Confidential – For Celgene Internal Use Only

Tim Wells, CSO, MMV

Defeating Malaria Together

Translational and product development at MMV Bali | 11 – 12 October 2017

Confidential – For Celgene Internal Use Only

Key needs and challenges in the development of new drugs for treatment of malaria

2

highly efficacious, preferably single-

dose treatment (SERC*)

Aim: replace 3-day

treatment regimens due to poor

compliance, and prepare tools for

malaria elimination

Challenge: potent molecules to

deliver a single efficacious dose safely

and to provide post-treatment protection

combination drugs with fixed-dose

formulations

Aim: reduce likelihood of

resistance and increase patient

compliance by co-formulating 2 drugs

Challenge: drug-drug compatibility

and suitable formulation availability

early in clinical development

for children and pregnant women

Aim: address most

vulnerable populations as best and quickly as

possible

Challenge: safety data package

generation and inclusion of the target

population early in clinical development

addressing drug resistance

Aim: provide new treatment options for countries to combat drug resistance

Challenge: geographical and

population variability in clinical development

*Single encounter radical cure

Dialogue and agreement with regulatory authorities

Confidential – For Celgene Internal Use Only

Injectable Prodrug Calibr

Miniportfolio 3 series GSK

SFK59 series H3D Cape Town

DHODH backups UTSW/UW/Monash

Open Source Series University of Sydney

Purines Celgene

DHODH Broad/Eisai

Phenotypic Lead Eisai

Phe tRNA lygase Broad Institute/Eisai

Pantothenates TropIQ/RUMC

Phenotypic Lead Daiichi-Sankyo

Molecular Target DDU Dundee

Strong pipeline of molecules in development

3

Translational Product development Access Preclinical Patient

confirmatory Post approval Human volunteers

Patient exploratory

Regulatory review

Research Candidate Profiling

Lead optimisation

OZ609 Nebraska, Monash, STPHI

P218 Janssen, (Biotec Thailand)

MMV253 Zydus Cadila

M5717 Merck KGaA

AN13762 (Anacor)

UCT943 H3D Cape Town

SJ733 Kentucky/Eisai

MMV048 (UCT)

Artefenomel/ Ferroquine Sanofi

Cipargamin Novartis

KAF156/ Lumefantrine Novartis

Tafenoquine GlaxoSmithKline

Dihydroartemisinin piperaquine Paediatric Sigma-Tau/Pierre Fabre

Rectal artesunate Cipla/Strides/WHO-TDR

Dihydroartemisinin- piperaquine Sigma-Tau /Pierre Fabre

Artesunate for Injection Guilin

Pyronaridine- artesunate Shin Poong

Artesunate- amodiaquine Sanofi/DNDi

Pyronaridine- artesunate granules Shin Poong

3

2

4

Artemether- lumefantrine Dispersible Novartis

6

Sulfadoxine pyrimethamine+ amodiaquine Guilin

4

1

3

Artesunate- mefloquine Cipla/DNDi/ Farmanguinhos

SAR121 Sanofi

DSM265 Takeda (UTSW/UW/ Monash)

5

Footnotes: Included in MMV portfolio after product approval; Global Fund Expert Review Panel (ERP) reviewed product – permitted for time-limited procurement, while regulatory/WHO prequalification review is ongoing. WHO Prequalified OR approved/positive opinion by regulatory bodies who are ICH members/observers. MMV support to projects may include financial, in-kind, and advisory activities Brand names 1: Coartem® Dispersible; 2: Artesun®; 3: Eurartesim®; 4: Pyramax® tablets or granules; 5: ASAQ/Winthrop®; 6: SPAQ-COTM; * For infants 3 – 12 months, ** for children 13-60 months

