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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis for Priority-Setting

Priority Medicines for Europe and the World"A Public Health Approach to Innovation"

Background Paper

Analysis of Pharmaceutical Development Issues for Malaria as

Basis for Priority-Setting

L Riopel, Ph.D Medicines for Malaria Venture

18 October 2004

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Table of Contents

Summary................................................................................................................3Introduction/Background.......................................................................................4Size and Nature of the Disease Burden (8,11-14).......................................................5Malaria in endemic area........................................................................................6Malaria in non-endemic area...............................................................................12

A) Autochthonous (Indigenous)........................................................................12b) Imported Malaria.........................................................................................13

Control Strategy..................................................................................................14Vector Control.....................................................................................................15Case Management...............................................................................................16Vaccines...............................................................................................................24Why does the disease burden persist? What can be learnt from past and current research?.............................................................................................................25What is the current pipeline?..............................................................................30

Development Projects......................................................................................30Discovery Projects............................................................................................31

Opportunities for research and what are the gaps between current research and potential research issues.....................................................................................33Conclusions and Recommendations....................................................................35References...........................................................................................................37

Appendix

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Summary

The worldwide resurgence of malaria is now well recognized. The sub-Saharan Africa bears the burden of the disease with over one million deaths and up to 500 million cases annually, affecting mostly young children and pregnant women. The social and economic costs of malaria are immense and hamper peoples’ lives and perpetuate underdevelopment. Malaria silently kills 3,000 children every day because access to preventive tools or basic treatment is lacking. Resistance has rendered the old and cheap treatments like chloroquine and SP useless in most parts of Africa and South East Asia.

Despite these staggering statistics the global community has not placed malaria high enough on the geopolitical agenda to mobilize the resources necessary to combat and prevent this devastating disease. As drug resistance was emerging in the 1970-80s, the pharmaceutical industry disengaged from innovative R&D in tropical disease as the cost of drug development was on the rise and the market incentive was simply not there.

Artemisinin-based combination therapies (ACT) are effective and today, are considered the best antimalarials in terms of efficacy and lower propensity to resistance. However, they are far from being ideal drugs because of their relatively high cost and unknown safety features in women of child bearing potential. Nevertheless, these are the best options in the immediate and to address the cost problem, the US National Academies of Science (IOM) recently published a report advocating annual subsidies of US$ 500 million annually to purchase ACT as first line treatments in disease-endemic countries.

In order to address the cost problem and expand the access to effective antimalarials, new alternative drugs to supplement and replace older drugs are urgently needed. Solutions to a cost effective approach to innovative drug research and development are emerging from public-private partnerships (PPP) such as the Medicines for Malaria Venture (MMV). With a total expenditure of about US$ 60 Million over four years, MMV has 21 projects in its drug portfolio and funding of at least 30 Million annually will be needed to achieve its mission of delivering new effective and affordable antimalarials for the disease-endemic countries and sustaining a pipeline of drugs to stay one-step ahead of drug resistance. This investment is small compared with the estimated US$ 12 billion lost GDP annually in Africa and the significant funding needed for ACT. However, the success of MMV and other PPPs involved in drug development will also depend on the innovation in applied sciences. Public and private sectors must redirect the research agenda to support transitional research geared toward the development of new and reliable experimental models allowing rapid and cost-effective screening of new drug candidates in order to progress them to clinical development with less risk of failures. The outlook for new medicines to tackle neglected diseases is better than it has been in decades. We must capitalize on this momentum and take advantage of the current quantum leaps in science by applying them efficiently and effectively.

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Introduction/BackgroundMalaria is one of the most ancient and deadly infectious diseases. Many historians believe that it was one of the key causes for the fall of the Roman Empire(1). A fatal periodic fever has been associated with biting insects since the antiquity but it is only in 1880 that the French scientist Laveran identified the protozoa Plasmodium, the causative organism of malaria(2). Today, approximately 120 species of the protozoa of the genus Plasmodium have been identified in the blood of mammals, reptiles and birds and are recognized by the presence of two types of asexual division: schizogony in the vertebrate host and, sporogony in the insect vector. Within the vertebrate host, schizogony is found within erythrocytes and in other tissues (exo-erythrocytic schizogony). The parasites of humans are exclusively transmitted by the anopheline mosquitoe. There are four human malarial parasites: the most pathogenic form, P. falciparum; and three less pathogenic but relapsing forms, P. vivax, P. malariae and P. ovale.(3)

