Drug development and evaluation.pdf

8/11/2019 Drug development and evaluation.pdf

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ANNUAL REPORT 2009

TDR BUSINESS LINE 6

Drug development and evaluationfor helminths and other

neglected tropical diseases


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Copyright World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases 2010

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Design: Lisa Schwarb Layout: Bruno Duret

Cover Pictures: WHO/TDR/Kuesel. Photo caption: Before (left) and after (right) construction of a clinical trial centre in Butembo,

Nord-Kivu, Democratic Republic of the CongoPrinted by the WHO Document Production Services, Geneva, Switzerland


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DRUG R&D FOR HELMINTHS AND OTHER NEGLECTED TROPICAL DISEASES BL6

3TDR BL6 2009 Report

Table of contents

List of tablesTable 1. Definition of terms .......................................................................................................................5

Table 2. HNR portfolio composition in 2009 by disease and strategic objectives ......................................14

Table 3. HNR portfolio planned for 2010 by disease and strategic objectives ...........................................15

Table 4. HNR projects, end products and expected outcomes .................................................................. 16

Table 5. Overview of clinical studies financed and managed by HNR in 2009 .........................................20

Table 6. Overview of capacity building conducted by HNR in 2009 ........................................................21

Table 7. Financial implementation 20082009 ........................................................................................22

Table 8. Expenditures by objective-disease matrix defined by HNR SAC 2009(Provisional as of data in GSM on 31 December 2009) ................................................................ 22

Table 9. Approved budget 20102011 ..................................................................................................... 24

Table 10. New projects initiated by HNR in 2009 ...................................................................................... 25Table 11. Progress and key achievements ................................................................................................... 26

TDR/BL6.10

List of abbreviations .........................................................................................................................4

Overview and highlights ................................................................................................................7

Background .............................................................................................................................................7

Strategic objectives ..................................................................................................................................7

Key activities in 2009 ..............................................................................................................................7Collaborations and leverage ...................................................................................................................10

1. Context, strategic objectives and framework ............................................................11

1.1 Context ...........................................................................................................................................11

1.2 Strategic objectives .........................................................................................................................12

1.3 Strategic framework ........................................................................................................................12

2. Key stakeholders, roles and responsibilities ................................................................20

3. Implementation plan 20082013 and progress ..........................................................21

3.1 Scope of activities in 20082009 ....................................................................................................21

3.2 Plan, progress and key milestones ...................................................................................................27

4. Leverage and contribution to empowerment and stewardship .........................404.1 Leverage .........................................................................................................................................40

4.2 Contribution to overall capacity building and stewardship activities ..............................................40

5. Critical issues and suggested solutions ...........................................................................41

6. Annexes............................................................................................................................................42

6.1 Overview of Moxidectin Development Plan and Status ...................................................................42

6.2 List of publications from HNR-funded or HNR-managed research ..................................................43

6.3 SAC membership ............................................................................................................................44

6.4 HNR projects, end products and expected outcomes .....................................................................45


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4 TDR BL6 2009 Report

DRUG R&D FOR HELMINTHS AND OTHER NEGLECTED TROPICAL DISEASESBL6

List of abbreviations

ALB Albendazole

ANC Antenatal clinic

APOC African Programme forOnchocerciasis Control

APW Agreement for Performance of Work

BENEFIT Benznidazole Evaluation ForInterrupting Trypanosomiasis

BL6 (HNR) Drug Development and Evaluation forNeglected Tropical Diseases

CD Chagas disease

CDI Community directed interventions

CDTI Community directed treatment withivermectin

CIR Community based interventions

CL Cutaneous leishmaniasis

DEC Diethylcarbamazine

DENCO Dengue control clinical study

DNDi Drugs for Neglected Diseasesinitiative

DQR Quality assured diagnostics

EC Ethics committee

EMEA European Medicines Agency

FDA Food and Drug Administration

FIND Foundation for Innovative Diagnostics

GCLP Good Clinical Laboratory Practice GCP Good Clinical Practice

GPELF Global Programme to EliminateLymphatic Filariasis

HAT Human African trypanosomiasis

HNR Drug Development and Evaluation forNeglected Tropical Diseases (BL6)

IV Intravenous

IVM Ivermectin

LF Lymphatic filariasis

MDA Mass drug administration

MMV Medicines for Malaria Venture

MoH Ministry of Health

MPR Anti-Malarial Policy & Access

NTD Neglected tropical disease

OCRC Onchocerciasis ChemotherapyResearch Centre

O.v. Onchocerca volvulus

OXQ Oxamniquine

PCR Polymerase chain reaction

PZQ Praziquantel

R&D Research and development

SAC Strategic and Scientific AdvisoryCommittee

SAE Serious adverse events

SoP Standard operating procedure

SPT Special Project Team advisorycommittee for projects requiringspecial expertise and/or more intenseongoing involvement of externalexperts than can be provided by theSAC (SPTs are in place for moxidectindevelopment, ivermectin responsemarkers research and Chagas diseaseprojects)

STAC Scientific and Technical AdvisoryCommittee

STH Soil transmitted helminths

TCC Technical Consultative Committee

TDR Special Programme for Research andTraining in Tropical Diseases

VL Visceral leishmaniasis

VLR Visceral leishmaniasis elimination

WHO World Health Organization


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Table 1. DEFINITION OF TERMS

Biomarker A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes,

pathogenic processes, or pharmacologic responses to a therapeutic intervention (Biomarkers Definitions

Working Group 1998).

Development Studies on the pharmacokinetics, safety and efficacy of a drug or drug combinations in humans aimed at

determining whether the drug or drug combination studied has the clinical target product profile required

for submission of a dossier for a decision on use of the drug or drug combination outside clinical trials (via

registration and/or recommendation of expert committees).

Development track

decision

Decision to initiate the studies required for a decision to conduct the first study in humans.

This decision includes recommendations on the types of studies required before the clinical studies for the

targeted indication can be initiated. The types of non-clinical and clinical safety studies required will depend

on the development and regulatory history of the drug candidate or combination of drug candidates.

Lead Compound efficacious in disease animal model with no overt toxicity and with characteristics potentiallysuitable for cost-effective scale-up.

Lead optimized Optimized lead compound with in vitro and in vivo activity, pharmacokinetic and toxicity profile potenti-

ally consistent with target product profile, and amenable to cost-effective scale-up of manufacturing can

be evaluated for development track decision.

Pharmaco-

epidemiology

The study of the use and effects of drugs in large numbers of people. [The importance of pharmacovi-

gilance. Safety monitoring of medicinal products, WHO 2002 (http://www.who.int/medicinedocs/collect/

edmweb/pdf/s4893e/s4893e.pdf)]

Pharmacology Science of drugs, including their composition/formulation, uses, pharmacokinetics, pharmacodynamics,

pharmacotherapeutics and toxicology

Pharmaco-surveillance

Regular monitoring of medications in real clinical practice for benefits and harms ( http://www.hc-sc.gc.ca/hcs-sss/pharma/nps-snpp/securit/guide_gloss-eng.php )

Pharmaco-

vigilance

The science and activities relating to the detection, assessment, understanding and prevention of adverse

effects or any other drug related problems Specific aims are to:

improve patient care and safety in relation to the use of medicines and all medical and paramedical

interventions;

improve public health and safety in relation to the use of medicines,

contribute to the assessment of benefit, harm, effectiveness and risk of medicines;

encouraging their safe, rational and more effective (including cost-effective) use; and

promote understanding, education and clinical training in pharmacovigilance and its effective

communication to the public.

[The importance of pharmacovigilance. Safety monitoring of medicinal products, WHO 2002 (http://www.

who.int/medicinedocs/collect/edmweb/pdf/s4893e/s4893e.pdf)]

All scientific and data gathering activities relating to the detection, assessment, and unders-

tanding of adverse events (FDA Guidance for Industry Good Pharmacovigilance Practices and

Pharmacoepidemiologic Assessment, March 2005, http://www.fda.gov/Cder/guidance/6359OCC.pdf)

For guidelines, see :

EMEA: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-9/pdf/vol9a_09-2008.pdf

FDA: http://www.fda.gov/Cder/guidance/6359OCC.pdf

ICH: http://www.ich.org/LOB/media/MEDIA1195.pdf

Pre-development Non-clinical safety studies required (e.g. by regulatory authorities) for a decision to conduct the first study

in humans.