Rectal artesunate Cipla/Strides/WHO-TDR

6

Sulfadoxine pyrimethamine+ amodiaquine ** Guilin

Confidential – For Celgene Internal Use Only

Injectable Prodrug Calibr

Miniportfolio 3 series GSK

SFK59 series H3D Cape Town

DHODH backups UTSW/UW/Monash

Open Source Series University of Sydney

Purines Celgene

DHODH Broad/Eisai

Phenotypic Lead Eisai

Phe tRNA lygase Broad Institute/Eisai

Pantothenates TropIQ/RUMC

Phenotypic Lead Daiichi-Sankyo

Molecular Target DDU Dundee

Strength in discovery

4

Translational Product development Access Preclinical Patient

confirmatory Post approval Human volunteers

Patient exploratory

Regulatory review

Research Candidate Profiling

Lead optimisation

OZ609 Nebraska, Monash, STPHI

Footnotes: Included in MMV portfolio after product approval; Global Fund Expert Review Panel (ERP) reviewed product – permitted for time-limited procurement, while regulatory/WHO prequalification review is ongoing. WHO Prequalified OR approved/positive opinion by regulatory bodies who are ICH members/observers. MMV support to projects may include financial, in-kind, and advisory activities Brand names 1: Coartem® Dispersible; 2: Artesun®; 3: Eurartesim®; 4: Pyramax® tablets or granules; 5: ASAQ/Winthrop®; 6: SPAQ-COTM; * For infants 3 – 12 months, ** for children 13-60 months

2-3 new candidates per year

Confidential – For Celgene Internal Use Only

Simplify therapy and fight resistance

All development compounds:

• Active against all clinical isolates

• Difficult to raise resistance in vitro

• No breakthrough in clinical studies

5

SERCaP single exposure

radical cure and prophylaxis

Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)

Long-acting post treatment prophylaxis

Kills hypnozoites

Transmission blocking

Fast clearance of parasitaemia

Confidential – For Celgene Internal Use Only

1. Building on an existing template

6

O

OO

OZ03 OZ277/ RBx11160

Reduce logP Improve solubility

O

OO

NHO

NH2

OZ439

Decrease interaction with ferrous iron (single electron)

O

O OO

OH H

H

O

OO O

N

O

Vennerstrom JL, et al. Nature 2004;430(7002):900–4 Charman SA, et al. PNAS 2011;108(11):4400–5 Toure OA Clin Infect Dis. 2016 15;62(8):964–71 (OZ277) McCarthy JS, Antimicrob Chemother;71(9):2620–7 (OZ439)

Less potent on embryos and on granulocytes Active vs artesunate resistance

Confidential – For Celgene Internal Use Only

2. Molecular Design: DHODH

7

DSM1 EC50 3D7 79 nM No oral efficacy

N

N

N

N

HN

DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mg/kg

N

N

N

N

HN

CF3

F

F

N

N

N

N

HN

SF5

FF

DSM265 EC50 3D7 8 nM ED90 Pf SCID 8.1 mg/kg

Coteron JM, et al. J Med Chem 2011;54(15):5540–61

Confidential – For Celgene Internal Use Only

3. Ask the parasite

8

Rottman M, et al. Science 2010;325:1175–80; Meister S, et al. Science 2011;334:1372–77; Gamo FJ, et al. Nature 2010;465(7296):305–10; Guiguemde WA, et al. Nature 2010;465:311–15; Wells TNC, et al., Science.2010;329:1153–54

Chemistry: All available molecules

HTS Whole parasite

Hits to leads

Identify resistance

New candidate molecules for development

Confidential – For Celgene Internal Use Only

Portfolio potential combination partners

Translational Product development Access Preclinical Patient

confirmatory Post approval Human volunteers

Patient exploratory

Regulatory review

Research Candidate Profiling

Lead optimisation

P218 Janssen, (Biotec Thailand)

MMV253 Zydus Cadila

M5717 Merck KGaA

AN13762 (Anacor)

UCT943 H3D Cape Town

SJ733 Kentucky/Eisai

MMV048 (UCT)

Artefenomel/ Ferroquine Sanofi

Cipargamin Novartis

KAF156/ Lumefantrine Novartis

SAR121 Sanofi

DSM265 Takeda (UTSW/UW/ Monash)

