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Ivan Scandale
Swiss TPH Winter Symposium 7 December 2017
DNDi Helminth 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
Screening: S. mansoni A. ceylanicum & T. muris
F 3 CN
N
ON
N
Cl
S N
NHN
HN N
S
N
MMV668309 in vivo: 58% S. masoni reduction
• Sanofi (aprox. 1000 cpds): repositioning library • S. mansoni: 17 hits with IC50 in micromolar range (structures not disclosed)
• MMV (aprox 400 cpds): • T. muris & S. mansoni: 3 hits with IC50 in micromolar range
• Epichem (aprox 50 cpds): Chagas program (CYP51 inhibitors) • T. muris & S. mansoni: 5 hits with IC50 in micromolar range
• Commercial library of FDA approved drugs
• Several starting points to conduct lead optimization have been identified
EPL-BS0431 in vitro: IC50 = 6.46 µM S. masoni
MMV011522 in vivo: 100% T. muris reduction
N H2
N
NNCl
Filarial Portfolio
Filarial Screening based on a repurposing strategy
Compound providers
Emodepside ABBV-4083
O
O
N
N
NS
O
O
N
O
O
N
O
O
N
O
O
O
N
O
N
O
O
O
O
N
O
A·WOL
ABBV-4083 Emodepside
Oxfendazole
Oxfendazole
Lead Optimization
H
OH
O O
OH
H
F
O
OO
O
NO
O
O
O
O
O
OMe
OMe
CHO
1 preclinical candidate 1 back-up
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
O
N
O
O
N
O
O
N
O
O
O
N
O
N
O
O
O
O
N
O License to Bayer
Efficacy emodepside (L. sigmodontis in jird)
V e h i c le F B Z 2 m g / k g s c E M O 5 d 1 0 m g / k g E M O 1 0 d 1 0 m g / k g
0
5 0
1 0 0
1 5 0
nu
mb
er
of
wo
rms
* *
p = 0 . 0 0 1 2
* *
p = 0 . 0 0 1 7
M i c r o f i l a r e m i a
Be f o
r e
2 4 h p
t
4 wk s p
t
8 wk s p
t
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
MF
/10
µl
In vitro1
1 Kulke et al. 2017 ASTMH
Tylosin Analogue Macrofilaricde ABBV-4083 • 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 program conducted by:
Analogues:
A-1535469
A-157083
O
N
H
OH
O O
OH
H
O
OO
O
NO
O
O
O
O
O
OMe
OMe
CHO
H
OH
O O
OH
H
F
O
OO
O
NO
O
O
O
O
O
OMe
OMe
CHO
CHO
OMe
OMe
H
O
O O
OH
H
O
OO
O
NO
O
O
O
O
O
Efficacy ABBV-4083 (L. sigmodontis in jird)
Microfilariae
11 w
pi
12 w
pi
13 w
pi2 w
pt3 w
pt4 w
pt5 w
pt6 w
pt7 w
pt8 w
pt9 w
pt
10 w
pt
11 w
pt
12 w
pt
13 w
pt
14 w
pt
15 w
pt1
10
100
1000
10000
ABBV-4083 100mg/kg 14d QDFBZ 2mg/kg 5d QDDoxy 40mg/kg 14d BIDUntreated
MF/
10µl
blo
od +
1
Treatment start
Adult Worm Wolbachia Levels 16wpt
Untreate
d
Doxycy
cline 4
0mg/kg
14d B
ID PO
AABV-4083
100m
g/kg 14
d QD PO
0.0001
0.001
0.01
0.1
1
1010.6
-99.72
FtsZ
/Act
in
Treatment MF negative animals 15wpt
Doxycycline 0/5
A-4083 6/6
Treatment MF negative animals 15wpt
Untreated 0/5
FBZ 3/3
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
Efficacy oxfendazole (L. sigmodontis in jird)
A d u l t w o r m b u r d e n J i r d s
Un
t re a t e
d
Do
x y 40 m
g/ k
g 1
4 d B
I D
FB