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Risk management Iterative process of (1) assessing a products benefit-risk balance, (2) developing and implementing tools

to minimize its risks while preserving its benefits, (3) evaluating tool effectiveness and reassessing the

benefit-risk balance, and (4) making adjustments, as appropriate, to the risk minimization tools to furtherimprove the benefit-risk balance. [(USA) Food and Drug Administration. Guidance for Industry Good

Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005 (http://fda.gov/Cder/

guidance/6359OCC.pdf)].

Risk management

plan

EMEA terminology: Consists of safety specifications, a pharmacovigilance plan, an evaluation of the need

for risk minimization activities and, if there is a need for additional (i.e. non-routine pharmacovigilance

practices) risk minimization activities, a risk management plan..

Synergy In contrast to the classical definition that includes the concept that the whole is greater than the sum

of the individual parts, synergy is used here to refer to collaboration between different units within

TDR which is expected to yield a better result or a more efficiently obtained result than if each unit was

pursuing the work separately.

Target product

profile

Summary of pharmaceutical, efficacy and safety properties a drug or drug combination requires for its

intended indication.


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Overview and highlights

Background

Neglected tropical diseases (NTDs) generate

morbidity and mortality in poverty-stricken

populations. They are regarded as a public health

priority for the World Health Organization (WHO).The WHO strategy includes:

1. Innovative and Intensified Disease Management

for diseases for which cost-effective control

interventions do not exist for wide-scale use (the

so-called tool-deficient diseases).

2. Preventive Chemotherapy and Transmission

Control which uses available drugs often

distributed to populations in combination to

prevent morbidity and/or reduce transmission

(the so-called tool-ready diseases)In either case, few drugs are available and these

are under-researched in general there is little

information on their mechanisms of action, and

their dosage regimens are based on insufficient

pharmacokinetic and pharmacodynamic data.

Furthermore, their extended use carries the risk

of drug resistance developing. Therefore, new

or improved drugs and more knowledge of the

pharmacology and the effects of the use of those

currently available is required to support both

strategies.

Strategic objectives

These considerations have informed the

definition of the strategic objectives of HNR (drug

development and evaluation for neglected tropical

disease BL6):

(1) Development, registration and field evaluation

of new drugs, and

(2) Generation of evidence to optimize the use of

available drugs for NTDs.

Key activities in 2009

Refinement of scope and portfolio:

Following the recommendations of the TDR

Scientific and Technical Advisory Committee

(STAC) in 2009, (see section 6.4), the scope and

portfolio of activities for the coming years were

redefined by the HNR Strategic and Scientific

Advisory Committee (SAC) with input from the

WHO/Neglected Tropical Diseases department and

other key partners to cover two specific objectives:

1. Development, registration and field evaluation of

new drugs for NTDs including identification ofsuitable development candidates and initiation of

development (or fostering the development) of

selected candidates.

2. Generation of evidence for improved use of

currently available drugs for NTDs:

a. Pharmacology and improved use of current

drugs;

b. Pharmaco-epidemiology in support of disease

control;

c. Markers and methods for evaluation of

treatment effects.

Highlights of current activities

The final data of three studies became available in

2009:

Initial lymph node and vessel pathology

can be reversed if lymphatic filariasis (LF) is

treated in childhood with a combination of

diethylcarbamazine plus albendazole. The

first-ever study in children with parasitological

or immunological signs of Brugia malayiinfection


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conducted in India shows that mass drug

administration not only affects transmission,

but also has the potential to have effects ondevelopment of pathology.

Albendazole treatment is not effective in

reducing the risk of severe adverse reactions to

ivermectin in areas of co-endemicity of loiasis with

onchocerciasis and/or lymphatic filariasis. These

continue to slow down implementation of CDTI

(Community Directed Treatment with Ivermectin)

in onchocerciasis-loa loa co-endemic areas and

prevent the implementation of mass treatment for

LF in LF-onchocerciasis-loa loa co-endemic areas.

A four-country study in intestinal schistosomiasis

showed no differences in safety and efficacy

between 40 and 60 mg/kg of praziquantel. These

results support the current WHO policy dose

recommendation (40mg/kg).

Interim results of the ongoing 18-country validation

of the new evidence-based classification of dengue

disease show that physicians value its user-

friendliness and support for clinical management

and triage decisions particularly during disease

outbreaks. Three countries adopted the revisedclassification in their national guidelines.

The Phase 2 study of moxidectin in Ghana was

completed and the Phase 3 study initiated in the

Democratic Republic of the Congo and Liberia.

Further details are provided below by disease and

HNR objective.

1. Development, registration and

field evaluation of new drugs forNTDs

Onchocerciasis and lymphatic filariasis

Moxidectin development Phase 2 completed,

Phase 3 started.Ivermectin does not sterilize or

kill the adult O. volvulus. Transmission could be

interrupted with a macrofilaricidal or macrofilaria

sterilizing drug; such a drug must be safe for

mass treatment. HNR is evaluating moxidectin

(a drug from animal health) for this indication in

collaboration with Wyeth Pharmaceuticals (Pfizer

as of October 2009). In 2009, two studies managed

by HNR were active in addition to three other

pharmacology studies sponsored by the commercial

partner. The phase 2 trial completed post-treatmentfollow-up at the Onchocerciasis Chemotherapy

Research Centre (OCRC) in Hohoe, Ghana, in

November 2009. The pivotal phase 3 study (to enrol

1500 patients) was initiated in April 2009 in Liberia

and in December 2009 in two sites in the Democratic

Republic of the Congo. Initiation in Ghana is

awaiting national regulatory approval. In preparation

for the trial, three new clinical research centres in

the Democratic Republic of the Congo and Liberia

were built or renovated and equipped; the research

teams were trained in Good Clinical Practice (GCP)and Good Clinical Laboratory Practice (GCLP) at the

OCRC by the OCRC staff and TDR staff.

2. Generation of evidence for

improved use of currently

available drugs for NTDs

Onchocerciasis and lymphatic filariasis

Markers for evaluation of effect of ivermectin in

Onchocerca volvulus a north-south collaborativeproject stimulated and under evaluation.Control

of onchocerciasis depends on one single drug

(ivermectin) and is thus vulnerable to parasite

resistance. Should resistance occur, early detection

is currently not possible as its molecular basis is not

known and markers are not available. At the request

of the African Programme for Onchocerciasis

Control (APOC) in 2009, TDR engaged

investigators in Africa, Australia and Canada to

develop a joint proposal addressing both research

and capacity building needs. Four of five invitedproposals were received and are undergoing review

by the responsible Special Project Team.

Pharmacology and improved use of current

drugs for lymphatic filariasis trial shows clinical

benefits of treating children.The first-ever study

in children with parasitological or immunological

signs of Brugia malayiinfection completed the

planned follow-up period in 2009. The data showed

that diethylcarbamazine (DEC) and albendazole

given twice a year can reverse early lymph node and

vessel pathology. This provides proof-of-concept


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that administration of the drugs used by the Global

Programme to Eliminate Lymphatic Filariasis

can provide benefits beyond the interruption oftransmission (Shenoy et al. 2009).

Pharmacology and improved use of albendazole

treatment of loiasis tested albendazole regimens

cannot make ivermectin distribution safer in areas

of loiasis co-endemicity.CDTI for onchocerciasis

control cannot be deployed in the standard way

in areas where loiasis coexists because of toxic

reactions induced by ivermectins killing of loa loa

microfilariae. Ivermectin (IVM) could be safely

used if the loa loa parasite load were reduced. The

clinical study in Cameroon determining the effect

of two different albendazole treatment regimens

on loa loa microfilarial loads completed follow up

in 2009. The results show that neither regimen

can reduce loa loa microfilaraemia enough to

allow implementation of standard CDTI in loiasis

co-endemic areas.