Following the mosquito bite, sporozoites injected into the blood stream invade the liver where they multiply. In vivax and ovale infection, the development is interrupted resulting in a dormant form, the hypnozoite, from which the infection may relapse months later. After 7-10 days in hepatocytes, schizonts rupture, releasing merozoites which invade the erytrocytes, where they develop through ring forms to trophozoites and finally multi-segmented schizonts. Pathological processes in malaria are the result of the erythrocytic cycle. In the case of P. falciparum, the process results in several changes in the morphology and physiology of the infected red cell resulting in the host immunological responses to the parasite antigens: stimulation of the reticulendothelial system, changes in regional blood flow and vascular endothelium, systemic complications of altered biochemistry, anemia tissue and organ hypoxia and marked systemic inflammatory response characterized by release of cytokines such as tumour necrosis factor-α (TNF- α) and interleukins, 4) which together are responsible for the fever and other flu-like symptoms of malaria. If not treated, P. falciparum can be fatal or cause serious neurological sequelae.

Until after the end of World War II, malaria was endemic throughout much of southern Europe and seasonal epidemics or outbreaks occurred as far north as Scandinavia. By 1970, malaria transmission was virtually eradicated from the continent following intensive control measures. However, the anopheline populations remain high in many countries, which pose the risk of renewed transmission should the number of infected human hosts increase. In the mid-1990's recrudescence of autochthonous (indigenous) malaria has been noted in many countries of the continent, reaching a total of nearly 91,000 cases in 1995 in the countries of the WHO European region. In addition, between 10,000 and 12,000 cases of imported malaria are reported in the European Union each year, a figure large enough to constitute a public health and economic burden on the countries into which malaria is imported. (5)

In the past century malariologists have made important achievements in epidemiology, pathophysiology, treatment and control and in the new Millennium, using molecular genetics, scientists have almost complete knowledge of the P. falciparum genome.(6) Despite these achievements, malaria still claims over one million lives annually with an incidence possibly increasing beyond 500 million cases each year.(7) Pregnant women and young children in sub-Sahara Africa are the most affected, bearing 90% of the global disease burden. Plasmodium vivax, although regarded as less threatening than P.

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falciparum also represents a significant health problem in many regions of the world with an estimated 70-80 million cases annually.(8) In developing countries malaria is a key contributor to social, economic and intellectual impoverishment of these communities.(7,9) (See Appendix 6.10.4)

Malaria is a preventable and curable disease but eradication programs have failed in the developing countries and control measures to stop the progression of this human and economic burden are also not reaching the set goals. However, in the past few years, there have been improvements in its political profile resulting in an increased funding for malaria prevention and interventions. Antimalarial drugs with selective actions on the different phase of the parasite life cycle have proved to be efficacious in the treatment or prophylaxis of malaria but resistance has spread widely making many of these drugs useless. Newer effective drugs such artemisinin-based combination therapies (ACTs) are now the recommended first line treatment,(10) but with a price tag that is 10-20 times more than the older drugs, they are unaffordable for the populations and governments of low income countries.(9,10)

New safe, effective and affordable treatments must be developed urgently. However, drug development is expensive and the pharmaceutical industry, lacking the market incentive, has significantly diminished its R&D investment in malaria and other neglected diseases. New approaches to develop safe and effective medicines are being implemented by various public-private partnerships (PPP), the success of which will depend not only on funding but also on the adequacy of the research agenda. This analysis will first provide the information necessary to appreciate the devastating effect of the disease, and will highlight the areas of research and development needed to roll back malaria globally.

Size and Nature of the Disease Burden (8,11-14)

Individuals exposed to P. falciparum in areas of stable transmission will alternate between periods when they are infected with the parasites and those where they are uninfected. Most individuals will, at some stages in their lives, develop an overt clinical response manifesting in most cases by febrile events. Without prompt medical treatment, these clinical events may progress to severe illness and death. However, the disease may naturally resolve or the patient may be cured with an appropriate intervention. There are several morbid consequences associated with each step of the disease process. Chronic, sub-clinical infections may render an individual anemic or predispose to under-nutrition, conditions that will influence the severity and outcome of other infections. Asymptomatic infection of the placenta of a pregnant woman significantly reduces the weights of their newborn children. Patients who survive a severe disease are likely to suffer from debilitating sequelae such as spasticity, epilepsy or retinopathy. Behavioral disturbances and cognitive impairment are now also recognized as major consequences of malaria.(See Appendix 6.10.3)

