoyl-Dab-Thr-Dab-Cys-Dab-Phe-Met-Dab-Dab-Cys 32 16 4
34 nonanoyl-Arg-Thr-Dab-Cys-Dab-Trp-Leu-Arg-Dab-Cys 8 8 4
79 decanoyl-Arg-Thr-Dab-Cys-Dab-Phe-Leu-Arg-Dab-Cys 16 8 8
85 dodecanoyl-Arg-Thr-Dab-Cys-Dab-Phe-Leu-Arg-Dab-Cys 32 8 8
16 nonanoyl-Arg-Thr-Dab-Cys-Dab-Phe-Leu-Arg-Dab-Cys 16 8 4
93 decanoyl-Lys-Thr-Arg-Cys-Lys-Trp-Leu-Arg-Lys-Cys 16 >64 64
100 decanoyl-Arg-Thr-Arg-Cys-Dab-Trp-Nle-Arg-Dab-Cys 4 64 8
101 nonanoyl-Dab-Thr-Arg-Cys-Dab-Phe-Leu-Arg-Dab-Cys 8 16 2
103 ------------------------------------------------------------------ 4 2 1104 ------------------------------------------------------------------ 4 1 4105 ------------------------------------------------------------------ 4 1 2
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Antibacterial Activity – in vitro (measured as Minimum Inhibitory Concentration, MIC, in μg/mL)
Up to 90 analogs synthesized and tested
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Antibacterial Activity – in vitro (measured as Minimum Inhibitory concentration, MIC, in μg/mL)
Comparison with reference marketed products. Species Analog
103Analog
104Analog
105
PxBG(-)
control
VancomycinG(+) control
DaptomycinG(+) control
GRAM -Pseudomonas aeruginosa 2 1 1 2 - >32
Escherichia coli 1 4 4 1 - >32
GRAM+
Mycobacterium phlei 4 4 2 16-32 - >32
Staphylococcus aureus 4 4 4 >32 1 2
• Resistance panel: ▫ 40b (clinical isolate): resistance to IMP ▫ 38a (clinical isolate): resistance to Ceftazidime; Ciprofloxacin; Imipenem ; Piperacillin-tazobactam ▫ NMD, New Delhi metallo-beta-lactamase: Amoxicillin 256 mg/L; Amoxicillin clavulanate 32 mg/L ;
Piperacillin/tazobactam 256 mg/L; Cefoxitin 256 mg/L; Cefotaxime 256 mg/L; Ceftazidime 256 mg/L; Cefepime 256 mg/L; Imipenem 8 mg/L; Meropenem 16 mg/L; Doripenem 6 mg/L; Ertapenem 24 mg/L; Aztreonam 256 mg/L; Gentamicin 8 mg/L; Amikacin 32 mg/L, Tobramycin 8 mg/L; Ciprofloxacin 32 mg/L
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Antibacterial Activity – in vitro (measured as Minimum Inhibitory concentration, MIC, in μg/mL)
In multi-drug resistant bacteria. Resistant and multi-resistant Gram negative bacteria Analog
103Analog
104Analog
105
P. aeruginosa40b Carbapenem-resistant strain 4 2 4
38a Highly-resistant strain 0,5 1 16
E. coli
MAC 21a Intermediate resistance to quinolones 0,5 1 2
VAL 10 Intermediate resistance to quinolones 0,5 0,5 1
VAL 5 Intermediate resistance to quinolones 0,5 0,5 1
NDM Highly-resistant strain 0,5 0,5 1
Moderate antibacterial activity in colistin-resistant Acinetobacter baumannii suggests an alternative mechanism of action
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Antibacterial Activity – in vitro (measured as Minimum Inhibitory concentration, MIC, in μg/mL)
In Colistin resistant a. baumannii strains. Colistin-Resistant Acinetobacter baumannii Colistin Analog
103Analog
104Analog
105
A. Baumannii
ATCC-wt Low resistance strain 1 8 2 4
ATCC In vitro mutant of ATCC with resistance to colistin
256 64 16 32
77778 In vitro mutant of a clinical strain with resistance to colistin
256 256 128 128
Ab 10 Clinical isolate resistant to colistin 512 32 16 8
Ab 19 Clinical isolate resistant to colistin 512 32 16 16
Mechanism of action
• By Flow cytometry
Propidium iodide Bis-(1,3-Dibutylbarbituric Acid)Trimethine Oxonol DIBAC4(3)
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
E. coli
S. aureus
Flow-cytometric tests show a different behaviour of lipopeptides in front Gram+ and Gram- bacteria
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Mechanism of action results
CONTROL, 120 min PEPT. 103, 120 min PXB, 120 min PEPT. 100, 120 min
In vivo Toxicity
• Acute toxicity test in mice for peptide 103
• LD50 = 283 mg/Kg
(subcutaneous) Polymyxin LD50 = 59,5 mg/Kg
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Protocol OECD 425. 5 reversals in 6 consecutive animals. Animals (3) administered at 200 mg/kg survived after 14 days; Necropsy indicated no visual damage in vital organs. Mice (3) administered at 400 mg/Kg died