Schistosomiasis

Pharmacology and improved use of

praziquantel in schistosomiasis trials support

WHO recommended regimen for intestinal

schistosomiasis.The dose of praziquantel for

treating intestinal schistosomiasis is not clearly

established. A multi-country study (800 subjects in

Brazil, Mauritania, the Philippines and the United

Republic of Tanzania) compared the safety and

efficacy of 40 versus 60 mg/kg of praziquantel.

In 2009 databases from the four trial sites were

harmonized and analysed both individually and

combined to generate an evidence-base for dosage

recommendations. There was no difference between

the two regimens and the current WHO policy

recommendation (40mg/kg) can be applied.

Leishmaniasis

Anthropometric database of patients with visceral

leishmaniasis (VL) multi-country database shows

that malnutrition is common and provides basis for

country-tailored drug cost calculations.The basic

demographic and anthropometric characteristics of

VL patients have not been investigated systematically.

In 2009, clinicians from south Asia, east Africa and

Brazil contributed nearly 30 000 patient data the

first database of this kind. Analysis of these data

showed marked differences across countries

and high proportions of malnourished patients,requiring control programmes to deliver nutritional

supplements. The database also allows general and

country-tailored estimates for drug and supplement

procurement and costs.

Clinical trial methods for cutaneous leishmaniasis

(CL) treatments experts design standardized

protocol. Studying treatment effects in CL is

complex. The lack of standardized methods makes

collation of study results and recommendations

difficult. In 2009 WHO/NTD and TDR/HNR

hosted a workshop of experts which developed astandardized protocol for CL.

Human African trypanosomiasis (HAT)

Improved use of eflornithine in stage 2 human

African trypanosomiasis (HAT) study completed

and analysis under way.Treatment for stage 2 HAT

by intravenous infusion of eflornithine 4 times a day

(each infusion taking 2 hours) is cumbersome and

difficult, particularly in remote areas. The NECT

(Nifurtimox-Eflornithine Combination Therapy)

phase 3 study in Uganda was conducted to evaluatean alternative treatment that would be as effective

as standard eflornithine while being cheaper, safer

and easier to administer. This study completed

follow-up in June 2009 and the database is under

preparation for analysis, aiming for a report by the

second quarter of 2010. This study will complement

existing information which supported the granting

of Essential Medicine status to NECT (filed by the

Drugs for Neglected Diseases initiative, DNDi).

Improved use of pentamidine for stage 1 HAT

trial recruiting.Current treatment of stage 1

HAT is by daily injections of pentamidine for one

week or more. This treatment is potentially toxic

and is impractical in field conditions; the drug

pharmacokinetics support a shorter treatment. The

ongoing study is comparing the safety and efficacy

of a three-day pentamidine regimen against the

standard seven-day regimen. In 2009, intensive

consultations with the WHO control programme

(NTD) and DNDi confirmed that this study is still a

priority for all stakeholders. An active partnership

was established with DNDi to speed-up and


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complete recruitment by the end of 2010. Due to

financial constraints and major investments in other

HAT-related programmes DNDi is unable to takepart in this study. HNR remains committed to the

study sites and patients and is identifying options

to complete the study in the most cost-effective and

responsible manner.

Chagas disease

Standardized PCR based method for clinical

diagnosis of Chagas disease method to be

tested in routine conditions.A multi-country

study generated a standardized methodology for

polymerase chain reaction (PCR) for diagnosis

of infection with T. cruzi. In 2009, plans for the

evaluation of this standardized method in different

settings and stages of infection were established

jointly with WHO/NTD and a preliminary proposal

was received and assessed by the SAC.

Dengue

New method for classification of dengue

new classification adopted by countries and

undergoing validation. In 2009, validation of

the new evidence-based classification of dengue

disease into three levels of severity was initiated

in 18 countries. Interim results show that dengue

physicians appreciate the new classification because

of user-friendliness, decision support for clinical

management and triage particularly during disease

outbreaks. Three countries adopted the revised

classification in their national guidelines.

Collaborations and leverage

Towards a TDR-wide approach to pharmaco-epidemiology.Pharmaco-epidemiology and

pharmacovigilance concern various business

lines (BLs) in TDR. In 2009, HNR initiated

discussions with the TDR research units for

Anti-malarial Policy and Access (MPR), Visceral

Leishmaniasis Elimination (VLR) and Community

Based Interventions (CIR) to evaluate strategies to

collect pharmaco-epidemiology/pharmacovigilance

information on drugs used for disease control.

Ongoing collaborations within and outside

WHO. Discussions with the Department ofNeglected Tropical Diseases (WHO/NTD), along

with the HNRs SAC, contributed to defining

the priority research agenda and identifying

specific research projects. HNR also has a long-

standing collaboration under a Memorandum of

Understanding with APOC.

HNR works with regional and country offices, as

well as in a project specific manner with researchers

in developing and developed countries, non-profit

organizations and the pharmaceutical industry.Leveraging contributions through interactions.

WHO/TDR support has attracted and leveraged

pharmaceutical company funding, free supplies

of study drugs and equipment, national control

programme support and infrastructure for clinical

trials, with the help and support of WHO country

and regional office staff.

Influencing high-level strategic framework.

In 2009, HNR contributed to the WHO-wide

interaction with the G8. Along with WHO/NTD,

HNR participated in activities which led to NTDs

being addressed in the final declaration of the G8

summit 2009 and various initiatives of the Italian

presidency to raise the profile of NTDs.


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For both groups of diseases, methods and systems

to monitor efficacy, safety, effectiveness and

potential emergence of resistance are needed.TDR is well positioned to undertake the work

required, based on its track record in drug

development and evaluation, its networks of

investigators and institutions and its history of

donor resourcing for this area of work.

1.2 Strategic objectives

The objectives defined in the 20082013 Business

Plan are:1. Development and registration of new drugs

for onchocerciasis, lymphatic filariasis,

schistosomiasis and other helminthiasis and field

evaluation of their effectiveness.

2. Generation of evidence for improved use of

currently available drugs to support disease

control, elimination or eradication strategies

for NTDs with emphasis on integrated disease

management or prophylactic chemotherapy

including:

Optimizing treatment regimens of available

drugs (efficacy and safety), including drug

combinations;

Assessing the efficacy and safety profiles of

drugs co-administered in mass distribution

programmes for different diseases;

Evaluating product safety and efficacy in

special populations (children and pregnant

women).

3. Development of products for other neglected

diseases when an opportunity emerges and no

other organization is available or is prepared to

undertake it.

In reviewing HNR activities, STAC in 2009

recommended to redefine the mission/objectives with

SAC input and to identify TDR/HNR added value (see

Section 6.4). A STAC-mandated special objective for

20092010 was thus to redefine HNR mission and

objectives with the end-product being a document

including a situation analysis, identifying research

needs in support of control and defining how HNRshould organize work to address those needs. HNR

objectives and priority activity areas were reviewed

in the context of the overall NTD control needs with

contributions from WHO/NTD and considering themandates of other relevant partners.

This situation analysis was completed in 2009,

and will lead to the completion in 2010 of a

modified business plan taking into account both

the priorities/areas of focus as per HNR SAC advice

and TDR and HNR financial and human resources.

Further information on the response to STAC

requests is provided in Section 6.4.

1.3 Strategic framework

The HNR SAC recommended to focus new HNR

activities as described below. An overview of the

foci of activities is provided in Table 2and Table 3

for 2009 and 2010, respectively.

Development, registration and

field evaluation of new drugs (for

short: New Drugs for NTDs)

For:

a) Onchocerciasis, lymphatic filariasis, soil-

transmitted helminthiasis, schistosomiasis,

foodborne trematodes and dengue.(These

diseases, unlike such diseases as visceral

leishmaniasis, African trypanosomiasis and

Chagas disease, do not have dedicated public

private partnerships to promote and support

drug development.)

b) Other neglected tropical diseases when the need

arises (e.g. diseases or indications not covered bydedicated organizations).

Activities include identification of drug

development candidates, transitioning from

pre-development into development, registration

and validation for use in the field, i.e. determination

of safety and effectiveness of the drugs in real-life

settings.

