Drug development and evaluation for helminths and other neglected tropical diseases

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tDR Business line 6

Drug development and evaluation

for helminths and other

neglected tropical diseases

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the use of content from this health information product for all non-commercial education, training and information purposes is en- couraged, including translation, quotation and reproduction, in any medium, but the content must not be changed and full acknowl- edgement of the source must be clearly stated. A copy of any resulting product with such content should be sent to tDR, World Health organization, Avenue Appia, 1211 Geneva 27, switzerland. tDR is a World Health organization (WHo) executed uniCeF/unDp/World Bank/World Health organization special programme for Research and training in tropical Diseases.

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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,

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List of abbreviations

ALB Albendazole ANC Antenatal clinic APOC African Programme for

Onchocerciasis Control

APW Agreement for Performance of Work BENEFIT Benznidazole Evaluation For

Interrupting Trypanosomiasis

BL6 (HNR) Drug Development and Evaluation for Neglected Tropical Diseases

CD Chagas disease

CDI Community directed interventions CDTI Community directed treatment with

ivermectin

CIR Community based interventions CL Cutaneous leishmaniasis DEC Diethylcarbamazine

DENCO Dengue control clinical study DNDi Drugs for Neglected Diseases

initiative

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 Eliminate Lymphatic Filariasis

HAT Human African trypanosomiasis HNR Drug Development and Evaluation for

Neglected 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 Chemotherapy

Research Centre O.v. Onchocerca volvulus OXQ Oxamniquine

PCR Polymerase chain reaction PZQ Praziquantel

R&D Research and development SAC Strategic and Scientific Advisory

Committee

SAE Serious adverse events SoP Standard operating procedure SPT Special Project Team – advisory

committee for projects requiring special expertise and/or more intense ongoing involvement of external experts than can be provided by the SAC (SPTs are in place for moxidectin development, ivermectin response markers research and Chagas disease projects)

STAC Scientific and Technical Advisory Committee

STH Soil transmitted helminths TCC Technical Consultative Committee TDR Special Programme for Research and

Training 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 potentially suitable for cost-effective scale-up.

Lead optimized optimized lead compound with in vitro and in vivo activity, pharmacokinetic and toxicity profile potentially 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 pharmacovigilance. 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 understanding 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 product’s 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 further improve 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 of suitable 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 malayi infection

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conducted in India shows that mass drug administration not only affects transmission, but also has the potential to have effects on development 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 revised classification 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 for NTDs

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-treatment follow-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 collaborative project 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 invited proposals 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 malayi infection 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 of transmission (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 ivermectin’s 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 a standardized 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 evaluate an 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 take part 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 of Neglected Tropical Diseases (WHO/NTD), along with the HNR’s 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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1.1 Context

The current WHO approach to control NTDs is based on two different strategies.

1. For diseases for which tools are not available or difficult to use (”tool-deficient diseases” such as Buruli ulcer, Chagas disease, human African trypanosomiasis and leishmaniasis outside the Indian subcontinent), the strategy focuses on increasing disease awareness, early case detection and making the current drugs available at an affordable price (“innovative, intensified treatment”).

2. For diseases for which there are safe and effective drugs (”tool-ready diseases” such as cysticercosis, dracunculiasis, foodborne trematode

infections, lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted

helminthiasis), the strategy is to administer these

drugs widely to populations at risk (“preventive chemotherapy”) for transmission control.

When different diseases coexist in the same area, drugs are co-administered (prophylactic chemotherapy).

For the first group of diseases, there is an urgent need to develop safe and affordable new drugs.

For the second group of diseases, drug doses and regimens need to be optimized - which requires additional data on pharmacokinetics, pharmacodynamics, drug interactions, and new formulations. Control of these diseases currently depends on a single drug (e.g. praziquantel for schistosomiasis, ivermectin for onchocerciasis) – which makes them vulnerable to the emergence of parasite resistance. Therefore, new drugs and drug combinations are needed for this group of diseases as well.

1. Context, strategic objectives and framework

Innovation/

pharmaceutical gap

Basic science Product discovery

Product development (R&D)

Product use

Schools, communities Health systems

“Operational”

research

“Tool ready”

Lymphatic filariasis, Leprosy, Onchocerciasis, Schistosomiasis, Helminthiasis, Trachoma, Yaws,

(visceral leishmaniasis – Indian subcontinent)

“Tool deficient”

Human African trypanosomiasis, Chagas dis.

Buruli ulcer, Leishmaniasis, Dengue

“Vulnerable diseases”

Lymphatic filariasis, Onchocerciasis, Schistosomiasis, (Helminthiases) Fig. 1. Context of HnR objectives

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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 2008–2013 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 2009–2010 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 HNR should 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 the mandates 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 2 and 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 by dedicated 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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HNR’s work requires the building and strengthening of local capacities and close interaction with disease control programmes, health systems and regulatory authorities 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 currently available drugs for NTDs (for short: 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 currently available 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 be combined 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. These data are essential to optimize the impact of

interventions. However, methods (including pharmacovigilance) to collect and analyse the relevant data are imperfect and not adapted to the 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 less cumbersome 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 and providing 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 4 presents 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 completing enrolment as soon as possible.

