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The Diversity of AMP mimetics ECCMID ESCMID 2018: April 24th 10:00-10:30 eLibrary Madrid, Spain

Dale G: April 24, Early development© news; ECCMIDby 2018 Madrid, Spainauthor Disclaimer Forward looking statements

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, affiliates, 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 ESCMIDan exemption from, or in a transaction not subject to, the registrationeLibrary 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. Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 2 Cationic Antimicrobial (cAMPS)

1. In a landmark study, Boman’ s group published the discovery of cecropins. Two antibacterial proteins involved in insect immunity (Steiner et al; Nature 1981; 292:246-8).

2. They showed that when insect is challenged by a pathogen it protects its inner inner milieu by releasing high concentrations of .

3. AMPs are now known to be widely expressed in both plants and animals, have been studied in human health and disease, and have been developed as human therapeutics.

4. More than 2500 AMPs have been described, thousands of publications, yet the development of novel antibacterials has been challenging 1. Discrepancy between in vitro and in vivo data 2. Low metabolic stability of the peptides (short half-life after iv administration) 3. Relatively high cost of goods may hamper the competiveness compared to small ESCMIDmolecules eLibrary 4. Regulatory hurdles as they are often seen as a“mix” of small molecule and biologic Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 3 AMPs in host defence Multiple function of AMPS in host defence Not only do they have a direct antimicrobial activity , AMPs often have immunomodulatory properties

ESCMID eLibrary The selective immunomodulation by AMPs helps to protect the host against (adapted from Hancock et al, 2001) Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 4 Animicrobial diversity

1. Sources of antimicrobial peptides 2. Sequence length of AMPs

3. Net charge of AMPS 4. Hydrophobic content of AMPs

ESCMID eLibrary Some facts about AMPS which were derived from the antimicrobial peptide database (http://aps.unmc.edu/AP/about.php) Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 6 Structural classes of of AMPs Host defense peptides can be grouped into structural classes

1. b-loop or b-hairpin host defense peptide 2. Mixed structure host defense peptide lactoferricin (PDB code 1LFC) Plectasin (PDB code 1ZFU)

3. a-helical host defense peptide human 4. Flexible extended /structure cathelicidin LL-37 indolicidin (PDB code 1G89)

ESCMID eLibrary

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 5 A number of cAMPs have been marketed Selected AMPs in use

Mechanism of Peptide product Source Activity Approved use action Damages Ophthalmic use Gramaicidin brevis Gram-positive membranes as solution

Binds to lipid II Lactococcus Food Nisin Gram-positive and inhibits cell lactis preservatives wall synthesis

Inhibits Gram-positive and peptoglycan Powder form synthesis Bacillus Damages Parenteral or B Gram-negative polymyxa membranes Ophthalmic

Paenibacillus Damages Gram-negative Parenteral polymyxa membranes

Gram-positive, Damages Topical S Bacillus brevis ESCMIDGram eLibrary-negative membranes applications

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 7 A number of cAMPs have been marketed Selected AMPs in development

Peptide Route of Description Indication Phase Company product administration Dipexium Pexiganan African frog peptide Diabetic foot not Topical Pharmaceuticals (Locilex) magainin analog infection approved Inc. Synthetic 12 amino CLS001 Cutanea Life acid cationic Multiple Topical Phase 1-3 (omiganan) Sciences, Inc peptide

WAP-8294A2 12 cyclic DAKOTA Sife MRSA Topical Phase 1 (Lotilibcin) peptide Sciences NP213 cyclic cationic Fungal nail Topical Phase 2 NovaBiotics (Novexatin) peptide infection Uncomplicat Synthetic LTX-109 ed Gram- antimicrobial Topical On hold Lytix Biopharma (Lytixar) positive skin peptidomimetic Oral Topical / Innovation peptidomimetic mucositis Phase 2 Intravenous Pharmaceuticals ESCMIDABSSSI eLibrary

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 8 Brilicidin- Novel membrane targeting

1. Rationally designed new class of amphiphilic arylamide polymers that capture the physical and biological properties of the magainin class of antimicrobial peptides

2. Broad spectrum antibacterial activity

3. Low rate of resistance development

4. Acts on the bacterial membrane by depolarisation

5. Showed promise when compared to in Phase 2 acute bacterial skin and skin structure infections

6. ESCMIDCurrent development in ABSSSI eLibraryis on hold Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 9 Generally considered mode of action of cAMPs