This work is conducted in partnership with

institutions from developed and developing

countries (private or public), including bio/pharmaceutical companies when relevant.


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HNRs work requires the building and strengthening

of local capacities and close interaction with disease

control programmes, health systems and regulatoryauthorities in developing countries.

The efficiency of the drug research and

development (R&D) process for the NTDs suffers

from the absence of reliable estimators of treatment

effects. We intend to contribute research on

methods and biomarkers to optimize and expedite

the process, hence potentially curtailing times and

costs of R&D (see 2c below).

Generation of evidence for

improved use of currentlyavailable drugs for NTDs (forshort: Treatment optimization &Biomarkers)

This activity supports the control strategies,

including both integrated, intensified disease

management (leishmaniasis, African and American

trypanosomiasis, dengue) and prophylactic

chemotherapy (helminths).

This activity is further subdivided into three areas:

a) Pharmacology and improved use of currentlyavailable drugs: The dosing regimens used for

treating many of the NTDs are often based on

incomplete pharmacological, efficacy and safety

information, and in many instances do not

address differences related to gender (especially

pregnancy), age or ethnicity.

Improved knowledge of the basic pharmacology

of these compounds is particularly important

as these drugs are often given concomitantly

for different diseases (drug mass administration

for integrated disease control) and may also becombined with other drugs for improved efficacy

(e.g. schistosomiasis, soil-transmitted helminths).

The availability of such information is essential to

optimize the use of currently available drugs, to

reduce the probability of resistance or to scale up

their use.

b) Pharmaco-epidemiology in support of disease

control: There is minimal information on

adherence (by prescribers and users) and

effects (efficacy, safety, effectiveness, resistance)

of interventions when used in real life. Thesedata are essential to optimize the impact of

interventions. However, methods (including

pharmacovigilance) to collect and analyse the

relevant data are imperfect and not adapted tothe conditions of use.

New paradigms need to be designed, tested and

optimized especially for community directed

interventions.

c) Markers and methods for evaluation of treatment

effects:Monitoring the effects of interventions is

particularly important when they are deployed

at the population level as resistance may occur.

Surrogate markers are also important to expedite

and optimize drug R&D. The additional benefit

will be improved case management with lesscumbersome tests for the patient.

Biomarkers for these diseases and standardized

methods for assessment of treatment effects for

many of these diseases need to be discovered

and validated.

Strategic considerations (including needs,

opportunities and resources) will guide the choice

of either of two management options: (i) direct

involvement management/funding of projects;

or (ii) playing a role in stimulating/fostering andproviding expertise in research projects.

The decision as to whether a new project should be

included in the HNR portfolio must weigh up the

resource implications, needs of ongoing projects

and the potential of innovative approaches to result

in a paradigm shift in NTD control strategies.

Furthermore, HNR needs to have sufficient

flexibility to address unanticipated control

programme issues.

Table 4presents an overview of all end-products

and expected outcomes for all ongoing projects

by strategic objective and disease. The portfolio

includes two clinical studies initiated before 2008

and not central to the current business line focus:

Clinical studies in Human African

Trypanosomiasis (NECT study). The follow-up

of the NECT study has been completed in 2009.

Final data are expected in 2010.

A three day pentamidine study; HNR will

continue to seek options towards completingenrolment as soon as possible.


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Table 2. HNR PORTFOLIO COMPOSITION IN 2009 BY DISEASE AND STRATEGIC OBJECTIVES

Diseaseactive in 2009

New drugsfor NTDs

Treatment optimization and biomarkers

Pharmacology& improved useof current drugs

Pharmaco-epidemiologyin support of

disease control

Markers & methodsfor evaluation oftreatment effects

Onchocerciasis/

LF

Moxidectin for Oncho

(Phase 3)

Drug develop-

ment candidate

identification

Eect of ALB on loa loa

microfilaremia

Eect of ALB+DEC on

LF in children

Pharmaco-

epidemiology/vigi-

lance in community

directed interventions

(Planning)

Markers of response

of O.v.to ivermectin

DEC patch for detec-

tion of O.v.infection

Schistosomiasis L-praziquantel

Drug develop-

ment candidate

identification

PZQ-OXQ combination

Praziquantel dose

comparison

Systematic reviews

(urinary & intestinal)

Dossiers on drugs in

use

STH Drug develop-

ment candidate

identification


use

HAT Nifurtimox + eorni-

thine (NECT) for 2nd

stage

Pentamidine short

treatment for 1st stage

Chagas disease Benznidazole

(BENEFIT)

Validation of PCR

protocol for Chagas

diagnosis in the clinic

Leishmaniasis Standardization of

methods for Dx and

TxFU of cutaneous

leishmaniasis

Dengue Drug develop-

ment candidate

identification

Validation of new

disease classification


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Table 3. HNR PORTFOLIO PLANNED FOR 2010 BY DISEASE AND STRATEGIC OBJECTIVES

Diseaseactive in 2009

New drugsfor NTDs

Treatment optimization and biomarkers

Pharmacology& improved useof current drugs


disease control

Markers & methodsfor evaluation oftreatment effects

Onchocerciasis/

LF

Moxidectin for Oncho

(Phase 3)

Drug develop-

ment candidate

identification

Eect of ALB+DEC on

LF in children

Pharmaco-

epidemiology/vigi-

lance in community

directed interventions

Markers of response

of O.v.to ivermectin

Schistosomiasis L-praziquantel

Drug develop-

ment candidate

identification

PZQ-OXQ combination

Systematic reviews

(urinary & intestinal)


use

STH Drug develop-

ment candidate

identification

Dossiers on drugs in use

Improved benzimidazoles

HAT Nifurtimox+eornithine

(NECT) for 2nd stage

Pentamidine short

treatment for 1st stage

Chagas disease Benznidazole (BENEFIT) Validation of PCR

protocol for Chagas

diagnosis in the clinic

Biomarkers of treat-

ment effect

Leishmaniasis Standardization of

methods for Dx and

TxFU of cutaneous

leishmaniasis

Biomarkers of treat-

ment effect

Dengue Drug develop-

ment candidate

identification

Validation of new

disease classification


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BL strategic objectives Disease Project

1. New drugs for onchocerciasis, LF, STH,

schistosomiasis, foodborne trematodes

and dengue

Onchocerciasis/LF Moxidectin for onchocerciasis (and

lymphatic filariasis)

Schistosomiasis L-praziquantel for schistosomiasis

Helminths, dengue Drug development candidates for helminths

and dengue

2. Generation of evidence for improved

use of currently available drugs (treat-

ment optimization and biomarkers)

All Dossiers on drugs currently used for NTDs

2a. Pharmacology and improved use of

current drugs

LF Therapeutic eect of albendazole +

diethylcarbamazine (DEC) in children with

lymphatic filariasis

Onchocerciasis / LF Efficacy of albendazole in reducing loa loa

microfilaremia

Schistosomiasis

Combination of praziquantel and oxam-

niquine for schistosomiasis

Eective and safe dose of PZQ for Tx of

schistosomiasis

Systematic reviews in urinary and intestinal

schistosomiasis

Leishmaniasis Anthropometric database on patients with

visceral leishmaniasis from different endemic

areas

Chagas disease Benznidazole for the treatment of patients

in the late indeterminate or early chronic

phase of T. cruzi infection (BENEFIT)

Table 4. HNR PROJECTS, END PRODUCTS AND EXPECTED OUTCOMES

Projects initiated/planned in 2009 are indicated in italics


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End products Expected outcomes

(i) Clinical data from Phase 2 and 3 trials to assess

whether moxidectin meets target product profile for

registration (2011)

(ii) community study data on effect on onchocerciasis

transmission and safety during mass treatment (2015)

(i) Filing by manufacturer for registration

(ii) EMEA scientific opinion (Art 58)

(iii) registration by concerned endemic countries

(iv) distribution and use in control programmes

(v) recommendation on use by control programmes

(vi) change of onchocerciasis control objective from elimina-

tion of onchocerciasis as a public health problem to eradica-

tion of infection

Data to assess whether enantiopure L-praziquantel meets

target product profile for registration (2015)

(i) Filing by manufacturer for registration and/or list of essen-

tial drugs; (ii) registration/adoption by concerned endemic

countries.

