Ivan Scandale

ISTND d3

May 16-17th 2017

Wellcome Trust London

Update of

DNDi’s

Filarial portfolio

Origins of DNDi

1999• First meeting to describe the lack of R&D for neglected diseases

• MSF commits the Nobel Peace Prize money to the DND Working Group

• JAMA article: ‘Access to essential drugs in poor countries - A Lost Battle?’

July 2003• Creation of DNDi

Brazil

India

Kenya

Malaysia

USA

DRC

Japan

Geneva

Headquarters

7 offices worldwide

Founding Partners

• Indian Council for Medical

Research (ICMR)

• Kenya Medical Research

Institute (KEMRI)

• Malaysian MOH

• Oswaldo Cruz Foundation, Brazil

• Médecins Sans Frontières (MSF)

• Institut Pasteur France

• TDR (permanent observer)

Research

Development

Translation Development Implementation

> 5 years

3-5 years

1-2 years

Long-

term

projects

• New chemical

entities (NCEs)

• New formulations

(fixed-dose

combinations)

• New indications of

existing drugs

• Completing

registration dossier

• Geographical

extension

DNDi Portfolio-Building Model: Address Immediate Patient Needs & Deliver Innovative Medicines

Medium-

term

projects

Short-

term

projects

Filarial diseases

Lymphatic filariasisLoiasis Onchocerciasis

Wuchereria bancrofti

Brugia spp.Onchocerca volvulusLoa loa

Filarial Portfolio

Filarial Screening based on a repurposing strategy

Compound providers

EmodepsideABBV-4083

A·WOL

ABBV-4083 Emodepside

Oxfendazole

Oxfendazole

Lead Optimization

Lead Optimisation

LO

Emodepside

• Anthelmintic veterinary drug for cats and dogs in combination with praziquantel(Profender®) and in combination with toltrazuril (Procox®).

• Emodepside showed remarkable in vivo and in vitro activity against a variety of filarial nematodes including O. volvulus.

• DNDi has an agreement with Bayer to develop emodepside for the treatment of onchocerciasis

License to Bayer

Tylosin Analogue Macrofilaricde (TylAMac)• Tylosin is a macrolide antibiotic used as food additive in veterinary medicine

• Tylosin targets the endosymbiont Wolbachia bacterium present in O. volvulus and W. bancrofti. This causes:

Inhibition of fertility (absence of microfilariae)

Possible macrofilaricide activity

• Tylosin is poorly bioavalible:

Optimization programconducted by:

Analogues:

A-1535469

A-157083

Oxfendazole

• Oxfendazole is a benzimidazole, anthelmintic treatment for farm and domestic animals.

• Oxfendazole is potent in vivo against a variety of filarial nematodes (L. sigmodontis, B. malayi, A. viteae)

• A Phase I trial evaluating safety and pharmacokinetics of oxfendazole is ongoing for two inductions:

Neurocysticercosis. Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Tenia Solium Infection. Sponsor: Johns Hopkins Bloomberg School of Public Health

Batch 1

50 mg

Batch 2

Mouse:200 mg

Jird:800 mg

in vitro efficacy

// Cytotoxicity

O. Gutturosa

Adult worm (male)

Parameters:

• Motility

• MTT

No toxicity at 10 µM or SI (cells/worms) > 5X

EC50 ≤ 1 µM EC50 ≤ 1 µMSolubility > 0.01mg/ml at pH 7.4Metabolic Stability: medium or highPermeability: medium or high

in vitro ADME / Chem. Charact.

in vivo ADME

Achievable plasma levels above EC50 for 24 hours

in vivo efficacy

L. sigmodontis

Adult worm

Parameters:

• Motility

• MTT

O. Lienalis

microfilariae

Parameters:

• Motility

Monkey kidney cells Feeder cell layer

Solubility, logD, permeability (MDCK-MDR1), protein binding, metabolism in liver microsomes (human + in vivo targetspecies)

In vivo mouse or jird pharmacokinetic profile at < 50 mg/kg

Exposure in mouse

Dosing groups overlap with in vivo study

Mouse or jird model

(L. sigmodontis)

< 50 mg/kg BID

Reduction of adult worms > 70%No toxicity

Mouse or jird model

(L. sigmodontis)

