Antibiotic Guardian Conference · Dale GE: June 27th 2018, Antibiotic Guardian Conference. London,...

Dale GE: June 27th 2018, Antibiotic Guardian Conference. London, United Kingdom

Antibiotic Guardian Conference June 27th, 2018 in London, United Kingdom.

OMPTAs: Outer Membrane Protein Targeting Antibiotics


Forward looking statements Disclaimer

This presentation does not constitute or form part of, and should not be construed as, an offer or invitation or inducement to subscribe for, underwrite or otherwise acquire, any securities of Polyphor Ltd. (“the Company” and together with its subsidiary, “we”, “us” or the “Group”), nor should it or any part of it form the basis of, or be relied on in connection with, any contract to purchase or subscribe for any securities of the Group, nor shall it or any part of it form the basis of, or be relied on in connection with, any contract or commitment whatsoever. Certain statements in this presentation are forward-looking statements, beliefs or opinions, including statements relating to, among other things, the Company's business, financial condition, future performance, results of operation, potential new market opportunities, growth strategies, and expected growth in the markets in which the Group operates. In some cases, these forward-looking statements may be identified by the use of forward-looking terminology, including the terms “targets”, “believes”, “estimates”, “anticipates”, expects”, “intends”, “may”, “will” or “should” or, in each case, their negative or other variations or similar expressions. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial consequences of the plans and events described herein. Actual results may differ materially from those set forth in the forward-looking statements as a result of various factors (including, but not limited to, future global economic conditions, changed market conditions, intense competition in the markets in which the Group operates, costs of compliance with applicable laws, regulations and standards, diverse political, legal, economic and other conditions affecting the Group’s markets, and other factors beyond the control of the Group). Neither the Company nor any of its respective directors, officers, employees, agents, affil iates, advisors nor any other person is under any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. You should not place undue reliance on forward-looking statements, which speak of the date of this presentation. Statements contained in this presentation regarding past trends or events should not be taken as a representation that such trends or events will continue in the future. Some of the information presented herein is based on statements by third parties, and no representation or warranty, express or implied, is made as to, and no reliance should be placed on, the fairness, accuracy, completeness or correctness of this information or any other information or opinions contained herein, for any purpose whatsoever. This presentation is intended to provide a general overview of the Group’s business and does not purport to deal with all aspects and details regarding the Company and the Group. This presentation is furnished solely for your information, should not be treated as giving investment advice and may not be printed or otherwise copied or distributed. The information contained in this presentation is not to be viewed from nor published, distributed or reproduced in nor taken or transmitted, in whole or in part, directly or indirectly, into the United States of America ("United States), its territories or possessions, Australia, Canada or Japan or any other jurisdiction where such publication, distribution or offer is unlawful, and does not constitute an offer of securities for sale in any of these jurisdictions. The securities offered by the Company have not been, and will not be, registered under the U.S. Securities Act of 1933, as amended (the “Securities Act”), or the securities laws of any state or other jurisdiction of the United States and such securities may not be offered or sold within the United States, except pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the Securities Act and applicable state or local securities laws. This presentation does not contain or constitute an offer

of, or the solicitation of an offer to buy or subscribe for, securities to any person or in any jurisdiction to whom or in which such offer or solicitation is unlawful.

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New antibiotics (Gram-negative) on the horizon

