Ivan Scandale ISTND d 3 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
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
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