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http://mednet3.who.int/prioritymeds/report/append/610snow_wp11.pdf

http://www.nap.edu/books/0309092183/html


Figure 1: The direct, indirect and consequential public health effects of P. falciparum malaria in Africa (Source: Snow and Gilles 2002) (11)

Malaria in endemic areaThe health impacts vary between countries and communities. In the absence of measures to reduce transmission, the impact will depend upon factors such as acquired immunity, access to effective case-management or host genetics. There are several published reports on attempts to estimate the global burden of malaria, more specifically on the burden of P. falciparum in Africa where the disease is recognized to be a major obstacle to human and economic development.(9-15,17) (See Appendix 6.10.4) Accurate statistics on malaria in Africa are difficult to collect and report because of the enormity of the disease problem, the weakness of health information systems, and the fact that the treatment of most malaria cases, as well as many deaths, occur outside the formal health system.(12) It is therefore generally agreed that figures published are rough estimates and that the precise number of fatal and morbid events will never be known. Table 1 summarizes the estimates of morbidity and mortality by WHO administrative region during 2001.

Recently, Snow et al (12) have re-analyzed the consequences of malaria in Africa using empirical epidemiological measures of disability, morbidity and mortality risks in function of age and malaria transmission. Consistent with the WHO estimates for year 2001, (15) Snow et al, estimated 1,144,572 deaths directly attributable to malaria in Africa in year 2000 (Table 2). Estimates presented in Tables 1 and 2 confirm the frequently quoted figures of about 90% of all malaria deaths in the world occur in Africa south of the Sahara mainly in children under 5 years of age.

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Table 1: Estimates of malaria morbidity and mortality by WHO administrative region during 2001 (13,15)

Morbidity Mortality

Total 396,676,285 1,123,764

Africa 342,814,347 962,736South East Asia 32,930,363 94,380Eastern Mediterranean 14,894,969 54,570Western Pacific 2,238,314 10,474The Americas 3,798,292 1,445Europe 0 160

Table 2: Estimated malaria specific mortality (IQR range) during 2000 (Source: Snow et al) (12)

0-4 years 5-14 years 15+ years

Southern Africamalaria risk (Class 4)

266[164 - 430]

482[297 - 779]

1’129[695 – 1’824]

1’1877[1’156 – 3’033]

Rest of Africa- low stable/epidemic risk (Classes 2+3)

57,688 32,588 49,079 139,355

Rest of Africa-stableEndemic risk (Class 4)

684,364[541,330 - 1,068,723]

182,113[76,072 - 319,274]

136,863[84,399 - 214,419]

1,003,340[701,801 - 1,602,415]

Total 742,318[541,494 – 1,069,153]

214,701[76,369 – 320,053]

187,071[85,094 – 216,253]

1,144,572[702,957 – 1,605,448]

__________________________________________________________________________ IQR = Interquartile range, which represents the range of values from the 25th percentile to the 75th percentile, essentially the range of the middle 50% of the data. Because it uses the middle 50%, the IQR is not affected by extreme values.Classification of areas:Class 1: no human settlement, or unsuitable climate for malaria transmission.Class 2: populations exposed to marginal risks of malaria transmission, uncommon in an average year.Class 3: populations exposed to acute seasonal transmission with a tendency toward epidemics.Class 4: populations exposed to stable, endemic malaria transmission. In southern Africa (Namibia, Swaziland, South Africa, Botswana, Zimbabwe) Class 4 areas, malaria still poses a risk but its extent and transmission potential are determined by aggressive vector control.SOURCE: Snow et al, (2003)Pregnant women, whose placentas are invaded by the malaria parasite, are particularly vulnerable to malaria. Infection with the parasite may cause various adverse consequences for both the mother and the newborn. These effects include maternal anemia, placental accumulation of parasites, low birth weight (LBW) from prematurity and intrauterine growth retardation (IUGR),

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fetal parasite exposure and congenital infection and infant mortality (IM). Most population-based studies were conducted in Africa where P. falciparum transmission is high, while fewer studies are reported from Asia and the Americas. Steketee et al, 2001(13) reviewed studies conducted in African populations between 1985 and 2000 and have summarized the malaria population attributable risk (PAR) that accounts for both prevalence of the risk factors in the population and the magnitude of the associated risk for anemia (Table 3). They have estimated that each year 71,000 to 190,000 infant deaths are associated with malaria infection in pregnancy. Antimalarial chemoprophylaxis, or intermittent preventive treatment (IPT) during pregnancy has been shown to reduce the risk of malaria infection and significantly increase the birth of healthy babies born to primigravidae (first-time mothers).(16)

However, access to drugs and IPT is still very limited, hence, deaths remain high in sub-Saharan Africa.