Compound Company Novel

MoA Market Clinical trials

Enterobacteriaceae Non-fermenters

ESBL KPC OXA MBL MDR-PA MDR-AB

Ceftolozane-tazobactam Merck No cUTI, cIAI HAP/VAP (P3) Y Partial

Ceftazidime-avibactam Pfizer No cIAI, cUTI,

HAP/VAP Y Y Y

Meropenem-vaborbactam Melinta No cUTI HAP/VAP (P3) Y Y Y

Aztreonam-avibactam Pfizer No cIAI & HAP/VAP (Ph3) Y Y Y Partial

Imipenem/cilastin-relabactam Merck No HAP/VAP (P3) Y Y Partial

Cefiderocol Shionogi No cUTI, HAP/VAP; BSI (P3) Y Y Y Y Y Partial

Plazomicin Achaogen No cUTI, BSI (under review) Y Y Y Partial

Sulopenem Iterum No cUTI, UTI (P3) Y

Eravacycline Tetraphase No cIAI (P3) Y Y Y Y Partial

Ceftaroline-avibactam Pfizer (halted?) No cUTI (P2) Y Y Y

Cefepime-AAI101 Allecra No cUTI (P2) Y Y Y

LYS-228 Novartis No cIAI, cUTI (P2) Y Y Y Partial

Meropenem-nacubactam Roche No Phase 1 Y Y Partial Partial

Cefepime-zidebactam Wockhard Partial Phase 1 Y Y Y Y Y Y

VNRX-5133 VenatoRX Partial Phase 1 Y Y Y Y

Piperacillin-AAI101 Allecra No Phase 1 Y Y Y

SPR-741 Spero Partial Phase 1 Partial Partial Partial Partial Partial Partial

GSK-3342830 Glaxo No Phase 1 Y Y Y Y Y Partial

AIC-499 + unknown BLI AiCuris No Phase 1 Y Y Y Partial Partial Partial

EXT2514 + sulbactam Entasis No Phase 2 Y Y Y

TP-6076 Tetraphase No Phase 1 Y Y Y Y Y

Murepavadin Polyphor Yes HAP/VAP (P3) Y

OMPTA Polyphor Yes Pre-clinical Y Y Y Y Y Y

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The discovery of murepavadin

4

POL6137 murepavadin Protegrin I POL0067 POL7001

Protegrin I

(1ZY6)

~ 300

analogues POL0067 POL6137

~ 300

analogues

~ 500

analogues

POL7001 murepavadin

~ 700

analogues

Pseudomonas specific! PK/ADMET optimization

Srinivas, S., et al. (2010) Science, 327: 1010 – 1012

Murepavadin an antibiotic against Pseudomonas aeruginosa with a new target and mode of action


Murepavadin targets selectively and potently Pseudomonas

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Type Strain ATCC/DSM MIC (µg/mL)

Pseudomonas aeruginosa ATCC 27853 0.06

Pseudomonas aeruginosa PAO1 0.25

Pseudomonas putida DSM 291 0.06

Pseudomonas fluorescens DSM 6147 0.06

Pseudomonas aureofaciens ATCC 15926 0.06

Pseudomonas syringae ATCC 12271 0.008

Escherichia coli ATCC 25922 >64

Klebsiella pneumoniae ATCC 13883 >64

Acinetobacter baumannii ATCC 19606 >64

Burkholderia cepacia ATCC 25416 >64

Stenotrophomonas maltophilia ATCC 13637 >64

Staphylococcus aureus ATCC 29213 >64

Potent in vitro activity against Pseudomonas aeruginosa strains


Murepavadin binds both to LPS and to LptD

Murepavadin: Targeted and Novel mechanism of action

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pharmacophore1 OMP binding

pharmacophore 2 LPS binding

LptD Murepavadin

Target LptD

Both pharmacophors are essential for the potent activity of murepavadin

Genetic studies reveal LptD as the potential target of Murepavadin (Science, 2010)

Photo-affinity labeling studies confirm LptD as the target (Science, 2010)

High affinity binding to the periplasmic domain of LptD demonstrated (ACS Chemical

Biology, 2018)


Murepavadin MIC Data

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There is little difference between geographies or MDR and non-MDR MIC distributions

Surveillance data (n=1,219) from Europe and USA (2014) and China (2012-2013) including 30.1% MDR pathogens

0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 ≥32

n=1,219 25 92 983 93 15 5 2 0 2 1 1

Cum % 2.1 9.6 90.2 97.9 99.1 99.5 99.7 99.7 99.8 99.9 100.0

0

200

400

600

800

1 000

0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 ≥32

Num

ber

of Is

ola

tes

MIC (mg/L)