Dossier on each potential candidate, expert evaluation, and

recommendation on transition into pre-clinical or clinical

development

Initiation of preclinical or clinical development, if indicated (with

or without HNR direct involvement)

(i) Compilation of non-clinical & clinical data publicly avail-

able for each drug used for treatment of NTDs (20102012)

(ii) Expert assessment for risks for flagging to disease

control programmes, design of studies to test and optimize

pharmaco-epidemiology/vigilance for NTDs, identification/

prioritization of HNR research (20102013)

Identification of research questions for treatment optimiza-

tion studies. Risk management plans established by WHO

disease control programmes and/or national disease control

programmes

Clinical evidence of the safety and efficacy in curing and

reversing lymphatic lesions in children infected with

Brugia malayi(20092012)

Lymphatic filariasis control programmes include cure of

infection and regression of early lymphatic lesions in children

(currently aiming only at interruption of transmission)

Proof of concept of efficacy of albendazole against loa loa

(2009)

Accelerated expansion of IMV use against onchocerciasis,

implementation of IV + ALB treatment in LF-loiasis co-

endemic areas

Data to assess the merits of drug combination for

schistosomiasis treatment (2011)

Adoption by schistosomiasis control programme as a means

to prevent emergence of drug resistance

Data to assess the safety and efficacy equivalence of 40

mg and 60 mg of praziquantel for Tx of schistosomiasis

(2009)

Use by national schistosomiasis control programmes for

decision on dose to be used

Evidence base for research and treatment policy recom-

mendations for schistosomiasis (2010)

Use of results to inform research priority setting and treat-

ment recommendations

Anthropometric database of patients with VL from all

endemic regions

Use of results to inform general and country-tailored drug

procurement strategies and complementary interventions (e.g.

nutritional)

Safety and efficacy (clearance of parasites -PCR) in the

chronic phase of T. cruzi infection in BENEFIT pilot (2010)

Contribute to a large multicentre study to demonstrate

reduction of risk of cardiac disease onset and progression in

T. cruziinfected individuals after Tx with benznidazole.

Change of treatment guidelines.


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BL strategic objectives Disease Project

2a. Pharmacology and improved use ofcurrent drugs (Type F)

Human Africantrypanosomiasis

Nifurtimox and eflornithine regimen(NECT) for the treatment of 2nd stage HAT

Three-day pentamidine treatment regimen

for 1st stage HAT

2b. Pharmaco-epidemiology in support

of disease control

Diseases controlled via

preventive chemotherapy

Testing and optimization of systems for

pharmaco-epidemiology/vigilance for com-

munity directed interventions

2c. Markers and methods of evaluation

of treatment effects

Onchocerciasis

Molecular markers of O. volvulus response

to ivermectin and tool for surveillance of

ivermectin response by control programmes

Transdermal delivery of diethylcarbam-

azine-citrate (DEC patch) as a diagnostic

tool for onchocerciasis

Chagas disease Standardized PCR for diagnosing Chagas

disease in the clinic

Dengue Revised dengue classification and updated

case management guide

Leishmaniasis Standardization of methods for diagnosisand evaluation of treatment effect

Projects initiated/planned in 2009 are indicated in italics

See also Section 6.6


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End products Expected outcomes

Data validating a 10-day regimen as providing efficacyequivalent to that of the standard 14-day eflornithine

treatment (2010)

Adoption by HAT control programmes, complement informa-tion which supported Essential Medicine status for NECT,

reduced workload for health systems, more acceptable

treatment for patients

Data validating the efficacy and safety of a three-day

regimen over the currently recommended seven-day

regimen (1Q 2013)

Adoption of a shorter pentamidine Tx course by control

programmes, improving compliance, reducing Tx related

complications and health system workload

New method(s) to collect safety, efficacy and resistance data

adapted to the conditions of use for community directed

intervention in countries where health systems are insuf-

ficiently developed

Provide control programmes with additional data to define

a surveillance plan and with methods to implement for

monitoring drug safety, efficacy and resistance. Contribute to a

better knowledge of drug effects (adverse events, efficacy and

resistance) and then a better use of the drug.

Three African laboratories with the infrastructure and

personnel capacity to participate in validation of molecular

markers (2011), Molecular markers indicative of the

response of O. volvulus to ivermectin (2012), Tool suitable for

large scale onchocerciasis control programme surveillance

(2014), Three African laboratories with the infrastructure

and personnel capacity to use the surveillance tool (2014)

Adoption of tool by onchocerciasis control programmes

Data from clinical and field studies showing that the DEC

patch can diagnose O. volvulus infection, is safe and suf-

ficiently specific (2008). Legal agreement between WHOand manufacturer on availability of DEC patch to WHO at

cost (2009)

Adoption by onchocerciasis control programmes as

epidemiological tool in data collection to assist in the

decision on when and where to stop ivermectin treatmentin areas with long-term onchocerciasis control and

surveillance post treatment discontinuation

Availability of DEC patch to control programmes at cost

Standardized and validated protocol for use of poly-

merase chain reaction (PCR) in the clinic to detect T. cruzi

Adoption as the standard for use in patient management,

blood screening, drug development and as reference meth-

odology for the development of new PCR kits

Clinical evidence to validate an improved dengue clas-

sification and case management guide (2010)

Adoption of a new dengue classification for better patient

identification and case management

A surrogate marker of treatment efficacy to reduce time forinitial determination of cure Improved case management; reduced clinical trial time andpossibly R&D time


20/48



2. Key stakeholders,

roles and responsibilities

The main stakeholders are the WHO Department

for the Control of Neglected Tropical Diseases

(WHO/NTD), disease control programmes on

an international and national level, not-for-profit

organizations and industry.

The international disease control programmes

include: the African Programme for Onchocerciasis

Control (APOC) and the Global Programme for

the Elimination of Lymphatic Filariasis. National

stakeholders include control programmes for

schistosomiasis, dengue, Chagas disease, African

trypanosomiasis, onchocerciasis and lymphatic

filariasis. These stakeholders play a pivotal role in

highlighting the needs and gaps in tools, in linking

TDR with key national institutions such as national

drug regulatory agencies and researchers, and in

advocating for increased research funding.

HNR works closely with not-for-profit organizations

such as the Drugs for Neglected Diseases initiative

(DNDi), whose mandate is to discover and develop

new drugs for diseases caused by trypanosomatids

[visceral leishmaniasis (VL), human African

trypanosomiasis (HAT) and Chagas disease].

While avoiding duplications (HNR is not involved

in drug R&D for these diseases), we collaborate

and complement work, in particular to facilitate

R&D (e.g. research for biomarkers) and optimizeimplementation of new tools.

HNR depends very much on partnerships with the

pharmaceutical industry to accomplish product

development and regulatory approval. These

partners provide expertise, hands-on activities and

financial contributions.

Research centres and experts from developing and

developed countries are key partners as advisors,

disease experts, and in implementation of research

activities.

In addition to the donors who provide undesignated

funding to TDR as a whole, the African Programme

for Onchocerciasis Control, Bayer, the EUs Sixth

Framework Programme, GlaxoSmithKline, LTS

Lohmann Therapie-Systeme, sanofi-aventis, the

Wellcome Trust, The World Bank, and Wyeth

Pharmaceuticals (now Pfizer) contributed cash orin-kind support.


21/48



3.1 Scope of activitiesin 20082009

Overview of portfolio

An overview of the portfolio has been providedin the context of the strategic framework where

Table 2shows an overview of HNR activities in

2009 by strategic objective and disease in the matrix

defined with the HNR SAC and Table 3shows the

scope of activities planned for 2010 in line with

STAC recommendations for the definition of new

strategic objectives and contingent upon availability

of funds for implementation.

Clinical studies

HNR continues to be a central player inTDR-sponsored clinical trials and is managing

clinical studies that involve 26 countries and 34

principal investigators around the world(Table 5).