Table 3: Summary of population attributable risk (PAR) estimates for P. falciparum malaria in pregnant women (from Steketee et al, 2001 (14) and Snow et al, 2003)(12) and applied to expected numbers of pregnancies in 2000 in areas outside southern Africa in risk areas class 3 & 4 (see legend Table 2) to estimate indirect mortality

Adverse event Prevalence/incidence

Risk estimate

PAR (%) Fatal events 2000 Attribute to malaria

Moderate or severe anemia

1-20% 1.5-2.5 2-15 -

Low birth weight

12-20% 1.4-1.8 8-14 -

Pre-term LBW 3-8% 2.2-3.5 8-36 -IUGR LBW 8-15% 1.7-5.5 13-70 -Infant mortality 105% NA 3-8 71,000-190,000

The magnitude of the economic burden of malaria is poorly documented. One can assume that the direct and indirect costs in treating and preventing the disease are large to the governments and families. According to the Africa Malaria Report 2003(17) an average of 30% of all outpatient clinic visits are for malaria and that 20% to 50% of hospital admissions are a consequence of malaria. (See Appendix 6.10.1) Malaria was ranked 8th highest global contributor in Disability Adjusted Life Year (DALY) and 2nd in Africa. (15) These estimates, however, were based largely on deaths as direct cause of malaria infection and on data available on morbid events following cerebral malaria. In their analysis of malaria burden, Snow et al(12) have also examined events consequential to the disease-related events such as, the consequences of clinical management including the immediate effects of adverse drug reactions or long-term residual effects of acquired HIV infection through blood transfusion. In addition, there are other life-long disabilities related to untreated clinical cases of malaria such as the short and long term residual neurological impairments following cerebral malaria. Table 4 summarizes the mortalities, morbidities and other events that should be taken into account in the estimation of malaria burden. It is important to note the estimated mortality directly associated to adverse drug reaction (ADR). Drugs such as chloroquine (CQ) can be toxic at excessive doses but yet, the authors observed that CQ seems to have the least documented ADR risk. If we assume a minimum risk of 1:20,000 subjects exposed to a drug will result in a severe ADR of which 50% are fatal, approximately 4,700 ADR and 2,350 deaths associated with treatment could be

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http://mednet3.who.int/prioritymeds/report/append/610pub_africa_malaria_report_en.pdf


expected each year among children living outside southern Africa.12 Those surviving the ADR may suffer various degrees of severity of hepatotoxicity, agranulocytosis and aplastic anemia which could require treatment for up to 6 months, assuming adequate medical management is available, which often is not the case.

Vivax malaria, while causing less fatal cases, is also a debilitating disease, resulting in deleterious effects on personal well-being, growth and development and, causing economic hardship at the individual, family, community and national levels. Most recent statistics available on incidence are those prepared for the 1999 World Health Report and were based on data obtained from the WHO regional offices between 1993 and 1998.

The global burden of vivax malaria is estimated to be approximately 70-80 million cases per year. Outside of Africa where P. falciparum is most prevalent, P.vivax accounts for 50% of all malaria cases. About 80-90% of P. vivax occurs in the Middle-East, Asia and the Western Pacific; the remaining 10-15% occurs in Central and South America. The rarity of P. vivax in Africa and more specifically in West Africa is linked to the prevalence of the Duffy negative trait, an inherited red cell phenotype that lacks the receptor for invasion of the human red cell by the merozoites of P. vivax. (8)

Populations living in endemic P. vivax areas where transmission is low to moderate do not achieve a high level of effective immunity. This means that for each new infection, clinical symptoms such as fever, body aches and headaches are likely to occur with various degree of severity. However, after several malaria attacks, the clinical manifestation is much attenuated.

P. vivax differs from P. falciparum not only in its pathogenicity but also in its transmission strategy. In P. vivax, the mature and infective germ cell or gametocytes appear in the blood of an infected person almost simultaneously with the asexual blood stage parasites before the clinical threshold of a blood infection is reached, while the gametocytes of P. falciparum emerge at least 10 days after the clinical threshold of an infection has been reached. This difference has important consequences in the pattern of selection of resistance and control strategy against these parasites. For instance, because vivax gametocytes are transmitted to mosquitoes during the pre-symptomatic period of P. vivax blood infection and before drug treatment, P. vivax will be less vulnerable to control by deployment of effective drug therapy. (8) In addition, the latent hepatic stage of vivax make control by deployment of drug therapy difficult as the time at which relapses will occur cannot be predicted.