Dose –response

At least three dose groups

PK/PDestablished

Reduction of adult worms > 70%

In vitro, in vivo safety profiling

Celgene program

75

In vivo Data: Gerbil L. sigmodontis Model

11

A d u l t w o r m b u r d e n g e r b i l

Un

t re

at e

d

FB

Z 2

mg

/ kg

5d

QD

Co

mb

ou

nd

D 3

0m

g/ k

g 1

0d

QD

Co

mp

ou

nd

D 3

0m

g/ k

g 5

d Q

D

Co

mp

ou

nd

B 3

0m

g/ k

g 1

0d

BI D

0

2 0

4 0

6 0

Re

co

ve

re

d a

du

lt w

or

ms

M i c r o f i l a r i a e b u r d e n g e r b i l

11

wp

i

12

wp

i

13

wp

i

2 w

pt

3 w

pt

4 w

pt

5 w

pt

6 w

pt

7 w

pt

8 w

pt

9 w

pt

10

wp

t

11

wp

t

12

wp

t

13

wp

t

14

wp

t

15

wp

t

1 1 0- 1

1 1 00

1 1 01

1 1 02

1 1 03

1 1 04

C o m p o u n d D 3 0 m g / k g 1 0 d Q D

C o m p o u n d D 3 0 m g / k g 5 d Q D

C o m p o u n d B 3 0 m g / k g 1 0 d B I D

F B Z 2 m g / k g 5 d Q D

U n t r e a t e d

MF

+1

/10

µl

blo

od

Acknowledgments

Milan BrunckoKevin CusackKarla DrescherTom von GeldernHerve GenestePaul JungJoe KalcsitsDale KempfKennan MarshShaun McLoughlinMarc ScanioIrini Zanze

Rob DonFrederic MonotIvan Scandale

Stacie S. Canan,

Natalie A. Hawryluk,

Vikram Khetani

Andrew FreemanSimon Townson Suzanne Gokool

Dominique BlömkerAchim HoeraufMarc Hübner

Coralie Martin

Hongjuan LiuJia WangMeijingWangZhongyuan WangSongling YuJingyu ZhangZhyuan Zhang

Gemma MolyneuxLaura MyhillGemma NixonNicolas PionnierRaman SharmaHanna SjobergAndrew Steven Mark TaylorJoe TurnerHayley TyrerStephen WardDavid WaterhouseGhaith AlijayyoussiAndy Cassidy Ana Castro GuimaraesRachel ClareDarren CookSusie CrossmanJill DaviesLouise FordJoanne Gamble Laura Hayward Kelly JohnstonSusan Jones

THANK YOU TO ALL OUR

PARTNERS & DONORS

by

Hepatitis

C

DNDi’s PRIORITY:

Neglected

Patients

Paediatric

HIV

Filarial

diseases

Sleeping

sickness

Chagas

disease

Leishmaniasis

MalariaMycetoma

…from Bench to Bedside

Responding to the Needs of Patients Suffering from Neglected Diseases…

© S

cott

Ne

lso

n f

or

The

Ne

w Y

ork

Tim

es

In vivo Data: Murine L. sigmodontis Model

15

veh

icle

FB

Z-S

igm

a 2

mg

/kg

SC

7033019 3

x30m

g/k

g

7033021 3

x30m

g/k

g

0

1 0

2 0

3 0

4 0

5 0

Re

co

ve

re

d A

du

lt W

orm

s

* *

80%red

56%red

Reduction of Adult Worms

5 days of dosing

100%red

FBZ SC2 mg/kg

B3x30 mg/kg

C3x30 mg/kg

vehicle

98%red

93%red

10 days of dosing

100%red

un

treate

d

FB

Z-S

igm

a 2m

g/k

g Q

D 5

d S

C

7033019 3

0m

g/k

g T

ID 1

0d

7011002 3

0m

g/k

g B

ID 1

d

0

2 0

4 0

6 0

8 0

p < 0 .0 5

p < 0 .0 1

p < 0 .0 0 1

Re

co

ve

re

d A

du

lt W

orm

sFBZ 5d SC2 mg/kg

E3x30 mg/kg

vehicle C3x30 mg/kg

Compound E (Ser A)

O. gutt EC50 = 27nM 1 day dosing

Compound B (Ser A)

O. gutt EC50 = 270nM

O. lien EC50 =3100nM

Compound C ( Ser B)

O. gutt EC50 = 699nM

O. lien EC50 >12500nM

In a decade of R&D, 6 new treatments delivered

• 30 projects, 6 diseases areas

• 15 entirely new chemical entities (NCEs)

• Over 130 partnerships, most in endemiccountries

• 150 staff, half in endemic countries & 600 people working on DNDi projects

• Over EUR 350 million raised equallyfrom public and private sources

• 3 regional disease-specific clinical trial platforms and 2 technology transfers

Easy to use Affordable Field-adapted Non-patented