1. DNDi and the Open Synthesis Network
Benjamin Perry PhD
(excerpts from original presentation)
Logo

2. Today’s talks 1. Background to DNDi (BP) 2. Leishmaniasis (BP)
3. DNDi discovery process (BP)
4. Open Synthesis Network (BP)

3. 1. Background to DNDi

4. Creation of DNDi 2003 Endemic Country Founders Founding Partners
Institut Pasteur, France
Indian Council of Medical Research, India
Kenya Medical Research Institute, Kenya
Médecins Sans Frontières
Ministry of Health, Malaysia
Oswaldo Cruz Foundation/Fiocruz, Brazil
WHO –TDR (Special Programme for Research and Training in Tropical Diseases) as a permanent observer
Intro slide – why we were created / history/ Bernard wants to modify wording
MARTA: I suggest several photos that illustrate the ‘problem’ – but they are not aligned etc.

5. DNDi’s PRIORITY: Neglected Patients
Responding to the Needs of Patients Suffering from Neglected Diseases…
© Sa'adia Khan-MSF
Hepatitis C
Sleeping sickness
DNDi’s PRIORITY: Neglected Patients
Malaria
Mycetoma
Chagas disease
Paediatric HIV
Filarial diseases
Leishmaniasis
…from Bench to Bedside

6. Treatment Limitations For Neglected Diseases Safe, Effective, Easy-to-Use Drugs Are Needed
Toxic
Painful injections
Difficult to use
Cause side effects
Sometimes high death rate with drug therapy
Expensive
Not registered in endemic regions
Poorly effective - parasites build resistance

7. 7 new treatments delivered, recommended, implemented
30 projects, 8 diseases areas
13 entirely new chemical entities (NCEs)
Over 160 partnerships, most in endemic countries
160 staff, half in endemic countries & 700 people working on DNDi projects
EUR 400 million raised equally from public and private sources
4 regional disease-specific clinical trial platforms/ networks and several technology transfers
2016
SUPERBOOSTER
THERAPY P
aediatric HIV/TB HI V
/TB
Easy to use
Affordable
Field-adapted
Non-patented

8. DNDi’s Strategy
Address Immediate Patient Needs And Deliver Innovative Medicines
New formulations
New indications for existing drugs
Completing registration dossier
Geographical extension
New chemical entities
(NCEs)
Long-
term projects
Medium-
term projects
Short-term projects
Research
Translation
Development
Implementation
Development
> 5 years
3-5 years
1-2 years

9. Universities & Research Institutes
DNDi’s success is possible
through innovative partnerships
PDPs
Int. Org.
& NGOs
Universities & Research Institutes
Biotechs
Pharmaceutical
companies
CROs
Over 160 partnerships worldwide
CRITERIA FOR SUCCESS
Share the same vision
Mutual understanding
Involvement throughout the whole process

10. Some of DNDi’s Open Innovation Projects
NTD Drug Discovery Booster
Est. 2015
Open Synthesis Network
Est. 2016
Open Source Mycetoma
Est. 2015
Anybody & Everybody!

11. 2. Leishmaniasis

12. Leishmaniasis 350 million at risk worldwide in 98 countries
Life-threatening disease transmitted by Sandflies
2 types
Visceral (VL)
fatal without treatment
Cutaneous (CL)
Skin lesions
Symptoms
prolonged fever, enlarged spleen & liver, large weight loss, progressive anemia
Elimination <1 in 10000, elimination goal for 2020
Treatment needs
Oral, safe, effective, low-cost and short-course treatment (in combo)

13. Two Major Forms of Leishmaniasis
VISCERAL FORM
400,000 cases per year
CUTANEOUS / MUCOCUTANEOUS FORMS
1.2 million cases per year
Localized
cutaneous
Diffuse
cutaneous
Muco-cutaneous
Fatal if
untreated
Emerging more Complicated Disease Forms
HIV/VL coinfection
Post-Kala Azar Dermal Leishmaniasis
Patients with chemo-immunosupression
.. And Asymptomatic Carriers

14. Leishmaniasis Visceral Leishmaniasis Cutaneous Leishmaniasis
L. donovani
L. infantum
Cutaneous Leishmaniasis
L. major
L. tropica
L. braziliensis
Elimination <1 in 10000, elimination goal for 2020

15. Drugs for Leishmaniasis - the good, the bad & the ugly
Variable efficacy, serious toxicities, only one is oral & rest are painful iv/im

16. DNDi efforts in Leishmaniasis
From Poor drugs to Effective drugs to Oral drugs

17. 3. DNDi Discovery

18. Drug Discovery Process
5-7 years +
5-7 years =
10-15 years>

19. Drug Discovery Process
5-7 years +
5-7 years =
10-15 years>

20. Drug Discovery Process
Screen
Hit to Lead
Lead Optimization
Preclinical
Output
Output
Output
«Hit» Compound
-Single compound demonstrating low-moderate anti-parasitic activity
«Hit» Series
-Collection of similar compounds, some with improved potency
«Lead» Series
- Large collection of compounds
- Optimized for Potency, PK, Pd, Tox…
1 Compound
>100 Compounds
>1000 Compounds

21. DNDi compounds in the evolving drug landscape for leishmaniasis
Lead Optimisation
Preclinical
Phase 1
Discovery
Preclinical
Phase I
DNDI-0690
(nitroimidazole)
2017
DNDI-6148
(oxaborole)
Aminopyrazole series
CGH
VL series 1
GSK /DDD (BA05 series)
GNF-6702
(proteasome inhibitor)
Candidate from DNDi discovery project
Candidate from DNDi discovery project
DNDi/Takeda discovery project
DNDi/Celgene discovery project

22. 4. Open Synthesis Network

23. Open Synthesis Network – Opportunity
Can DNDi benfit from the synthetic firepower of university training to further DNDi projects?
and
Can DNDi help and enable undergraduate and postgraduate medicinal chemistry training through exposure to active projects
Open Synthesis Network

24. DNDi - Centralised biological and physicochemical screening
Open Synthesis Network – The Idea
DNDi Medicinal Chemistry Challenge
e.g. Improve metabolic stability of a drug hit
University Partners
Synthetic Chemistry Exercise
Select one or more compounds to synthesise as under/post graduate exercise
Small Team of Medicinal Chemists
Propose a number of compounds to
test different hypotheses.
Medicinal Chemistry Exercise
Option to design and synthesise additional compounds
DNDi - Centralised biological and physicochemical screening
DNDi
Combined data posted in public domain
Medicinal Chemistry Teaching Resource
DNDi
Incorporate data into research
Contribution to public health initiative
Open Synthesis Network

25. Open Synthesis Network – 2016-2017

26. Open Synthesis Network – Project 1
Based around Aminopyrazole series
Annotating SAR avenues previously put on hold
Started Oct 2016
Building chemical probes for use in MoA studies
Starting Jan 2017
Open Synthesis Network

27. Open Synthesis Network – Web Portal
Access to Web Portal to be provided for Imperial College collaborators in coming weeks
Open Synthesis Network

28. Questions ?
Open Synthesis Network