Infrastructure and personnel capacity

building

Because study subject requirements are a major

driver of clinical study site selection, HNR is a

central player in TDR-sponsored capacity-building

activities including development of new health

research and health systems infrastructure as well

as personnel capacity. Total investment in 2009 was

US$ 3.2 million. Table 6provides a summary of

these activities.

Financial and human resource analysis

The budget originally assigned to HNR for the

biennium 20082009 was US$ 8.55 million,

revised to US$ 7.86 million in June 2009, and

the amount made available was US$ 6.53 million.

Table 7shows the provisional implementation rates(expenditures) with respect to the latter.

3. Implementation plan20082013 and progress


22/48



Disease Number/type ofstudies

CountriesNumber

ofsubjects

Number ofprincipal

investigators

Number of healthprofessional staff

(total staff)

Onchocerciasis /

LF (loa loa)

1 Phase 2 clinical trial

moxidectin for oncho

(one site)

Ghana 172 1

Democratic Republic

of the Congo 14 (23),

Democratic Republic

of the Congo 16 (28),

Ghana 18 (40),

Liberia 9 (16)

1 Phase 3 clinical trial

of moxidectin for

oncho (three countries,

4 sites)

Democratic Republic

of the Congo, Ghana,

Liberia

172/1500 4

1 clinical field study of

effect of ALB on loa loa(one site)

Cameroon 60 1 3

Schistosomiasis 4 clinical trials Brazil, Mauritania, the

Philippines, United

Republic of Tanzania.

800 4

1 clinical trial Sudan 1

STH

HAT 1 phase III clinical trial Uganda 109 1 (2 sites) 20 (10 per site)

1 phase III clinical trial Uganda 100 1 (2 sites) 20 (10 per site)

Chagas disease 1 clinical trial Argentina, Brazil,Colombia.

3

Leishmaniasis

Dengue 18 18 countries (Argentina,

Bolivia, Brazil, Colombia,

Cuba, Ecuador, El

Salvador, India,

Indonesia, Malaysia,

Mexico, Nicaragua,

Paraguay, the

Philippines, Puerto Rico,

Saudi Arabia, Singapore,Venezuela.)

NA 18 36

Table 5. OVERVIEW OF CLINICAL STUDIES FINANCED AND MANAGED BY HNR IN 2009


23/48



Table 6. OVERVIEW OF CAPACITY BUILDING CONDUCTED BY HNR IN 2009

Table 7. FINANCIAL IMPLEMENTATION 20082009 PROVISIONAL AS OF DATA IN GSM ON 31 DECEMBER 2009

Country(project) Infrastructure building

Personnel capacity building

(project)

Liberia (1 site)

Democratic

Republic of the

Congo (2 sites)

Ghana (1 site)

(Moxidectin

Phase 3)

New research centre built (Liberia, 1 site in Democratic

Republic of the Congo) or buildings unused since the war

renovated to serve as research centre (1 site in Democratic

Republic of the Congo)

Provided to sites in Liberia and Democratic Republic of the Congo:

All clinical, ophthalmological and laboratory equipment

required to conduct Moxidectin Phase 3 study

Oce equipment (4 computers, 1 photocopier, 1 scanner,

1 projector per site)

Two 13 seaters, 0-1 pick-up, 2-10 motorbikes per site

2-3 generators, fuel reserve tanks/site Satellite based internet connection

Provided to OCRC in Ghana: upgrade of laboratory and

ophthalmological equipment, subject accommodation and

transport, satellite based internet connection

Total investment: US$ 2.8 million

GCP training, clinical and ophthalmological

standard operating procedures (SOPs) for all

study team members

GCLP training, laboratory SOPs for all

laboratory staff

Practical training on conduct of GCP

compliant study from Informed Consent

taking via screening, treatment and

treatment follow up through OCRC staff

during observation of conduct of Phase 2

study for key study team members in Liberiaand Democratic Republic of the Congo

Total investment: US$ 0.3 million

Uganda

(Pentamidine

3 days vs 7 days).

1 car provided to both studies (NECT and Pentamidine),

1 generator, 2 microscopes, centrifuge, laptop, printer,

rehabilitation of beds, renovation of ward

Total investment: US$ 70 000

Training of the research team on Good

Clinical Practice

Lab technician trained on HAT diagnosis

Total investment: US$ 4600

18 countries None Dengue clinical training courses (two days each)

Title

JCB approvedbudget

20082009US$ 121 million

A

Fundsavailable

B

Expenditures20082009

C

Implementationas a % of funds

availableD

BL6 Drugs for Helminths/NTDs

8 550 000 6 530 000 5 707 425 87%

New drugs for helminths 6 888 639 4 702 248

Improved use of drugs 1 166 455 507 907

Products for other NTDs 416 205 425 675

Coordination 78 701 71 595


24/48



Disease activein 2009

New drugsR&D

Treatment optimization

Coor-dination

Pharmacology& improved

use of currentdrugs


disease control

Markers &

methods for

evaluation of

treatment effects

Onchocerciasis/

LF

4 562 754 77 759 0 1 978

71 595

Schistosomiasis 107 556 0 0 0

STH 0 0 0 35 375

HAT 0 439 736 0 0

Chagas disease 0 14 874 0 0

Leishmaniasis 0 0 0 0

Dengue 0 0 0 395 798

Total 5 707 425

Table 8. EXPENDITURES BY OBJECTIVEDISEASE MATRIX DEFINED BY HNR SAC 2009

PROVISIONAL AS OF DATA IN GSM ON 31 DECEMBER 2009

Table 9. APPROVED BUDGET 20102011

TitleJCB-approved budget 20102011

US$ 121 million

Development and registration of new helminth drugs 6 300 000

Evidence for improved use of currently available drugs 1 010 000

Development of products for other NTDs 390 000

Coordination 160 000

Total BL6 - Drug development and evaluation for helminths

and other neglected tropical diseases

7 860 000


25/48



Table 8shows the breakdown of implementation

(expenditures) in 2008/2009 by strategic objective

and disease according the new SAC-revised

work plan.

Fig. 2compares the planned budget breakdownacross the different strategic objectives of HNRbased on the US$ 7.86 million revised budget to theactivities that could be conducted with the availableUS$ 6.53 million (expenditures + encumbrances).

Funds made available in 20082009 were

US$ 6 530 000 (76% of the US$ 8 550 000approved budget). The figures reported in Tables7and 8are the provisional expenditures (vs. totalobligations of US$ 6 480 408, i.e. 99.2% of theavailable funds) reflected in the data. Moxidectindevelopment accounts for 80% of expenditures.

An additional related project is research forbiomarkers reflecting response of O. volvulustoivermectin. Both of these projects are primarilyfinanced by designated funding obtained from

Wyeth Pharmaceuticals/Pfizer and under thebipartite agreement between TDR and the AfricanProgramme for Onchocerciasis control.

Fig. 3shows the personnel resources available forHNR projects and the fraction of time they spent ondifferent projects by strategic objective and disease.Note that the FTEs available (2.12 G and 2.39P staff FTEs) are lower than the number of staff

assigned to HNR. The reason for one G and two Pstaff not being 100% in HNR is that they are alsoworking on a project assigned to another BL.

HNR human resources are insufficient to ensurethat projects can be advanced as quickly asnecessary and consistent with the originallyestablished timelines for the projects (see section 5,Critical issues and suggested solutions).

