Open Source Drug

Discovery: From screen to

Malaria Box Timothy N.C. Wells

MMV in Open Source: powering three projects

Malaria Box

(MB)

Pathogen

Box (PB)

Exploiting

the

Pathogen

Box

400 Diverse Compounds

Active against a

range of pathogens

Launches Q4 2015

Will stimulate neglected

Disease research

400 Diverse Compounds

with Antimalarial activity

Launched Dec 2012

Generated many

neglected diseases

projects

Hit series

+ biological targets

From PB

Planned start 2015

Delivers drug discovery

project opportunities

Next generation: target based

Genome: All drug

able targets

Validate Knock-out organisms

Assay Set-up

Validation

HTS Specific Target

DHFR: Yuthavong Y et al., 2012 in preparation DHODH: Coteron JM et al., 2011 J Med Chem 54 5540-61

Next Generation: ask the parasite

Chemistry:

All available

molecules

HTS

Whole

parasite

Hits to leads

Identify

resistance

New business model: ‘screen first’

Screened over five million compounds, 25’000 hits

Fast: screen to human trials in less than four years

Eight molecules already in clinical or preclinical

Identifies new targets (resistance or pull-down)

Rottman M., et al, Science 325 1175-1180 (2010)

Meister S., et al Science 334 1372-1377 (2011)

Gamo FJ, et al., Nature 465 (7296): 305–310 (2010)

Guiguemde WA, et al., Nature 465, 311–315 (2010)

Wells TNC Science 329 1153-1154 (2010)

New

candidate

molecules for

development

Lessons from phenotypic screening

5

Compound

Collection

Compounds

screened

Number of

hits1

% Hit-

rate

Public?

Novartis 810’000 5930 0.73 Yes

GSK 1,986,056 13,533 0.68 Yes

St Jude 309,474 561 0.18 Yes

Pharma A 502,868 3274 0.65 Some hits

Pharma B 155,554 1147 0.74 Some hits

Diversity A 256,263 339 0.13 2013?

Sanofi2 1600 306 19.1 No

Broad Institute 100’000 465 0.47 2014

Diversity B 35,000 222 0.63 Hits

1 Exact definitions variable – usually confirmed hit is non-cytotoxic and has IC50 < 2mM 2Compounds selected inhibited human targets that have orthologues in Plasmodium

Screening new diversity deck (500k) against multiple pathogens

MMV Portfolio: May 2014

Research

Miniportfolio Novartis

1 Project Novartis

Miniportfolio GSK

Miniportfolio Sanofi

Aminopyridines UCT

Heterocycles Univ Campinas

Miniportfolio AstraZeneca

Heterocycles Celgene

3 Projects GSK

Oxaboroles Anacor

Whole Cell Leads AstraZeneca

Tetraoxanes Liverpool

STM/Liverpool Uni

DHODH UTSW/UW/Monash

Orthologue Leads Sanofi

Open Source

Drug Discovery Univ Sydney

Amino-alcohols Merck Serono

Screening Daiichi-Sankyo

Other Projects 16 Projects

Screening Takeda

Screening Eisai

Pathogen Box MMV

Research Lead optimisation Registration Phase IIa Phase IIb/III

OZ439/PQP (Monash/UNMC

/Swiss TPH)

Tafenoquine GSK

Pyronaridine-

Artesunate

Paediatric Shin Poong/U Iowa

DHA Piperaquine

Paediatric Sigma-Tau

KAE609 Novartis

KAF156 Novartis

In registration

Development Patient exploratory Patient confirmatory Phase IV

Post

Approval * Preclinical Phase I

ELQ300 Takeda

MMV390048 (UCT)

DSM265 Takeda

P218 DHFR (Biotec/Monash/

LSHTM)

(+)-SJ557733 St Jude/Rutgers

DDD107498 (DDU Dundee)

Translational Pr eclinical Human volunteers

OZ439/FQ

Sanofi

Rectal Artesunate MMV/WHO-TDR

Artesunate for

injection

Guilin

Artemether-

Lumefantrine

Dispersible Novartis

Pyronaridine-

Artesunate Shin Poong

DHA -

Piperaquine Sigma-Tau

1

2

3

Research Lead

Optimisation Under review *

Development Patient

exploratory

Patient

confirmatory

Translational

Preclinical Human

volunteers

5

6

4

Access

Artesunate

Amodiaquine Sanofi /DNDi

Artesunate-

Mefloquine CIPLA/DNDi

Lead

Generation

Sulfadoxine

Pyrimethamine+

Amodiaquine Guilin

New chemical

entities since

2007

New presentations

of existing

molecules

20% 50% 10%

Launch

Probability

2020+ 2018 2022+

>90%

2016

Case Study 1: Spiroindolone

New target and new compound class

Singleton “Hit”

EC50 NF54 90nM

EC50 NF54 9.2nM

Clint (hu, m) unstable

7- to 6- ring

Enantiomer

Bromo- to chloro-

EC50 NF54 0.7nM

Clint (hu, m) stable

ED90 Pb 2.7mg/kg

Fix metabolic

Instability with

halo-substitution

Science, 2010, 1175; J Med Chem 2010, 53, 5155

NITD-609

Currently in phase IIa

trials in Thailand

Case Study 2: Aminopyridine

Drug discovery built from Africa

Original hit donated by Diversity Company

Compound optimized by African led project team

Moving towards First in Human in Cape Town

EC50 NF54 49nM

Metabolic instability

EH 0.48

J Med Chem 2012, 55, 3479

EC50 NF54 51nM

Improved stability

EH 0.26

Replace hydroxy/methoxy

phenyl

EC50 NF54 25nM

EH < 0.07

Rat F: 51%

Replace methoxy

New models for lead optimisation: teams need

high quality validated starting points

New Hits to leads paradigm

Dedicated teams: medicinal

chemists, cell pharmacology

Academic and industrial

consortia

Partnering in disease endemic

countries

• India, South Africa,

Thailand, Brazil

MMV experienced Mentors

Experienced in-house project

directors

Open Access: Empowering Research

• More than 20’000 compounds in the public domain

• Researchers want ‘physical compounds’ to test

• Chose 400 compounds – based on being commercially available

• Available without restriction malariabox@mmv.org

Malaria whole cell screen

Malaria target basedassayNeglected diseases

Infectious diseases

Others

• 153 Copies shipped

• Requests by Disease Area

• Excellent exposure, oral bioavailability

• Rapid Progression of leads to in vivo models

• Mechanistic studies ongoing, target ID

• Encouraging groups to deposit/publish data

• Sharing the success with the NTD17 and beyond

J Burrows,,T Spangenberg, T Wells, P Willis etal The Malaria Box: a catalyst for drug discovery, Malaria Journal, 2012, 11, 136

Malaria Box: Catalysing neglected

disease drug discovery

Open Source: lessons learned from Malaria

Box

Drug discovery in neglected disesases has limited

access to new starting scaffolds

Early access to data on pharmacokinetics and

metabolism is key to progressing compounds

Successful projects have spun out collaborations with

research teams in disease endemic countries

Better to specifically make compounds: more

novelty, less supply issues

Start with diversity from screens against different

pathogens, not just malaria

MMV in Open Source: powering three projects

Malaria Box

(MB)

Pathogen

Box (PB)

Exploiting

the

Pathogen

Box

400 Diverse Compounds

Active against a

range of pathogens

Launches Q4 2015

Will stimulate neglected

Disease research

400 Diverse Compounds

with Antimalarial activity

Launched Dec 2012

Generated many

neglected diseases

projects

Hit series

+ biological targets

From PB

Planned start 2015

Delivers drug discovery

project opportunities