Best Science for the Most Neglected - DNDi · Best Science for . the Most Neglected ... (e.g. malaria, paediatric HIV, filarial infections) • To strengthen capacities in a sustainable
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14-15 May 2019HNN 2.0 Training "International Cooperation and L&F issues in SC1" (Warsaw, PL)
Dr. Olaf Valverde MordtHAT-r-ACC Project Coordinator
Best Science for the Most Neglected
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
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Neglected diseases affect patients worldwide
Persistence of the fatal imbalance
• 1.1% of new products for NTDs, malaria and TB
• But 12% of global disease burden
Sources: Fatal Imbalance: The Crisis in Research and Development for Neglected Diseases, MSF, 2001Pedrique B et al. The drug & vaccine landscape for neglected diseases (2000-11) Lancet Global Health, Oct 2013
• 756 products registered (excluding vaccines & biologicals)
• 1% of 336 new chemical entities approved for NTDs, malaria and TB
• 1% of 148,445 clinical trials registered for neglected diseases
1975-1999 2000-2011
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
New models to fill the gap in R&D for neglected diseases: Product Development Partnerships (PDPs)
Current PDP landscape working areas include:
• Vaccine R&D• Diagnostics R&D• R&D for new or
improved treatments
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
Origins of DNDi1999• First meeting to describe the lack of R&D for neglected diseases • MSF commits the Nobel Peace Prize money to the Drugs for Neglected
Diseases Working Group
• JAMA article: ‘Access to essential drugs in poor countries - A Lost Battle?’
July 2003• Creation of DNDi• 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
• To develop new drugs or new formulations of existing drugs for people suffering from neglected diseases.
• To develop drugs for the most neglected diseases (such as sleeping sickness, leishmaniasis, and Chagas disease), while consideringengagement in R&D projects for other neglected patients (e.g. malaria, paediatric HIV, filarial infections)
• To strengthen capacities in a sustainable manner, including through know-how and technology transfers in the field of drug R&D for neglected diseases.
• To adopt a dynamic portfolio approach
DNDi’s mission
DNDi’s PRIORITY:
Neglected Patients
PaediatricHIV
Filarialdiseases
Sleeping sickness
Chagasdisease
Leishmaniasis
MalariaMycetoma
…from bench to bedside
Responding to the needs of patients suffering from neglected diseases
HepatitisC
©Sa
'adi
aKh
an-M
SF
+ incubation with WHO of:
Address immediate patient needs & deliver innovative medicines: short- and long-term
New formulations
New indications for existing drugs
Completing registration dossier
Geographical extension
ResearchDevelopment
New chemical entities (NCEs)
Long-term projects
Translation Development Implementation
Medium-term projects
Short-term projects
> 5 years
3-5 years
1-2 years
DNDi’s success is only possible through innovative partnerships Universities& Research
Institutes
PDPs
Int. Org.& NGOsBiotechs
CROs Pharmaceutical companies
CRITERIA FOR SUCCESS Share the same vision Mutual understanding Involvement throughout the
whole process
Over 160 partnerships worldwide
Partnering and research capacity building withMoHs and national control programmes
VL
Major role of regionaldisease platforms:
• Strengthening local capacities
• Conducting clinical trials (Phase II/III studies)
• Facilitating registration
• Accelerating implementation of new treatments (Phase IV & pharmacovigilance studies)
• Defining patients’needs and target product profile (TPP)
Superbooster Therapy Paediatric HIV/TBPAEDIATRIC HIV
‘4-in-1’ LPV/r/ABC/3TC
LPV/r pellets with dual NRTI
MYCETOMA Fosravuconazole
HCV Ravidasvir/SofosbuvirRavidasvir
Screen Hit to lead
DNDi R&D Portfolio December 2018
DISCOVERY
BenznidazolePaediatric dosage form
SSG&PM Africa
New VL treatmentsAsia
Nifurtimox-Eflornithine (NECT) Combination therapy