With over one billion inhabitants potentially at risk of vivax infection, vivax malaria may increasingly contribute to the public health burden of malaria globally and the need for research in effective control strategy is warranted.(8, 13)

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Table 4: A summary of the burden of P. falciparum malaria - Africa during 2000 (Source Snow et al, 2003) (12)

0-4 years 5-14 years 15+ years Total

Malaria specific mortality

742,318[541,494-1,069,153]

214,701[76,369-320,053]

187,071[85,094-216,253]

1,144,572[702,957-1,605,448]

Maternal mortality attributed to malaria-anemia

-- -- 5,300 5,300

Infant mortality attributed to malaria during pregnancy

71,000-190,000 -- -- 71,000-190,000

Fatal adverse drug events

2,350 Unknown Unknown 2,300

Fatal HIV risks from blood transfusion used to manage SMA

5,300-8,500 Unknown 5,300-8,500

Premature mortality of poorly managed epilepsy developed through cerebral malaria or complex seizures

-- Unknown Unknown Unknown

Role of infection on anemia, under-nutrition and HIV as indirect mortality effects

Unknown Unknown Unknown Unknown

Malaria morbid attacks (thousands)

108,519[64,240-163,982]

74,077[48,514-120,577]

30,953[21,284-40,067]

213,549[134,322-324,617]

Estimated number of morbid days (thousands)

553,447[327,624-836,263]

168,053[110,572-265,852]

82,199[56,220-196,757]

803,699[494,416-1,298,872]

Neuro-cognitive sequelae following cerebral malaria

Numbers

Hemiparesis360-400 Unknown 360-400

Quadriparesis/Severe deficit 770-860 Unknown 770-860Hearing impariment 650-730 Unknown 650-730Visual impairment

300-330 Unknown 300-330Behavioral difficulties 1,540-1,720 Unknown 1,540-1,720Language deficits

7,000-7,800 Unknown 7,000-7,800Epilepsy

2,700-3,000 Unknown 2,700-3,000Effects of infection on cognitive performance

Unknown Unknown Unknown Unknown

Estimating the costs of malaria is difficult because there is no consensus as to which approaches or methodologies to employ to evaluate the economic burden. Recent work on defining the economic costs of malaria appears in the report

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published by the Institute of Medicine National Academy of Sciences.(9) (See Appendix 6.10.4) Effects of malaria at a macroeconomic level include those on household living standards, demographics, human capital, trade and foreign investment and, at a microeconomic level, the economic effects of malaria were based on costs of household and government expenditures on prevention and treatment as well as indirect costs associated to lost of wages resulting from incapacity to work. The bottom line figure often quoted is that malaria represents an estimated $US 12 billion lost in GDP in Africa.(9)

In absence of effective control measures the problem can grow even bigger as illustrated in the recent work of Hay et al. (13) (See Appendix 6.10.2) Using summary procedures in geographic information systems and endemicity maps, they have found that between 1900 to 2002 the area of human malaria risk has been reduced by around half, from 53% to 27% of the Earth's land surface (Table 5). However, because the global human population has grown geometrically, the number of people at risk have increased from 0.9 to 3 billion during the same period. The authors estimate that at the turn of the 21st century, 48% of the global population remains exposed to the risk of malaria, a situation that has deteriorated since the early 1990s.

Table 5: Global population at risk from malaria from pre-intervention to 2010 (1900-2010) (Source: Hay et al, 2004) (13)