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Current status of development
Design & Synthesis Of New Compounds
In vitro Efficacy
(MIC)
MoA SAR
In vitro TOX
IN VIVO EFFICACY
IN VIVO TOX. (LD50)
Design
Synthesis
In vitro Efficacy
MoA
NH2
HNO
NH
NH2
O
HN
ONH
OH2N
NHO
NH
O
SS
NH
ONH2
HN
O
OH
NH
O
NH2
HN
O
ONH2
IPR Protection
• 2 different patents • ES 200802626 Granted
• ES 2.374.779 A1 Filed - Priority March 2010
PCT/ES2011/070153 Published as WO2011110716 - ISR Positive
• Ownership
– University of Barcelona 100%
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Weaknesses • No Oral Administration (not confirmed) • Early stage project. Few in vivo tests performed. • Need of partner to accelerate development
Threats • Efficacy in in vivo model. • PK/PD & ADME development. • Additional Toxicology development • Patent going to National phases in Sep. 2012
Pitfalls & Risks to be considered
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Strengths • Good antibacterial activity front both pathogen and multi-drug
resistant bacteria • Better in vivo and in vitro tox. profile than PxB • MoA independent of membrane receptors • Easy Synthesis • Intl. patent file WO2011110716. Priority march 2010- Positive ISR. • Ownership 100% UB
Opportunities • Market Needs of new antibacterial compounds with wide spectrum /
low toxicity profile. • In vivo efficacy tests in 2012
Pitfalls & Risks to be considered
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Market competitors PolyMedix, for S. aureus Several products in preclinical studies for indications such as tuberculosis, malaria, bacterial infections. PMX-30006 is a potent broad spectrum antibiotic, which is active against a number of bacterial strains. PMX-30006 is being developed for the treatment of bacterial infections. Cubist ; CB-182804, macrolactam PxB CB182804 is a lipopeptide which interacts with cell membranes and rapidly shuts down bacterial DNA, RNA and protein synthesis. CB182804 was under development as intravenous injection for the treatment of serious infections caused by multi-drug resistant (MDR) gram-negative bacteria. – Discontinued in phase I in 2009. Northern Antibiotics (complex synthesis: macrolactam) NAB 7061 is a polymyxin derivative that sensitizes target bacteria to other antibiotics such as rifampin and clarithromycin. NAB 7061 is being developed for the treatment of serious gram-negative hospital infections.
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Partnering Opportunities
The project is available to licensing out through a collaboration and license agreement.
Contact details
Salvador Mena Project Manager
Tel: +34 93 403 97 95 [email protected]
Acknowledgments
Funding has been provided by: ▫ Ministerio de Ciencia e Innovación (CTQ2008-06200) ▫ Generalitat de Catalunya (VALTEC 08-1-0016, ACC10) ▫ Fundació Bosch i Gimpera (UB)
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
THANK YOU FOR YOUR ATTENTION!
Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
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Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
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Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
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Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Summary: -Proof of concept in vitro for EC, PA and SA -Activity in resistant and MDR bacteria
-In vivo toxicity (acute, sc) better than PxB
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Programa Cooperación Farma-Biotech Jornada 1-2012: Áreas Terapéuticas de Inflamación, Infección y Respiratorio
Optimized chemical synthesis and scale up (i. e, octreotide, lanreotide)
NH2
HNO
NH
NH2
O
HN
ONH
OH2N
NHO
NH
O
SS
NH
ONH2
HN
O
OH
NH
O
NH2
HN
O
ONH2
HN O
NHO
HN
O
NHO
NH
O
SS
NH
O
H2N
ONH
OH
HN
NH2
OH2N
Lanreotide:H-D-2-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2
Lanreotide is a synthetic analog of somatostatin with properties similar to octreotide