It wasESCMID assumed for many years, thateLibrary all cationic AMPs mode of action was based on cytoplasmic membrane permeabilization...... But is it true?? (adapted from Nguyen et al, 2011) Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 10 Many cAMPs have a very specific Mode of Action Not all cAMPs are are punching holes in membranes

Compound Source Activity Mechanism of action Reference

Binds to lipid II and Lactococcus Nisin Gram-positive inhibits cell wall Tol et al; 2015 lactis synthesis

Inhibits cell wall and Bacillus Bacitracin Gram-positive peptoglycan Mishra et al, 2017 subtilis synthesis Podisus Thanatin Gram-negative cell agglutination Sinha et al; 2017 maculiventris Binds to lipid II and Paenibacillus inhibits cell wall Tridecaptins Gram-negative Cochrane et al; 2016 polymyxa synthesis

Murepavadin Fully Synthetic P. aeruginosa Targets LptD Srinivas et al; 2010 ESCMID eLibrary

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 11 The discovery of

Protegrin I POL0067 POL6137 POL7001 POL7080

Pseudomonas specific! PK/ADMET optimization ~ 300 ~ 300 analogues analogues POL0067 I POL6137 (1ZY6)

~ 500 analogues

POL7080 POL7001 ~ 700 analogues ESCMID eLibrarySrinivas, S., et al. (2010) Science, 327: 1010 – 1012 Murepavadin (formally POL7080) an antibiotic against with a new mode of action Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 12 Murepavadin targets selectively and potently Pseudomonas

Potent in vitro activity against strains

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 ATCC 13883 >64 ATCC 19606 >64 Burkholderia cepacia ATCC 25416 >64 ESCMIDStenotrophomonas maltophilia eLibraryATCC 13637 >64 aureus ATCC 29213 >64 Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 13 Murepavadin: Targeted and very effective mechanism of action Murepavadin binds with LptD1 and thereby blocks LPS1 translocation and outer membrane biogenesis

. Genetic studies reveal LptD1 as the potential target of Murepavadin (Science, 2010)

. Photo-affinity labeling studies confirm LptD1 as the target (Science, 2010)

. In vitro resistance development leads to mutations in periplasmic domain of LptD1 (ECCMID, 2018)

D115N A243T . High affinity binding to the periplasmic 1 G247S domain of LptD demonstrated (ACS F315Y Chemical Biology, 2018) D319N

ESCMID219-43 Aa duplication eLibrary

Source: Andolina et al; 2018. A Peptidomimetic Antibiotic Interacts with the Periplasmic Domain of LptD from Pseudomonas aeruginosa. ACS Chem Biol. 2018 Jan 23. doi: 10.1021/acschembio.7b00822 Srinivas et al, 2010. Peptidomimetic target outer-membrane biogenesis in Pseudomonas aeruginosa. Science. 327:1010-3 Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 14 Murepavadin Mode of Action Murepavadin binds both to LPS and to LptD

Murepavadin LptD

Target LptD

pharmacophore1 pharmacophore 2 OMP binding LPS binding

ESCMID eLibrary Both pharmacophors are essential for the potent activity of murepavadin Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 14 Murepavadin MIC Data

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

1,000

800

600

400 NumberofIsolates Murepavadin target MIC 200

0 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 ≥32 MIC (mg/L) 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 CumESCMID % 2.1 9.6 90.2 97.9 eLibrary99.1 99.5 99.7 99.7 99.8 99.9 100.0 There is little difference between geographies or MDR and non-MDR MIC distributions Source: Company information Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 16 Murepavadin: MIC Data in XDR (extensively drug- resistant isolates Surveillance data of 785 XDR isolates from Europe (n=353) and USA (432) collected in 2016-17

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 >4 169 362 190 38 8 8 4 7 All XDRs (n=785) (21.5) (67.6) (91.8) (96.7) (97.7) (98.7) (99.1) (100) 16 16 28 1 Colistin-R (n=50) (10.0) (42.0) (98.0) (100) 58 100 57 10 1 2 0 3 Ceftolozane--R (n=231) (25.1) (68.4) (93.1) (97.4) (98.8) (98.7) (98.7) (100) 93 204 95 13 4 3 -R (n=412) (22.6) (72.4) (95.1) (98.3) (98.3) (100) 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 MurepavadinESCMID exhibited potent activity eLibrary against a large collection of clinical XDR isolates of P. aeruginosa, including isolates resistant to colistin, ceftolozane-tazobactam, and/or tobramycin Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 17 Murepavadin is active against XDR Isolates Comparator shows little activity