Footnotes: Included in MMV portfolio after product approval; Global Fund Expert Review Panel (ERP) reviewed product – permitted for time-limited procurement, while regulatory/WHO prequalification review is ongoing. WHO Prequalified OR approved/positive opinion by regulatory bodies who are ICH members/observers. MMV support to projects may include financial, in-kind, and advisory activities Brand names 1: Coartem® Dispersible; 2: Artesun®; 3: Eurartesim®; 4: Pyramax® tablets or granules; 5: ASAQ/Winthrop®; 6: SPAQ-COTM; * For infants 3 – 12 months, ** for children 13-60 months

10 new candidates, 7 new targets

9

Confidential – For Celgene Internal Use Only

Key translational platforms (1/2)

10

Confidential – For Celgene Internal Use Only

Key translational platforms (2/2)

11

3 AREA

Controlled human malaria infection (CHMI) model Collaboration with QIMR-Berghofer

Product vision • Part of single exposure radical cure • Potential for use in severe malaria

MoA • PfATP4 inhibitor

Key features

• First validated new molecular target in 20 years: very rapid killing of parasites

• 75mg human dose gives concentrations above Minimal Parasiticidal Concentration for >8 days

• Potential for transmission blocking in Standard Membrane Feeding Assay

Challenges • Safety profile to be further characterized in malaria patient study

Status • Completed first phase IIa (short-duration monotherapy PoC in patients)

Next milestone • Dose escalation study in patients

Previously • Names NITD609, KAE609: discovery

partnership with Novartis, STPHI and Wellcome

MMV Project Director • Dr Marc Adamy

NH

NH

NHO

Cl

F

Cl

Cipargamin Novartis

31 July 2017 – Interim

Product vision • Part of a single exposure radical cure • Potential for chemoprotection

MoA • Plasmodial dihydroorotate dehydrogenase (DHODH) inhibitor

Key features

• Novel mechanism of action • 400mg human dose gives concentrations

above Minimal Parasiticidal Concentration for >8 days

Challenges • Cost of goods for API, and formulation • Reduced relative activity against P. vivax • Single enzyme target; potential for resistance

Status • Phase IIa in Peru in patients with P. falciparum

or P. vivax malaria complete • Controlled Human Malaria Infection Study of

combination with OZ439 complete

Next milestone • Complete human challenge models with P.

falciparum sporozoites • Prioritise combination partner for phase IIb

Previously • Discovery Partnership with University of Texas

Southwestern, Washington University and Monash University

MMV Project Director • Dr Jörg Möhrle

N

N

N

N FF

HN

SFF

F

FF

DSM265 Takeda

31 July 2017 – Interim

Product vision • Part of a single exposure radical cure • Potential for chemoprotection

MoA • PfPI4K inhibitor

Key features

• 80mg dose predicted to give coverage above Minimal Parasiticidal Concentration for >8 days

• Good prophylactic activity against P. cynomolgi, in vivo after single dose

• Long half-life in human

Challenges • Development of new formulation reducing exposure variability

Status • Phase I and human volunteer challenge model with new formulation

Next milestone • Start of Phase IIa protocol in Ethiopia (2017)

Previously • Name MMV390048: Discovery and Phase I

partnership with H3D, University of Cape Town and South African Technology Innovation Agency

MMV Project Director • Dr Cristina Donini

N

NH2N

F

F

F

S OO

MMV048 (UCT)

31 July 2017 – Interim

Product vision • Part of a single exposure radical cure • Transmission blocking activity

MoA • PfATP4 inhibitor

Key features

• Novel chemotype for clinically validated

pathway; First validated new molecular target in 20 years: very rapid killing of parasites

• Good physical properties and developability • Predicted dose to give coverage above Minimal

Parasiticidal Concentration for over 8 days is 500mg

Challenges • Cost of goods: chiral molecule • Potential variability in human PK

Status • First in Human study recruiting

Next milestone • Complete first in human studies with three day multiple rising dose

Previously

• Name (+)-SJ000557733; Discovery Partnership

with St Judes Children’s Research Hospital, Rutgers University and US NIH

MMV Project Director • Dr Lidiya Bebrevska

N(S)

(S)