FDC ASAQ | FDC ASMQ
LEISHMANIASIS
HAT
Lead opt. Pre-clinical Ph I Ph IIa/PoC Ph IIb/III Registration AccessTRANSLATION DEVELOPMENT IMPLEMENTATION
Leish H2LBooster
H2LDaiichi-
Sankyo LH2L
New treatmentsfor HIV/VL
New treatmentsfor PKDL
MF/Paromomycin
combo for Africa
New VL treatments
Latin America
Chagas H2LBooster H2L
Daiichi-Sankyo CH2L
CHAGAS
FILARIA
New Chemical Entity (NCE)
MALARIA
Acoziborole
FexinidazoleT.b. rhodesiense Fexinidazole
New CLcombination
Biomarkers
DNDI-5421DNDI-5610
AminopyrazolesCGH VL series 1
LeishL205 series
ChagasC205 series
MacroFilaricide 3
DNDI-6148DNDI-0690
DNDI-5561GSK3186899DDD853651GSK3494245DDD1305143CpG-D35 (CL)
Oxfendazole Emodepside
New Benzregimens +/-
fosravuconazole
Fexinidazole
SCYX-1330682SCYX-1608210
ABBV-4083
8 new treatments delivered since 2007 Easy to use Affordable Field-adapted Non-patented
2007 ASAQMalaria>500 million patients reached
2008 ASMQMalariaUsed in Africa and Asia
2009 NECTSleeping sickness100% of stage-2 patients
2010 SSG&PMVisceral leishmaniasis in E AfricaNow 1st line in all countries
2011 PAEDIATRIC BENZNIDAZOLEChagas diseaseTwo sources developed
2011 NEW VL TREATMENT ASIAVisceral leishmaniasis in AsiaSupport to disease elimination
2016 SUPERBOOSTER THERAPYPaediatric HIVRecommended by WHO
2018 FEXINIDAZOLESleeping sicknessApproved by European Medicines Agency, first all-oral treatment
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
Two phases of human disease
In the classical model HAT is characterized by two phases
Clinical progression varies from patient to patient
Haemolymphatic (early) stage Neurological (late) stage
19
HAT elimination: progress
2,164 < 1,000
32,850
26,850
24,415
20,477
17,65216,333
11,825
10,771
10,639
9,870
7,139 6,747
7,2016,314
3,797 2,8001,446
0
5000
10000
15000
20000
25000
30000
3500020
00
2001
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2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
Case
s
Year
Cases reportedCases expected
T.b.g. 98%
T.b.r. 2%
• Number of new cases reported and WHO benchmark
Chart1
328502000200032850
268502001200126850
244152002200224415
204772003200320477
176522004200417652
163332005200516333
118252006200611825
107712007200710771
106392008200810639
9870200920099870
7139201020107139
6747201120116747
7201201220127201
6314201320136314
3797201420143797
2800201520152800
2164201620162164
1446201720171446
100020182018
20192019
20202020
Cases reported
Cases expected
Year
Cases
< [VALUE]
32850
26850
24415
20477
17652
16333
11825
10771
10639
9870
7139
6747
7201
6000
6314
5500
3797
5000
2800
4500
2164
4000
1446
3500
3000
2500
2000
Sheet1
Cases reportedCases reportedCases reportedCases expected
2000328503285032850
2001268502685026850
2002244152441524415
2003204772047720477
2004176521765217652
2005163331633316333
2006118251182511825
2007107711077110771
2008106391063910639
2009987098709870
2010713971397139
2011674767476747
20127201720172016000
20136314631463145500
20143797379737975000
20152800280028004500
20162164216421644000
20171446144614463500
201810003000
20192500
20202000
Sheet1
Cases reported
Cases expected
Year
Cases
Sheet2
200020012002200320042005200620072008200920102011201220132014201520162017
T.b.gambiense258412609523799199411710015624113721046610380968069736632709162283679272921101409
T.b.rhodesiense70975561653655270945330525919015611511086118715327
Total reported328502685024415204771765216333118251077110639987071396747720163143797280021631436
2000 - 20172008 - 20172013 - 2017
T.b.gambiense2071495691116155
T.b.rhodesiense58201185355
tbg%97.27%97.96%97.85%
tbr%2.73%2.04%2.15%
Sheet3
3rd WHO stakeholders meeting on Rhodesiense HAT elimination 10-11 April 2019, Geneva
755
617
536 552
710
453
305259
150 156113 110
86118
71 5431
0
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800
2001
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2004
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2012
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2018
No.