Time Global population

Land area malarious

Countries at risk

Population exposed

Years n Km2 % n n %1900 1 158 409

47277 594 480

53-16 140 892 373 056 77-03

1946 2 391 400 960

58 565 752

40-12 130 1 635 815 808

68-40

1965 3 363 417 344

53 492 988

36-65 103 1 924 360 320

57-21

1975 4 085 759 488

48 075 780

32-93 91 2 121 086 592

51-91

1992 5 419 255 808

43 650 812

29-90 88 2 565 702 144

47-34

1994 5 582 432 256

39 537 020

27-08 87 2 570 555 136

46-05

2002 6 204 095 488

39 758 172

27-24 88 2 996 419 584

48-30

2010 6 807 085 056

39 758 172

27-24 88 3 410 862 080

50-11

The area totals were generated using the maps of all-cause malaria risk distribution through time. The percentage of Earth malarious was calculated from a total global land surface area of 145 975 899 km2. To estimate countries at risk territorial designations for 2002 were used throughout (Environmental Systems Research institute, Inc, Redlands, California, USA). Country-specific “medium variant” population growth rate from the World Population Prospects database (http://esa.un.org/unpp) between 1950 and 2010 were applied to the Gridded Population of the World (GPW) v2.0 to generate population distribution maps for 1900, 1946, 1965, 1975, 1992, 1994, and 2002 to match with the malaria risk distribution maps and were also projected to 2010 to enable evaluation of potential future changes in global malaria risk. Global summary counts of these population distribution maps give accuracy to within 5% of the UNDP global population estimate (http://esa.un.org/unpp) for all calculated years. All area and population summaries from these polygons were processed in Idris Kilimanjaro (Clark Labs, Clark University, Worcester, MA, USA). ____________________________________________________________________________

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http://esa.un.org/unpp

http://esa.un.org/unpp

http://mednet3.who.int/prioritymeds/report/append/610review_and_opinion.pdf



Malaria in non-endemic areaTo further appreciate the risk that lack of control could have on malaria and to provide some insight to the potential economic burden in developed countries, it is worthwhile to examine the malaria situation within the WHO European Region published in a recent report: The vector-borne human infections of Europe- Their distribution and burden on public health. (5)

A) Autochthonous (Indigenous)

Autochtonous or indigenous malaria refers to cases that are transmitted locally by mosquito species living in the area.

Italy P. falciparum disappeared from Italy in 1950 while P. vivax persisted until

1955 (18) Most of southern and rural Italy remains receptive to malaria

transmission, due to the presence of high density of An. labranchiae and other mosquito vectors. (19) However, most of these species are not susceptible to the African strains P. falciparum.

In 1977, index case of malaria has been attributed to local anophelines infected with exogenous P. vivax. (20)

The NetherlandsLast case of indigenous malaria was reported in 1960 (21)

The Dutch malaria vector cannot transmit P. falciparum The only malaria vector in the Netherlands An Atroparvus is near extinction

(22) Recrudescence of transmission due to increased mosquito population is

possible but not considered a threat given the current environmental conditions.

Spain A case of locally transmitted P. ovale has been reported recently. (23)

Because of the proximity of the airport, it is speculated that a local An. labranchiae or An. atroparvous may have bitten a gametocyte-carrying migrant worker.

Russian Federation & Moscow Region Malaria was endemic throughout the region until DDT vector program

combined with active case detection began in 1945. The number of imported malaria cases has been increasing since 1966

which led to the renewed local transmission to a level that is currently higher than the imported cases (24)

In year 2000, a total of 763 cases of malaria were registered, 47 of which were indigenous and included locally transmitted P. vivax in the Moscow area. (24)

The incidence of indigenous malaria doubled between 1997 and 2001 necessitating the implementation of an active vector programme. (Note: No cost figures for such an implementation programme were found).

Newly Independent States (Azerbaijan, Tajikistan) and TurkeyMalaria resurgence is serious and constitutes a threat to those areas of Europe especially the Balkans. Table 6

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Most cases are due to P. vivax although there have been a number of P.falciparum(Note: no data provided on mortality, morbidity or the cost of treatment)

Influx of refugees from malaria endemic area, the breakdown in health services, the lack of vector control and failure to carry out surveillance and control measures contribute to the resurgence of malaria in these countries.

Table 6: Autochthonous(Indigenous) malaria reported in eastern Europe (5)

Country 1996 1997 1998 1999 2000Armenia 149 567 542 329 56Azerbaijan 13,135 9,911 5,175 2,311 1,526Georgia 3 0 14 15 244Russian Federation

10 31 63 77 43

Tajikistan 16,561 29,794 19,351 13,493 19,064Turkey 60,634 35,376 36,780 20,908 11,381Turkmenistan 3 4 115 10 18

b) Imported Malaria

Imported malaria cases refer to acute malarial disease detected in travelers (tourists, military personnel or business people) returning from malaria-endemic countries. Airport malaria resulting from inadvertent transport of live infected mosquitoes aboard an aircraft arriving from a malaria-endemic country is considered imported malaria although the transmission of the parasite to human occurs locally. (5)

The WHO Regional Office for Europe reported a total of 15,528 cases of imported malaria in the year 2000. (5) In the European Union, 10,000 to 12,000 cases are recorded each year (2-3/100,000 population) but the actual number may be as high as 20,000 per year if one considers that a large number of cases are not diagnosed and/or reported (Table 7).