Fig. 2. (b) 20082009 obligations (expenditures + encumbrances)

based on available funds (US$ 6.53 million)

Fig. 3. HNR personnel resources available expressed as FTEs

(full time equivalents)

Fig. 2. (a) HNR budget breakdown as planned based

on budget reduction in June 2009 (US$ 7.86 million)

New drugs R&D - moxidectin;$5,600,000

New Drugs R&D - Other;$150,000

Pharmacology & improveduse of current drugs;

$450,000

Coordination;$160,000

Markers & Methodsfor evaluation of

treatment effects;

$1,200,000

Pharmaco-epidemiologyin support of disease control;

$300,000

New drugs R&D - moxidectin;$5,173,326

New Drugs R&D - Other;$119,183

Pharmacology & improveduse of current drugs;

$663,516

Coordination;$71,605

Markers & Methods for evaluationof treatment effects;

$452,781

Pharmaco-epidemiologyin support of disease control; $0

0.00

0.20

0.40

0.60

0.80

1.00

P. Edmonson

E. Chapin

V. Robert

P. OlliaroA. Kuesel

O. Lapujade

A. Kroeger


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3.2 Plan, progress and keymilestones

3.2.1. Overview of new projects

initiated in 2009

In 2009, six new projects and activities were

initiated in line with the redefined strategic focus as

recommended by STAC and the HNR SAC and as

summarized in Table 10.

3.2.2. Progress and milestones bystrategic objective

Objective 1: Development, registration and

field evaluation of new drugs (New drugs for

NTDs)

Development of moxidectin for onchocerciasis and

lymphatic filariasis.

Principal Investigator: Dr Kwablah Awadzi,

Onchocerciasis Chemotherapy Research Centre

(OCRC), Hohoe Hospital, Hohoe, Ghana.

TDR project manager: Dr Annette Kuesel.

Moxidectin (a macrocyclic lactone registeredworldwide (including the United States of America,

USA) for prevention of canine heartworm and

treatment of parasites in cattle, sheep, and horses)

has been developed since 2000 in collaboration

with Wyeth Pharmaceuticals Pharmaceuticals

(now Pfizer). The objective is to see whether

moxidectin has the macrofilaricidal/macrofilaria

sterilizing properties and is a safe enough drug to

be administered through the community directed

mechanism to cure the patient and permanently

interrupt transmission of the disease. Thisdevelopment programme is supported by the

APOC.

Nonclinical study results and clinical data

obtained to date support clinical trials for the oral

administration of moxidectin in subjects 4 years.

Up-to-date complete animal safety data has been

compiled, a suitable tablet formulation has been

developed and 5 clinical pharmacology studies in

healthy volunteers have either been completed or

successfully enrolled in Europe. Phases 2 and 3 are

being conducted in endemic countries. The goal of

Objective / area of HNR focus Projects initiated in 2009

1) New drugs for onchocerciasis, lymphatic

filariasis, soil-transmitted helminthiasis, schis-

tosomiasis, foodborne trematodes and dengue

Identification of potential drug candidates for helminths

2) Treatment optimization & biomarkers Dossiers compiling publicly available data for drugs currently

used for NTDs as a basis for decisions on further activities/

prioritization (e.g. risk-identification and guidance for pharmaco-

epidemiology/vigilance activities)

2a) Pharmacology and improved use of current

drugs

Anthropometric database on patients with visceral leishmaniasis

from different endemic areas

2b) Pharmaco-epidemiology in support of

disease control

Framing of development of methods for pharmaco-epidemi-

ology/vigilance in community directed interventions

2c) Markers and methods of evaluation of

treatment effects

Molecular markers of O. volvulusresponse to ivermectin and tool

for surveillance of ivermectin response by control programmes

Standardization of methods for diagnosis and evaluation of treat-

ment effect in cutaneous leishmaniasis

Table 10. NEW PROJECTS INITIATED BY HNR IN 2009


27/48



this initiative is to obtain a Scientific Opinion from

the European Medicines Agency (EMEA) according

to article 58 and subsequent approval for use by the

endemic countries (targeted for 2013). Deployment

as a validated control tool could occur by 2015.

If results for onchocerciasis are encouraging,development for lymphatic filariasis will be

considered. An overview of the development plan is

presented in section 6.1.

Progress and key achievements (2008)

EMEA scientic advice on preclinical and clinical

development strategy and plan obtained.

Milk excretion study initiated (by Wyeth

Pharmaceuticals).

Phase 2 study enrolment completed (N=172).

Phase 3 study site infrastructure and personnel

capacity building initiated in Liberia and

Democratic Republic of the Congo.

Go decision for initiation of Phase 3 study with 8

mg dose, submission of clinical study protocol to

Ethics Committee (EC) in Liberia and Democratic

Republic of the Congo (08/08), clinical trial

application and import permit request submitted

to Liberia and Democratic Republic of the Congo,

ministries of health (MoH).

Phase 3 study authorization from Liberia (EC,

MoH, Import permit).

Progress and key achievements (2009)

EMEA scientic advice for paediatric study plan

obtained.

Drug interaction and food effect study initi-

ated and completed enrolment (by Wyeth

Pharmaceuticals).

Milk excretion study completed enrolment.

Phase 2 study completed follow up.

Paediatric clinical study protocol approved bythe Special Project Team and submitted to WHO

Ethics Committee (for feedback prior to submis-

sion to Ghana Ethics Committee).

Phase 3 site infrastructure and personnel capacity

building completed.

Phase 3 study initiated in Liberia in April 2009(172 subjects enrolled as of December 2009) and

in Democratic Republic of the Congo in December

2009.

Phase 3 study EC approval obtained in Ghana,

Clinical Trial Application and import permit

request under review by Ghana Food and Drugs

Board.

Project implementation status versus plan

Based on the safety data from the Phase 2 study,

the clinical pharmacology studies in healthy

volunteers conducted by Wyeth Pharmaceuticals

were initiated earlier than originally planned.

Initiation of Phase 3 in Liberia was put back by

9 months due primarily to delays in site capacity

building caused in turn by delays in finalization

of the legal agreement, WHOs implementation

of its new administrative system, delivery of

WHO ordered equipment to the sites (transport,

custom clearance), finalization of documentation

for the ethics committee and regulatory authority

submissions, and longer than anticipated timefor obtaining authorization for study conduct.

Initiation of Phase 3 in the Democratic Republic

of the Congo was further delayed by 8 months

due to logistical challenges and time to receive all

required approvals.

Implications of progress/delays and changes in

the global context for the 20082013 plans

The delay in starting the Phase 3 study jeopardizes

recruitment of the 1500 subjects not treated with

ivermectin for at least 6 months, required as perdiscussions with the EMEA, since implementation


28/48



of ivermectin treatment (CDTI) in the study

areas is expected to occur before all subjects are

recruited. The protocol will have to be amended

and buy-in from the EMEA obtained to allow

recruitment of subjects treated with ivermectin to

reach the total enrolment target and to conduct anadditional safety study. Less than 1500 subjects not

previously treated with ivermectin in the ongoing

study will not affect the ability to draw statistically

valid conclusions regarding the relative efficacy

of moxidectin or ivermectin. This is because the

study size was determined based on the desire to

have 1000 moxidectin-treated subjects for safety

evaluation and this resulted in overpowering from

an efficacy point of view.

Specific activities for 2010

Final analysis of Phase 2 data.

Initiate Phase 3 study in Ghana.

Prepare and submit Phase 3 protocol amendment

to allow enrolment of subjects who are not

ivermectin-nave.

Prepare conduct of and potentially initiate

paediatric study.

Identify sites for community studies, invite

and evaluate proposals, establish contracts

and conduct capacity building for community

studies.

Prepare protocols for community studies

and submit to responsible committees and

authorities.

Leverage

Wyeth Pharmaceuticals investment in

manufacturing site preparation and qualification

(including regulatory inspection), study drug

manufacture and qualification, pre-clinical

toxicology and pharmacology studies, assembly

of regulatory submissions, operational support

for Phase 2 study data management, operational

support of Phase 3 data management,

consultation with European regulatory

authorities (EMEA), regulatory reporting of

drug related Serious Adverse Events (SAEs),

completion of 2 clinical pharmacology studies,conduct of 3 additional clinical pharmacology

studies required for the submission of an

application for a scientific opinion from the

EMEA and drug registration in onchocerciasis

endemic countries.

Wyeth Pharmaceuticals grant of US$ 6 million to

TDR for the conduct of the Phase 3 study.

Other

In October 2009, the takeover of Wyeth

Pharmaceuticals by Pfizer was completed.Discussions between TDR and personnel of

Pfizer in the Emerging Markets unit, to which

moxidectin has been assigned, have been initiated.