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Table 2. HnR PORTfOLiO COmPOSiTiOn in 2009 By DiSeaSe anD STRaTegiC OBjeCTiveS

Disease

active in 2009 New drugs for NTDs

Treatment optimization and biomarkers pharmacology

& improved use of current drugs

pharmaco-epidemiology in support of disease control

Markers & methods for evaluation of treatment effects onchocerciasis/

lF

• Moxidectin for Oncho (phase 3)

• Drug development candidate identification

• Effect of ALB on loa loa microfilaremia

• Effect of ALB+DEC on lF in children

• Pharmaco- epidemiology/vigilance in community directed interventions (planning)

• Markers of response of o.v. to ivermectin

• DEC patch for detection of o.v. infection

schistosomiasis • L-praziquantel

• PZQ-OXQ combination praziquantel dose comparison

• Systematic reviews (urinary & intestinal) Dossiers on drugs in use

stH • Drug develop-

ment candidate identification

• Dossiers on drugs in use

HAt • Nifurtimox + eflorni-

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-

• Validation of new disease classification

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Table 3. HnR PORTfOLiO PLanneD fOR 2010 By DiSeaSe anD STRaTegiC OBjeCTiveS

Disease

active in 2009 New drugs for NTDs

Treatment optimization and biomarkers pharmacology

& improved use of current drugs

pharmaco-epidemiology in support of disease control

Markers & methods for evaluation of treatment effects onchocerciasis/

lF

• Moxidectin for Oncho (phase 3)

• Effect of ALB+DEC on lF in children

• Pharmaco- epidemiology/vigilance in community directed interventions

• Markers of response of o.v. to ivermectin

schistosomiasis • L-praziquantel Drug development candidate identification

• PZQ-OXQ combination

• Systematic reviews (urinary & intestinal)

• Dossiers on drugs in use

stH • Drug develop-

Dossiers on drugs in use improved benzimidazoles

HAt • Nifurtimox+eflornithine

(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 treatment effect

leishmaniasis • Standardization of

methods for Dx and txFu of cutaneous leishmaniasis

• Biomarkers of treatment effect

Dengue • Drug develop-

• Validation of new disease classification

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BL strategic objectives Disease Project End products Expected outcomes 1. new drugs for onchocerciasis, Lf, STH,

schistosomiasis, foodborne trematodes and dengue

onchocerciasis/lF Moxidectin for onchocerciasis (and lymphatic filariasis)

(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 elimination of onchocerciasis as a public health problem to eradication of infection

schistosomiasis l-praziquantel for schistosomiasis Data to assess whether enantiopure l-praziquantel meets target product profile for registration (2015)

(i) Filing by manufacturer for registration and/or list of essential drugs; (ii) registration/adoption by concerned endemic countries.

Helminths, dengue Drug development candidates for helminths and dengue

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)

2. generation of evidence for improved use of currently available drugs (treat- ment optimization and biomarkers)

All Dossiers on drugs currently used for NTDs (i) Compilation of non-clinical & clinical data publicly avail- able for each drug used for treatment of NTDs (2010–2012) (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 (2010–2013)

Identification of research questions for treatment optimiza- tion studies. Risk management plans established by WHO disease control programmes and/or national disease control programmes

2a. Pharmacology and improved use of current drugs

lF Therapeutic effect of albendazole +

diethylcarbamazine (DeC) in children with lymphatic filariasis

Clinical evidence of the safety and efficacy in curing and reversing lymphatic lesions in children infected with Brugia malayi (2009–2012)

lymphatic filariasis control programmes include cure of infection and regression of early lymphatic lesions in children (currently aiming only at interruption of transmission) onchocerciasis / lF efficacy of albendazole in reducing loa loa

microfilaremia

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

schistosomiasis Combination of praziquantel and oxamniquine for schistosomiasis

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

Effective and safe dose of PZQ for Tx of schistosomiasis

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

systematic reviews in urinary and intestinal schistosomiasis

evidence base for research and treatment policy recommendations for schistosomiasis (2010)

use of results to inform research priority setting and treatment recommendations

leishmaniasis Anthropometric database on patients with visceral leishmaniasis from different endemic areas

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)

Chagas disease Benznidazole for the treatment of patients in the late indeterminate or early chronic phase of T. cruzi infection (BeneFit)

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. cruzi infected individuals after tx with benznidazole. Change of treatment guidelines.

Table 4. HnR PROjeCTS, enD PRODuCTS anD exPeCTeD OuTCOmeS

Projects initiated/planned in 2009 are indicated in italics

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