Murepavadin target MIC

Source: Company information


Murepavadin: MIC Data in XDR (extensively drug-resistant isolates

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Number of isolates (cumulative %) inhibited at murepavadin MIC (mg/L) of:

XDR* isolates (n) ≤0.06 0.12 0.25 0.5 1 2 4 >4

All XDRs (n=785) 169 (21.5) 362 (67.6) 190 (91.8) 38 (96.7) 8 (97.7) 8 (98.7) 4 (99.1) 7 (100)

Colistin-R (n=50) 16 (10.0) 16 (42.0) 28 (98.0) 1 (100)

Ceftolozane-tazobactam-R (n=231) 58 (25.1) 100 (68.4) 57 (93.1) 10 (97.4) 1 (98.8) 2 (98.7) 0 (98.7) 3 (100)

Tobramycin-R (n=412) 93 (22.6) 204 (72.4) 95 (95.1) 13 (98.3) 4 (98.3) 3 (100)

Murepavadin exhibited potent activity against a large collection of clinical

XDR isolates of P. aeruginosa

Surveillance data of 785 XDR isolates from Europe (n=353) and USA (432) collected in 2016-17

R: Non-susceptible based upon EUCAST Clinical Breakpoint Tables v. 7.1, valid from 2017-03-10

* Defined by Magiorakos et al, 2012, Cin. Microbiol. Infect.

50 (6.4%) of the XDR isolates are Colistin-resistant.

231 (29.4%) of the isolates are ceftalozane-tazobactam-resistant

412 (52.4%) of the isolates are Tobramycin resistant


Activity against 175 colistin-resistant P. aeruginosa

Murepavadin maintains potent activity against colistin-resistant P. aeruginosa

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0

10

20

30

40

50

60

70

0 5 10 15

MIC

(m

g/L

)

Passage 0

10

20

30

40

50

60

70

0 5 10 15

MIC

(m

g/L

)

Passage

Lower propensity to develop resistance vs. comparators

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ATCC 27853 ATCC BAA-2113

murepavadin meropenem

ceftazidime amikacin

meropenem >8 mg/L

ceftazidime >8 mg/L

amikacin > 16 mg/L

EUCAST

breakpoints

Resistance development: serial passage


Murepavadin is active against XDR Isolates

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Neutropenic mouse lung infection model

0

1

2

3

4

5

6

7

8

9

Log

10

CF

U/g

ram

lung

NCTC 13437 MIC Murepavadin (0.125 mg/L)

0

1

2

3

4

5

6

7

8

9

Log

10

CF

U/g

ram

lung

Clinical isolate 12 MIC Murepavadin (0.25 mg/L)

Static

-1-Log

-2-Log

LoD

Static

-1-Log

-2-Log

LoD

Increasing Murepavadin

TDD

Increasing Murepavadin

TDD

Comparator Polymyxin B shows little activity


New MoA / New class (OMPTA)1

Pathogen specific

Bactericidal

Highly potent including MDR2 / XDR3

High lung penetration

Low rate of resistance (no resistant mutants observed to date in clinical studies)

Targeted at nosocomial pneumonia

First OMPTA1 already in Phase 3 development for P.aeruginosa infections

Murepavadin

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Notes:

1 Outer Membrane Protein Targeting Antibiotic

2 Multidrug-Resistant

3 Extensively Drug-Resistant

Source: Company information


OMPTA Scaffold

Pa specific

Gram-negative Protegrin I

(1ZY6)