Table 7: Imported cases of malaria in Europe 1996-2000 (5)

Country 1996 1997 1998 1999 2000Austria 87 75 80 93 62Belgium n/a n/a 334 369 337Denmark 191 213 174 207 202France 5,109 5,377 5,9401 6,1271 8,0561

Germany 1,021 1,017 1,008 918 732Italy 760 814 931 1,006 986Netherlands 308 223 250 263 691Norway 101 107 88 74 79Russian Federation

601 798 1,018 715 752

Spain 224 291 339 260 333Sweden 189 183 172 153 132Switzerland 292 319 339 313 317United Kingdom 2,500 2,364 2,073 2,045 2,069

1 Preliminary dataThe number of imported cases has been increasing in all European countries over the period 1996-2000. Most of the cases are of P. falciparum and the most common area of origin is Africa. In continental France and the United Kingdom,

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where the largest numbers are recorded, imported malaria cases constitute both a serious public health problem and often grave medical problems for the infected patients.

The overall burden of malaria cases (indigenous or imported) in Europe is not known. However, based on available data and observations listed below, it appears that the risks may be underestimated and that the lack of attention to the problem could result in a more serious public health and economic burden in Europe.

Level of underreporting is estimated to be 20% in Finland, 55% in France and 59% in The Netherlands. (25) (Note: No other country data was found on estimated underreporting.(26)

Within a decade (1989-1999) 680 people died of P. falciparum imported malaria cases in the WHO European Region. Deaths often result from delayed diagnosis because physicians are not often confronted with this disease and the increasing frequency of drug-resistant strains among the imported cases.

Most countries where important surveillance data are available report that travelers’ compliance to prophylactic drugs or prevention measures are extremely poor due to unpleasant side effects, complicated regimen and incorrect information provided by health care professionals or tour operators.

In France, the overall cost of an uncomplicated case of malaria (medical expenses and an average sick leave of two weeks) has been estimated at 6,400 Euros for inpatients and 1,400 Euros for outpatients.(27) Thus, for the more than 8,000 cases in the year 2000, the total cost to the country could have been nearly 20 million Euros.

In Switzerland the average cost of the treatment of a single case of malaria was CHF 44,000.(28)

Control StrategyIn the 19th century, the distribution of malaria was widespread occurring not only in the tropics, but in much of the temperate regions of the world, including parts of England, Holland, central and southern Europe and in North Americas as far north as Montreal.(9,13) The Global Eradication Campaign, which took place between 1955 and 1964 has clearly restricted malaria distribution by eradicating it from North America and Europe. The campaign largely relied on insecticides and drugs to wipe out the disease. Changes in agricultural practices, improvement of lifestyle and quality of households as well as political and social will and large funding commitments all contributed to its success in the developed countries. However, the eradication campaign failed in the developing countries. Today, it is generally accepted that eradication may not be a realistic goal in many parts of the world. Nevertheless, controlling malaria and significantly reducing its burden on the disease endemic countries are acknowledged as attainable goals, at least in the short to medium term. (9,29)

The control of malaria is aimed at reducing mortality and disease incidence until it is no longer a public health issue. It requires a good understanding of epidemiology by the communities and health care providers. It also requires capacity strengthening of the health care systems in many areas due to the

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spectrum of clinical manifestations of the disease from mild cases in semi-immune individuals to severe life-threatening illness requiring challenging medical management especially for children and pregnant women.

In 1952 Russell(30) proposed a classification of measures for the prevention and control of malaria. Beales and Gilles published a comprehensive review of the principles driving prevention and control, including those established earlier by Russell.(29)

For the purpose of this analysis, control strategies have been classified and summarized as follows:

Vector control Case management Vaccine

Vector control aims at reducing the vector’s capacity to infect individuals by using personal protection to block contact between humans and mosquitoes, diminishing the breeding environment of mosquitoes and, using insecticide to reduce the mosquito population. Case management includes the early diagnosis and treatment of infected persons. Vaccines may offer protection but to date there is no malaria vaccine with proven efficacy.