As of November 2009, the personnel in the Pfizer

development team are the same as those that

conducted the project withWyeth Pharmaceuticals.

L-praziquantel (L PZQ) for schistosomiasis

Principal Investigator: Dr Matthew H. Todd, Senior

Lecturer, School of Chemistry, the University of

Sydney, Australia.

TDR project manager: Dr Piero L. Olliaro.

This project aims to assess whether synthetic routes

for enantiomer pure L PZQ exist that are chemically

feasible, scalable and economically viable by

identifying and testing routes in the laboratory.

Praziquantel (PZQ) preparations that are available

on the market are racemic 50:50 mixtures of

two stereoisomers. It was shown by the original

developers of the drug that the anthelmintic activity

is concentrated in the laevorotatory ()-isomerwhich has (R)-configuration. This notion was


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repeatedly confirmed by in vitro and in vivo tests.

Most importantly, a randomized double-blind study

on 139 matched pairs of patients infected with S.

japonicumshowed that a single 20 mg/kg dose of

(R)-PZQ was as efficacious as 40 mg/kg of racemic

praziquantel, but (R)-PZQ produced fewer sideeffects than racemic PZQ.

There are several valid reasons for developing an

enantiomer pure PZQ: a decrease in side effects,

closer conformity to guidelines of drug regulatory

agencies, easier administration (currently-used 600

mg PZQ tablets often create swallowing problems).

With WHO/NTD and Medicines for Malaria Venture

(MMV) assistance, we have gathered expertise on

stereosynthesis and identified projects to support

the University of Sydneys approach.

The results of this project will be shared with the

entire community for further refinement and work

via the open source approach.

Progress and key achievements

With the help of WHOs legal department, we

have resolved a series of contractual constraints

and research has now started at the University

of Sydney with substantial support from the

Australian government (Australian Research

Council projects); Research started.


On track.

Leverage

TDR contribution was instrumental in leveraging

the Australian Research Council contribution.


Continue to provide support to open source

project;

Fund specic projects on feasibility.

NEW ACTIVITY: Identification of development

candidates for helminths and dengue.


Searches for potential candidates are being

conducted with the support of SAC members andother experts. For potentially eligible candidates,

dossiers are being prepared by external experts

based on publicly available information and,

whenever indicated and possible, proprietary

information from the owner. Three compounds

of interest have been identified and dossiers are

expected to be available by the end of the first

quarter of 2010.

Objective 2: Generation of evidence for

improved use of currently available drugs

(Treatment optimization & Biomarkers)

Objective 2 a) Pharmacology and improved

use of current drugs

Onchocerciasis/lymphatic filariasis

Therapeutic effect of albendazole + DEC in

children with lymphatic filariasis

Principal Investigator: Dr R.K. Shenoy, Filariasis

Chemotherapy Unit, HDS Building, Near

District TB Centre, TD Medical College Hospital

Compound, Alappuzha - 688 011, Kerala, India.

TDR project manager: Dr Janis K. Lazdins-Helds

(new manager: Dr Annette Kuesel).

This project is aimed at defining early pathological

changes in children infected with Brugia malayi and

evaluating whether these are affected by 6-monthly

treatment with diethylcarbamazine and albendazole.

In many tropical countries, the vector-borne

disease lymphatic filariasis (LF) is a major cause

of considerable chronic and acute disability.

Until recently, LF was considered to be a disease


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of adults. Globally, 22 million children under

the age of 15 are estimated to have LF infection,

but little information is available on the clinical

manifestations, particularly of Brugia malayi

infection, in children.

The study titled, A cross sectional study of

children to define the clinical and pathological

changes caused by Brugia malayi infection in an

endemic area, was initiated in 4Q04. Following the

screening of 7 934 children, (3 to 15 years of age),

200 were recruited. All the children enrolled in the

study were followed up every six months over 36

months for occurence of any entry lesions, acute

adenolymphangitis or swelling of the limbs via

routine blood and urine examination, night blood

examination for microfilaria count by Nucleporemembrane filtration, Doppler sonography and

lymphoscintigraphy. At the start of the study and at

each follow-up visit, the children were treated with

single doses of diethyl carbamazine 6 mg/kg and

albendazole 400 mg.


The last child enrolled completed the final follow

up planned in January 2009 and final data became

available in July 2009. Lymphoscintigraphy revealed

lymph-node and lymph-vessel damage in 82% ofthe children at enrolment. In about 67% of the

children this pathology was markedly reduced by

the end of the follow-up period. Microfilaremia and

Bm14 antibody levels had declined.

The results were published (Shenoy et al. 2009)


Project as originally planned was completed.

Leverage

A new (non-TDR) study on Effect of Albendazoledose and interval, sponsored by the LF Global

Programme, will be started under a Bill & Melinda

Gates Foundation research grant.

Implications of results

These results show that the drugs used by the

Global Programme to Eliminate Lymphatic Filariasis(GPELF) can reverse subclinical lymphatic damage

in children and that appropriate mass administration

can provide benefits beyond interruption of

transmission in endemic areas. This provides an

important motivation to ensure inclusion of young

children in the mass treatment programmes and a

potent advocacy tool for the GPELF.


Follow up will continue beyond the originally

planned study end to see whether further reversal of

pathology will occur (pending approval of external

advisors and Ethics Committees).

Budget for 20102011

None required the investigator reported that

sufficient funds for additional follow up are

available from last years budget.

Reduction of loa loa microfilaremia by albendazole

to reduce the risk of ivermectin-induced SAE in loa

loa infected individuals (completed)

Principal Investigator: Dr Joseph Kamgno, Filariasis

Research Centre, Yaound, Cameroon


The objective of this project was to evaluate

whether two or six two-monthly treatment

of subjects with loa loa infection reduce the

microfilaremia sufficiently to reduce the risk of

severe and/or serious adverse reactions to treatment

with ivermectin, for onchocerciasis or lymphaticfilariasis control.


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Loiasis is a parasitic infection endemic in the rain

forest areas in sub-Saharan Africa caused by the filarial

nematode loa loa. People heavily infected with loa loa

who take ivermectin can have severe and/or serious

adverse events , including encephalopathy and death.Implementation of Community Directed Treatment

with Ivermectin (CDTI) in onchocerciasis-loa loa

co-endemic areas can progress only very slowly since

appropriate medical care has to be made available in

case of such SAEs. The fear of serious and/or severe

adverse events leads to a reduced participation of

the population in CDTI. Following an analysis of

SAEs during onchocerciasis control and a risk-benefit

assessment, it was decided not to move albendazole-

ivermectin mass treatment into areas that are

co-endemic for lymphatic filariasis and loiasis.


The study was completed in 2009. The results show

that neither treatment regimen examined reduces

loa loa microfilaremia to the extent required to

substantially reduce the risk of severe or serious

adverse events upon mass-treatment with ivermectin

for onchocerciasis or LF control in loa loa co-endemic

areas. Thus, this study will not have the anticipated

outcome (accelerated expansion of the use of

ivermectin against onchocerciasis and implementation

of ivermectin + albendazole treatment in lymphatic

filariasis loiasis co-endemic zones).

Leverage

GSK, The World Bank, and APOC provided

designated funds to TDR for the study. The study

drug was donated by GSK.

Schistosomiasis

Evaluation of praziquantel combination with

oxamniquine for schistosomiasis

Principal investigator: Professor Mamoun Homeida,

Academy of Medical Sciences and Technology,Khartoum, Sudan.

TDR project manager: Mr Olivier Lapujade.

This is a study designed to evaluate the

pharmacokinetics efficacy and safety of using

both drugs in combination with the purpose of

enhancing not only efficacy but also to protect

praziquantel from resistance, especially in view of

the dramatic expansion of its use.

The study has been on hold for more than a year

due to difficulties in accessing oxamniquine (theonly source is in Brazil).

Effective and safe dose (40 versus 60 mg/kg) of

praziquantel for treatment of schistosomiasis

Principal Investigators: Dr Otvio Pieri, Laboratory

of Eco-epidemiology & Control of Schistosomiasis

& Soil-transmitted Helmi

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