Murepavadin

Pre-clinical/Phase 1/Phase 2

Today

OMPTA Scaffold 1

OMPTA Scaffold 2

OMPTA 1 P0263409

Today

Phase 3

Pseudomonas specific

Early pre-clinical

Gram-negative Potent in vitro / in vivo activity PK/ADMET optimisation

OMPTA platform The discovery of broad-spectrum Gram-negative antibiotics

In 2015, Polyphor reinitiated the search for broad-spectrum Gram-negative agents

T T

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https://www.google.ch/url?sa=i&rct=j&q=&esrc=s&source=imgres&cd=&cad=rja&uact=8&ved=2ahUKEwjIsLTz4s3bAhXFa1AKHZY3CbgQjRx6BAgBEAU&url=https://commons.wikimedia.org/wiki/File:Wellcome_Trust_logo.svg&psig=AOvVaw3EFs_rRxllol5H8j2BiwMX&ust=1528880786527953


OMPTA: Targeting the Gram-negative ESKAPE1 and the WHO priority 1 pathogens

14 Susceptible Non-susceptible

OMPTA compounds Comparators

Organisms P0262769 P0263409 P0264507 Meropenem Ceftazidime Tobramycin Ciprofloxacin Colistin

A. baumannii A369 0.06 0.06 0.03 >64 >64 8 >64 0.25

A. baumannii 863866 0.06 0.06 0.03 32 >64 4 32 64

A. baumannii 872842 0.06 0.125 0.06 >8 >8 0.25 >8 >8

P. aeruginosa UU6419 0.25 0.25 0.25 64 >64 >64 16 0.5

P. aeruginosa 22409 0.25 0.25 0.5 32 >64 8 32 1

P. aeruginosa 401190 0.125 0.125 0.125 >64 >64 >64 >64 0.5

E. cloacae 950265 0.06 0.06 0.06 0.125 64 >64 32 8

E. coli 959670 0.06 0.06 0.06 ≤0.06 64 32 32 4

E. coli 402788 0.06 0.03 0.03 64 >64 >64 >64 0.125

E. coli 926415 0.06 0.125 0.06 0.03 >8 >8 >8 8

K. pneumoniae 403575 0.06 0.125 0.06 64 >64 16 >64 4

K. pneumoniae 946897 0.25 0.25 0.25 >64 >64 16 >64 16

K. pneumoniae RV 9959 0.125 0.06 0.06 32 >64 16 >64 1

S. aureus ATCC 29213 >64 >64 >64 0.125 >8 >8 0.125 >8

Active towards the pathogens of critical concern and high unmet medical need


P0263409 maintains potent activity against colistin-resistant P. aeruginosa

Activity against 175 colistin-resistant P. aeruginosa

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MIC (mg/L) 0.03 0.06 0.125 0.25 0.5 1.0 2.0 4.0 8.0 16.0 32.0 64.0 >64

P0263409 3 29 65 43 24 8 3

(1.7) (18.3) (55.4) (80.0) (93.7) (98.3) (100)

Colistin 79 44 12 17 9 14

(45.1) (70.3) (77.1) (86.9) (92.0) (100)


P0263409 shows potent in vivo activity Neutropenic thigh infection murine models

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1. The OMPTA platform of compounds enables Polyphor to develop novel antibiotics which can address the unmet medical needs

2. The First compound (Murepavadin) has entered Phase 3

3. The new broad spectrum Gram-negative compounds display:

A potent and broad spectrum of activity towards Gram-negative pathogens

Potent in vivo activity

A much reduced nephrotox potential compared to colistin as observed in animal models

OMPTA

The OMPTA program has promise to deliver the next generation Gram-

negative compounds with a novel mode of action

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Polyphor Ltd | Hegenheimermattweg 125 | 4123 Allschwil | Switzerland T +41 61 567 16 00 | [email protected] | www.polyphor.com

Polyphor Francesca Bernardini Emile Brabet Petra Chiquet Nicolas Desjonquères Hans Locher Anatol Luther Daniel Obrecht Tobias Remus Sarah Stiegeler Grégory Upert Carolin Verbree Peter Zbinden

Thank you for your attention CROs Evotec (UK) Fidelta (Croatia) JMI labs (United States) This work was supported by the Wellcome Trust [grant number 202728/Z/16/Z]

Antibiotic Guardian Conference · Dale GE: June 27th 2018, Antibiotic Guardian Conference. London,...

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