Z 2
mg
/ kg
5d
QD
Ox f
2 5 mg
/ kg
10 d
BI D
Ox f
1 2 . 5m
g/ k
g 1
0 d B
I D
Ox f
5 mg
/ kg
10 d
BI D
0
2 0
4 0
6 0
8 0
1 0 0
Wo
rms
[to
tal
co
un
t]
M i c r o f i l a r i a e
1 1 wp
i
1 2 wp
i
1 3 wp
i
2 wp
t
3 wp
t
4 wp
t
5 wp
t
6 wp
t
7 wp
t
8 wp
t
9 wp
t
1 0 wp
t
1 1 wp
t
1 2 wp
t
1 3 wp
t
1 4 wp
t
1 5 wp
t
0 . 1
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
O x f 2 5 m g / k g 1 0 d B I D
O x f 1 2 . 5 m g / k g 1 0 d B I D
O x f 5 m g / k g 1 0 d B I D
F B Z 2 m g / k g 5 d Q D
D o x y 4 0 m g / k g 1 4 d B I D
U n t r e a t e d
MF
+1
/10
µl
blo
od
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 µM Solubility > 0.01mg/ml at pH 7.4 Metabolic Stability: medium or high Permeability: 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 target species)
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/PD established
Reduction of adult worms > 70%
In vitro, in vivo safety profiling
Celgene program 75
Efficacy (L. sigmodontis in jird)
14
A d u l t w o r m b u r d e n g e r b i l
Un
t re a t e
d
FB
Z 2
mg
/ kg
5d
QD
Co
mb
ou
nd
D 3
0 mg
/ kg
10 d
QD
Co
mp
ou
nd
D 3
0 mg
/ kg
5d
QD
Co
mp
ou
nd
B 3
0 mg
/ kg
10 d
BI D
0
2 0
4 0
6 0
Re
co
ve
red
ad
ult
wo
rms
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
1 1 wp
i
1 2 wp
i
1 3 wp
i
2 wp
t
3 wp
t
4 wp
t
5 wp
t
6 wp
t
7 wp
t
8 wp
t
9 wp
t
1 0 wp
t
1 1 wp
t
1 2 wp
t
1 3 wp
t
1 4 wp
t
1 5 wp
t
1 × 1 0 - 1
1 × 1 0 0
1 × 1 0 1
1 × 1 0 2
1 × 1 0 3
1 × 1 0 4
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 Bruncko Kevin Cusack Karla Drescher Tom von Geldern Herve Geneste Paul Jung Joe Kalcsits Dale Kempf Kennan Marsh Shaun McLoughlin Marc Scanio Irini Zanze
Sabine Specht Frederic Monnot Ivan Scandale
Stacie S. Canan, Natalie A. Hawryluk, Vikram Khetani
Andrew Freeman Simon Townson Suzanne Gokool
Dominique Blömker Achim Hoerauf Sabine Specht Marc Hübner
Nathaly Coralie Martin
Hongjuan Liu Jia Wang MeijingWang Zhongyuan Wang Songling Yu Jingyu Zhang Zhyuan Zhang
Gemma Molyneux Laura Myhill Gemma Nixon Nicolas Pionnier Raman Sharma Hanna Sjoberg Andrew Steven Mark Taylor Joe Turner Hayley Tyrer Stephen Ward David Waterhouse Ghaith Alijayyoussi Andy Cassidy Ana Castro Guimaraes Rachel Clare Darren Cook Susie Crossman Jill Davies Louise Ford Joanne Gamble Laura Hayward Kelly Johnston Susan Jones
THANK YOU TO ALL OUR
PARTNERS & DONORS
by
D0 3 months post infection 9-12 weeks post
treatment
Begining of tratment
Worm recovery & analysis - parasite numbers - microfilariae counts
Patency
Randomization (weight, mf)
Jird model of filariasis: Litomosoides sigmodontis
When the treatment begins, patency is established: Adult worms are fully mature and produce microfilariae
Natural infection or Transplant or Injection of mf
L4
Ad
L1