Neutropenic mouse lung infection model

NCTC 13437 Clinical isolate 12 MIC Murepavadin (0.125 mg/L) MIC Murepavadin (0.25 mg/L) 9 9

8 8

7 7

6 6 Static Static 5 5

-1-Log -1-Log CFU/gramlung

CFU/gramlung 4 4

10 10 10

-2-Log -2-Log Log Log 3 3

2 2 LoD LoD 1 1

0 0 Increasing Murepavadin Increasing Murepavadin TDD1 TDD1 ESCMID eLibrary

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 18 Murepavadin First OMPTA1 already in late-stage development for Pseudomonas aeruginosa infections

. New MoA / New class (OMPTA)1

. Pathogen specific

. Bactericidal

. Highly potent including MDR2 / XDR3

. High lung penetration

. Low resistance potential

. QIDP4 (additional 5 year exclusivity) and fast track status

. Targeted at nosocomial

Source:ESCMIDCompany information eLibrary Notes: 1 Outer Membrane Protein Targeting Antibiotic 2 Multidrug-Resistant 3 Extensively Drug-Resistant 4 Qualified Infectious Disease Product Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 19 OMPTA platform The discovery of broad-spectrum Gram-negative antibiotics

Today T T

OMPTA Pa specific Murepavadin Phase 3 Scaffold

Protegrin I (1ZY6) Gram-negative Pseudomonas specific Pre-clinical/Phase 1/Phase 2

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

Today

OMPTA OMPTA OMPTA 1 Early pre-clinical ESCMIDScaffold 1 eLibraryScaffold 2 P0263409

Gram-negative PK/ADMET optimisation Potent in vitro / in vivo activity Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 20 OMPTA: Targeting the Gram-negative ESKAPE1 and the WHO priority 1 pathogens

Gram-negative infections with limited treatment options MICs (μg/ml) against resistant isolates2

OMPTA compounds Comparators Organisms P0258982 P0262769 P0263409 P0264507 P0265488 P0267005 Tobramycin Colistin A. baumannii A369 0.06 0.06 0.06 0.03 0.06 0.06 >64 >64 8 >64 0.25 A. baumannii 863866 0.25 0.06 0.06 0.03 0.125 0.06 32 >64 4 32 64 A. baumannii 872842 0.25 0.06 0.125 0.06 0.125 0.125 >8 >8 0.25 >8 >8 P. aeruginosa UU6419 0.25 0.25 0.25 0.25 0.25 0.25 64 >64 >64 16 0.5 P. aeruginosa 22409 0.5 0.25 0.25 0.5 0.25 0.125 32 >64 8 32 1 P. aeruginosa 401190 0.125 0.125 0.125 0.125 0.125 0.06 >64 >64 >64 >64 0.5 E. cloacae 867213 0.25 0.06 0.125 0.06 0.125 0.06 ≤0.06 >64 16 0.125 >64 E. cloacae 950265 0.125 0.06 0.06 0.06 0.06 0.03 0.125 64 >64 32 8 E. coli 959670 0.25 0.06 0.06 0.06 0.06 0.06 ≤0.06 64 32 32 4 E. coli 402788 0.06 0.06 0.03 0.03 0.03 0.03 64 >64 >64 >64 0.125 E. coli 926415 0.25 0.06 0.125 0.06 0.06 0.06 0.03 >8 >8 >8 8 K. pneumoniae 403575 0.25 0.06 0.125 0.06 0.125 0.06 64 >64 16 >64 4 K. pneumoniae 946897 2 0.25 0.25 0.25 1 0.5 >64 >64 16 >64 16 K. pneumoniae RV 9959 0.125 0.125 0.06 0.06 0.06 0.03 32 >64 16 >64 1 S. aureus ESCMIDATCC 29213 >64 >64 >64 >64 eLibrary>64 >64 0.125 >8 >8 0.125 >8 Sensitive Non-susceptible Notes: 1 ESKAPE pathogens: faecium, , Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. 2 Breakpoints are based upon EUCAST Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 21 Gram-negative infections with limited treatment options

Active towards the pathogens of critical concern and high unmet medical need 1. and 3rd generation -resistant Enterobacteriaceae 2. Carbapenem-resistant Acinetobacter baumannii 3. Carbapenem-resistant Pseudomonas aeruginosa 4. Active against Colistin-resistant A. baumannii, Enterobacteriaceae, and P. aeruginosa

A. baumannii Enterobacter spp. E. coli K. pneumoniae P. aeruginosa

MIC (mg/L) MIC (mg/L) MIC (mg/L) MIC (mg/L) MIC (mg/L)

