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

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

S

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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


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


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


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

2002

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

100

200

300

400

500

600

700

800

2001

2002

2003

2004

2005

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2007

2008

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2010

2011

2012

2013

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2015

2016

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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)


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


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


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


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

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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