Cas
es
Year
HAT elimination: progressionNumber of rHAT cases reported 2001-2018
T.b.gambiense
T.b.rhodesiense
(2008-2012)
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
Target product profile: • Effective in both stages• Broad spectrum (T.b. gambiense and rhodesiense)• Clinical efficacy >90% at 18 month follow up• Safe for pregnant and breastfeeding women• Adult and paediatric formulation • No need to monitor for adverse effects• Maximum 10 days orally once a day• Stability in zone 4 during >3 years• Cidal•
Sleeping sickness: two new treatments in developmentto support sustainable elimination
15 years agoMelarsoprol:Toxic, resistantEflornithine:Not available
Since 2009NECTImproved therapy
2018FexinidazoleOral treatment(10 days)
Future objectiveAcoziboroleSingle-dose, oral treatment
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
• To extend the indication of fexinidazole for the treatment of r-HAT (WP1)
• To ensure proper execution of clinical trials through strengthening capacity of treatment and care (WP2)
• To engage the local community to improve treatment access and extend case detection (WP3)
• Direct intervention• Makerere (Uganda)
Trial lead and Social Sciences
• UNHRO (Uganda) and MoH (Malawi) Trial execution and Community intervention
Partners in HAT-r-ACCDNDi Project coordination and trial management
• Training and follow up• IHMT Lisboa Medical• Swiss TPH Good
Clinical Practice• IRD France Laboratory• Epicentre France Data
management
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
3rd WHO stakeholders meeting on Rhodesiense HAT elimination 10-11 April 2019, Geneva
Kenya, 25 (0%)
Malawi, 645 (13%)
Mozambique2 (0%)
Tanzania, 1310 (26%)
Uganda, 2977 (58%)
Zambia, 123 (2%)
Zimbabwe, 30 (1%)
2001-2017
Malawi, 139 (39%)
Tanzania, 11 (3%)
Uganda, 164 (46%)
Zambia, 33 (9%)
Zimbabwe, 9 (1%)
2013-2017
5,134 cases declared 356 cases declared
Cases by country T. b. rhodesiense
33
• Neglected diseases• The PDP model• DNDi• Human African trypanosomiasis• DNDi in HAT• HAT-r-ACC• R-HAT• DNDi-FEX-07-HAT
Summary
• Protocol Number: DNDi-FEX-07-HAT• Study title: Efficacy and safety of fexinidazole in patients with
human African trypanosomiasis (HAT) due to Trypanosoma brucei rhodesiense: A multicentre, open-label clinical trial
• Design: multicentre, open-label, non-randomized• Recruitment target: 34 evaluable stage-2 r-HAT patients• Study sites :
• Lwala Hospital (Uganda)• Rumphi District Hospital (Malawi)• Patients from neighbouring Health centers: Kaberamaido/Dokolo Districts
(Uganda) and Rumphi/Mzimba North District (Malawi) and Chama (Zambia) will be transported to the sites for treatment
Clinical Trial
Ultimate Objective: To show that fexinidazole offers an alternative over melarsoprol in stage-2 r-HAT patients and over suramin in stage-1 r-HAT patients
Trial Objectives and Endpoints
• 2 years recruitment and 1-year follow-up• If the recruitment of 34 evaluable stage-2 patients is
shorter than 2 years, the duration of the study can be shortened.
• Each patient’s participation will be 12 to 13 months
Study duration
Initiation Any death -> DSMB: Futility Analysis
Follow-up visits at EOH, M1, W9, M6, EoS
End FU M12 feasibility and pre-study visits
Site close-out visits
• Principal Investigator: • Prof. Dr. Enock Matovu• Makerere University
• Coordinating Investigators:• Uganda: Charles Wamboga: Ministry of Health• Malawi: Marshal Lemerani, Ministry of Health
• Site Investigators:• Lwala (Uganda): Dr Eriatu Anthony• Rumphi (Malawi): Dr Westain Nyirenda
Investigators
DNDi thanks all the HAT donors
Thank you
Thank you
Slide Number 1SummarySummarySlide Number 4Persistence of the fatal imbalance�SummarySlide Number 7SummarySlide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16SummaryTwo phases of human disease HAT elimination: progressSlide Number 20Slide Number 21Summary�Target product profile: �Sleeping sickness: two new treatments in development to support sustainable eliminationSummarySlide Number 26Partners in HAT-r-ACC�DNDi Project coordination and trial managementSlide Number 28SummarySlide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34SummaryClinical TrialTrial Objectives and EndpointsStudy durationInvestigatorsDNDi thanks all the HAT donorsSlide Number 41
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