OCF3

N NH

FCN

O

SJ733 Kentucky/Eisai

31 July 2017 – Interim

Product vision • Potential for Chemoprotection

MoA • P. falciparum dihydrofolate reductase (DHFR) inhibitor

Key features • Clinically validated pathway • Activity against wild type, and antifolate

resistance-conferring quadruple mutants

Challenges • Human half-life difficult to predict • 10 fold difference between P. falciparum

and P. vivax IC50 in ex-vivo field isolates

Status • First in human study recruiting

Next milestone • Go/no go decision to initiate controlled human malaria infection cohort

MMV Project Director • Dr Emilie Rossignol

N

NH2N

NH2O O

HO O

P218 (BIOTEC Thailand)

31 July 2017 – Interim

Product vision • Part of single exposure treatment of

uncomplicated malaria • Potential for chemoprotection

MoA • P. falciparum EF2 inhibitor Novel Mechanism of Action

Key features

• Comparable activity across all stages of the malaria parasite lifecycle

• Predicted dose to give coverage above Minimal Parasiticidal Concentration for over for 8 days is 16-145mg

• Excellent transmission blocking potential

Challenges

Status • Approved by Merck for progress as pre-clinical candidate 1Q 2016

Next milestone • Initiate First in Human studies 2017

Previously • Names DDD107498; DDD498, MMV121;

Discovery collaboration with the University of Dundee Drug Discovery Unit

MMV Project Director • Dr Lidiya Bebrevska

N

F

HNO

N

NO

M5717 Merck KGaA

31 July 2017 – Interim

Confidential – For Celgene Internal Use Only

MMV’s SERC combination drug development strategy aims at early de-risking

18

Classical drug-combination

development strategy

MMV`s SERC combination drug

development strategy

• Converging development pathways between drug A and B

• Priority on adults (formulations, participants in clinical trials)

Drug A

Drug B

Combo

• Integrated development plan and testing of multiple drug-combos in pre-clinical and phase I

• Priority on vulnerable populations (treatment of children in Phase II, child-friendly formulation)

• Use of translational tools, modelling & simulation

Saves time & resources via early de-risking Satisfies FDA drug combination rule using non-

clinical and early clinical data (to be agreed)

• Potential for late-failure high sunk costs • FDA drug combination rule satisfied with

large Phase II trials

Drug A Combinations

Drug B C

D

Confidential – For Celgene Internal Use Only

Find the right partner

19

Trusted friend or beautiful stranger? Can you afford to wait for perfection?

https://plus.maths.org/content/kissing-frog-mathematicians-guide-mating

Confidential – For Celgene Internal Use Only

20

NH

NH

NHO

Cl

F

Cl

O

OO O

N

O

N

N

N

N

HN

SF5

FF

N

NH2N

SO2Me

F3C

NCl

HN N

Fe

NCl

HNN

N O

N

OHNCl

N

N

NN

N

Cl

Cl

Cl

Cl

HO

N

Older Newer Newest

NN

N

NH

O

F

F

H2N

Confidential – For Celgene Internal Use Only

Drug combination scoring tool to select drug combinations for further testing in translational models

21

1

Scoring Efficacy as SERCaP

Safety

Dev Stage

Time over MPC

Total Dose

DCS class Prophylaxis-Liver Stage Resistance

Food Effect

DDI between partners

MOA

IP Flexibility

CoG & formulation

SCID mouse and human challenge model

Confidential – For Celgene Internal Use Only

We can help choose the right one

• Combination Selection Tool

• SCID mouse data – in vivo: additivity /synergy

• Metabolic interactions: Simcyp

• Human Challenge Model

22

Confidential – For Celgene Internal Use Only

Putting the combination together

23

SINGLE STUDY: PHASE 2a/2b Drug A / Drug B Combination

Limited Dose

Finding in 2-5y

Ph2a Highest Combo

Doses in adults

Exposure Ranging

In > 12 y**

Safety Satellite in

2–12y

Safety Satellite in

0.5–2y

Drug A – Individual Agent

Phase 1a SAD + FE

Phase 1b Challenge

Drug B – Individual Agent

Phase 1a SAD + FE

Phase 1b Challenge

Satellite Study

PopPK & PKPD

Ph2b Healthy Volunteers Pre-Clinical

Ph1a: What is the maximum well tolerated dose (& dose ratio)?