MIC50 MIC90 Ranges MIC50 MIC90 Ranges MIC50 MIC90 Ranges MIC50 MIC90 Ranges MIC50 MIC90 Ranges (n=30) (n=28) (n=28) (n=31) (n=29)

P0258982 0.06 0.125 0.03-0.25 0.25 1 0.06-8 0.06 0.25 0.03-0.5 0.125 0.25 0.06-2 0.125 0.25 0.06-0.5

P0262769 0.03 0.06 0.016-0.06 0.06 0.25 0.03-0.5 0.03 0.06 0.03-0.125 0.06 0.125 0.03-0.5 0.125 0.25 0.06-1

P0263409 0.03 0.06 0.016-0.125 0.125 0.25 0.06-1 0.03 0.125 0.03-0.125 0.06 0.125 0.03-0.5 0.125 0.25 0.06-0.25

P0264507 0.03 0.06 0.016-0.06 0.06 0.125 0.03-0.25 0.03 0.06 0.03-0.06 0.06 0.25 0.03-0.25 0.125 0.25 0.03-0.5

P0265488 0.03 0.06 0.016-0.125 0.125 0.5 0.06-4 0.03 0.06 0.03-0.125 0.06 0.125 0.03-1 0.125 0.25 0.03-0.25

P0267005 0.03 0.03 ≤0.0078-0.125 0.06 0.25 0.03-0.5 0.03 0.06 0.016-0.125 0.03 0.25 0.03-0.5 0.125 0.25 0.03-0.25

Colistin 0.25 8 0.125->64 >64 >64 2->64 0.125 8 ≤0.06-8 0.125 >64 0.125->64 0.5 1 0.125-2

Meropenem 16 64 0.25->64 ≤0.06 0.125 0.03-2 ≤0.06 >64 0.03->64 1 >64 0.03->64 2 >64 ≤0.06->64 Ceftazidime ESCMID>64 >64 8->64 0.5 64 0.125- >64 eLibrary16 >64 0.125->64 >64 >64 0.125 ->64 4 >64 1->64 Sensitive Resistant Notes: 1 ESKAPE pathogens: , Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. 2 Breakpoints are based upon EUCAST Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 22 OMPTA: Lower propensity to develop resistance than the comparators

Comparison of pathogen resistance to meropenem, ciprofloxacin and colistin

ESCMID eLibrary

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 23 OMPTA shows potent activity in neutropenic thigh infection models

ESCMID eLibrary

Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 24 Mouse model

Histology t C /mg AUC/mg score 1/2 max

P0263409 2 0.94 443 953 P0267003 1 1.39 369 617 P0258982 1 0.96 415 862 No to mild nephrotox P0270874 2 1.02 347 807 P0270697 3 1.69 686 1482 P0265488 4 1.02 475 913 P0265487 6 1.03 441 926 P0265490 10 1.34 533 959 Mild nephrotox P0266496 16 0.82 736 1331 P0264378 24 1.47 287 570 P0267009 24 1.3 207 595 Mild to moderate nephrotox P0265489 24 1.14 422 905 “Colistin like” P0262769 24 1.06 345 668 P0264381 24 1.02 325 580 ESCMIDP0264507 eLibrary24 1.12 533 1064 Renal toxicity does not correlate with exposure (e.g. P0263409 vs. P0265489) but is rather structure-dependent. Colistin score is 24 Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 25 OMPTA

1. The OMPTA platform of compounds enables Polyphor to develop novel antibiotics which can address the unmet medical needs 2. The lead compound displays:  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 3. The current program is on track to deliver a pre-clinical candidate in H2 2018

ESCMIDThe OMPTA program has promise eLibrary to deliver the next generation Gram-negative compounds with a novel mode of action Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 26 Summary cAMPS

1. A number of cAMPS have been described with potent antibacterial activities

2. Many compounds are selective towards Gram-negative organisms and have a specific mode of action distinct from the “hole punching” mechanism

3. The compounds can be optimized for potency, selectivity, stability, and in vivo activity.

ESCMIDAMPs are a relatively under utilizedeLibrary source for new antibacterials which may offer a new mode of action Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor 28 THANK YOU!!!

Polyphor Ltd | Hegenheimermattweg 125 | 4123 Allschwil | Switzerland

TESCMID +41 61 567 16 00 | [email protected] | www.polyphor.com eLibrary cover gettyimages.com photo | © Dale G: April 24, Early antimicrobial development© news; ECCMIDby 2018 Madrid, Spainauthor

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