Ph1b Mono: What is the initial estimated active dose range?

Ph2a Combo: Confirm minimum efficacy at maximum feasible* dose

PONV: No Go if probability of combination efficacy >95% ACPR is low at maximum feasible* dose

Ph2b: Confirm tolerability & efficacious doses/exposures across age / weight range & dosing weight bands

Ph3: Pivotal efficacy for filing

Go/No Go

Phase 1a Combo safety

SCID mouse P.f. individual

agents & combo

Phase 1b Combo

challenge

Ph1b Combo: How do individual agents work together? Demonstrate the contribution of the individual agents to overall effect of the combo. What is the initial estimated active dose range?

Dose selection rationale for Phase 3 Ph3/4: Safety & Efficacy on re-dosing

Pre-clinical Mono: & Combo Demonstrate antimalarial activity (kill rate & time to recrudescence) & contribution of individual agents to the overall effect of the combo., including potential PD interaction. Rank potential combination partners

Go/No Go (or Combination selection)

*Highest clinically feasible dose includes tolerability, Toxicology margins, dose size and potential for commercial formulation ** alternative age minimum depending on local regulations *** Dose with optimal balance of efficacy, duration & tolerabiliy PONV – Proof of non-viability

Test multiple combination partner & select best

Rank combination partners

Phase 3 Studies in Africa, Asia &

LATAM Optimal

Combination Dose vs SOC in adults

& children

Ph 3 / 4 Multiple exposures study

Ph3

Confidential – For Celgene Internal Use Only

MMV’s development strategy will allow early de-risking based on translational science*

24

2

Early-stage clinical development Pre-clinical

Pre-clinical

Late-stage clinical development

Drug A

Drug B

Combination Early clin dev

Early-stage or in combination with other drugs

Info on whether drug combo works

His

toric

str

ateg

y

Info on whether drug combos work Best combo taken forward to Ph II

* to be discussed & agreed with regulatory authorities; assuming predictive translational models & PKPD modelling

Late-stage clinical development

Translational (SCID mouse, human challenge …)

Translational (SCID mouse, human challenge, …)

Translational (SCID mouse, human challenge, …)

Drug A

Combination (A+B, A+C, …)

Futu

re s

trat

egy

Drug B C

D

Pre-clinical

Pre-clinical

Pre-clinical

HIGH cost- and resource-intensity stage LOW cost- and resource-intensity stage

Focus on individual drugs

Confidential – For Celgene Internal Use Only

Leveraging the potential of translational science, modelling & simulation will de-risk anti-malaria drug development

25

3

Historic • Limited translational

tools for prediction of efficacy

• Decision making after Phase IIb futility

Current • Combo partner ranking

at pre-clinical & Ph Ib • Earlier evidence of

clinical efficacy with lower investment Ph II (Part 1) drop combos with low probability of success

• M&S to aid dose setting & scaling in children

Future • Estimation of dose

efficacy via translational methods

• Identify combos with highest prob. of success

• Earlier derisking & lower probability of failure due to efficacy in Ph II and III

• FDA combination rules satisfied using SCID mouse &/ or human challenge model*

* To be confirmed

Optimisation

Confidential – For Celgene Internal Use Only

Model-informed drug development at MMV

26

4 C

onfidence

Preclinical package

SCID mouse data

First in human data

Non-clinical or clinical data

Modelling & simulation

Confirmation of safety & efficacy

PBPK/PD model for extrapolation to other

population (e.g. children)

Translation from mouse to human

Drop non-viable combos. Dose-

selection for Phase III

Human challenge

model data

Ph II Efficacy highest feasible dose & dose

ranging

Dose-concentration-effect relationship. Est. Day28 ACPR

PBPK

Confidential – For Celgene Internal Use Only

If you want to go fast, go alone If you want to go far, go together

27

Confidential – For Celgene Internal Use Only

The aspiration for PK/PD modelling is to be able to predict (single and combo) drug efficacy in humans

28

3

Humanized SCID mouse

Aspirational PK/PD Modelling:

Predict parasitemia profile in humans Prioritize combinations for testing in humans

Predict drug-drug interactions

Human challenge model Phase II