Other important strategies are advocated by the WHO(31) and include: forecasting epidemic outbreaks, development of epidemiological information systems, capacity building in basic and applied research and ongoing assessment of ecological, social and economic determinants of disease in affected regions.

Vector ControlVector control has proven to be effective if employed adequately. The present discussion will be limited to a brief description of the tools currently recommended and how they can prevent human infection or transmission.(9,17,29)

1) Insecticide treated bed nets and other materials (ITN):

Bed nets and clothes impregnated with pyrethroid insecticides provide a chemical and physical barrier between mosquitoes and individuals. They are useful in African settings where the insects feed indoors during nighttime. In addition, insecticide helps reduce the density of insects provided that the level of coverage and the use by the local population is significant, thus limiting further transmission.

Pyrethroids are synthetic derivatives of pyrethrum, an extract of dried chrysanthemum flowers, which act as nerve poisons that rapidly permeate and kill insects but show low toxicity to mammals. The major limitation is the short-lived action, which results in the need for re-treatment every 6 to 12 months. Long-lasting insecticide nets (i.e: with insecticide incorporated directly in net fibers) would eliminate the need for frequent re-treatment. Early prototypes introduced on the market gave unsatisfactory results but research and development continues.

This method proved very successful in China and Vietnam, where governments promoted the use of bed nets and also offered re-treatment free of charge. The

6.10-15


WHO-Roll Back Malaria strongly advocates the use of ITN and several programs are in place to provide large scale coverage.(17) Personal protection has been shown to significantly reduce the risks of infection but their use is highly dependent upon the level of education and family incomes.(11)

2) Indoor Residual Insecticide Spraying (IRS):

This method, consisting of spraying the inside surface of walls and ceilings of houses, was introduced on a large scale in the 1930s, first, with pyrethrum and later with DDT. IRS works by preventing a large proportion of mosquitoes from surviving 12 to 14 days, which is the time it takes for the malaria parasite to develop to the infective stage within the mosquito. A daily mosquito mortality rate of up to 40-50% can be achieved and, if used on a large scale, can help reduce transmission in a community, even in non-users.(9-11) DDT-based IRS has declined over the past 30 years, in part because of the development of DDT resistance in vector and also because the general disapproval of DDT by the international community. The International Convention of Persistent Organic Pollutants now contains an amendment specifically excluding DDT for vector control from being banned. DDT-based IRS is particularly appropriate in situation of epidemics as it was the case in Madagascar in the 1980's.(32)

3) Environmental and Biologic Management (source reduction):

This approach aims at preventing or reducing the breeding of mosquitoes or destroying the larvae. This can be achieved by construction of dams, formation of reservoir and irrigation systems, modifying the boundaries of rivers or their run-off systems, drying rice field intermittently or other ecosystem modifying approaches. These methods can produce results where the vector breeding sites are few in number and can be identified, such as in India and in Southeast Asia.

The WHO has shown a renewed interest in environmental control of malaria vector and issued two important publications on engineering and technical aspects of as well as individual and community vector control:

Manual on environmental management for mosquito control, with special emphasis on malaria vectors. WHO Offsets Publications, No.66 Geneva, Offsets Publications, 1982a

WHO Vector Control. Geneva, World Health Organization 1997b

Case Management

1) Diagnosis

The success of disease management relies on a prompt and accurate diagnosis, which is based on confirmation of parasite in the blood. Young children may develop complications of P. falciparum very rapidly and ideally treatment should be initiated within 12 hours of onset of symptoms. Optimal diagnosis is made by microscopic examination requiring trained laboratory technicians, well maintained equipment and reagents, all of which, is time consuming and expensive. Because many health facilities in developing countries cannot meet these requirements, diagnosis is based on clinical signs and symptoms, which include chills, fever, diarrhea, general body aches or headaches. This clinical picture mimics that of many other common diseases and in absence of a microscopic diagnosis treatment is initiated on "presumptive" basis. Such practices result in 60% over-treatment and increases costs significantly in

6.10-16


addition to the potential health hazards associated to excessive drug exposure and increased propensity for drug resistance.(17) This wastage could be reduced if clinical diagnosis was done according to criteria based on epidemiology (transmission season), age and gender of the patient.

Rapid diagnostic tests (RDTs), which are based on plasmodium antigen detection incorporated onto a disposable dipstick and are easy to use by laypeople, have been introduced recently. The test is sensitive but there is little information on its effectiveness yet.(9) (See appendix 6.10.4)

2) Treatment of malaria cases

Malaria can be effectively treated with drugs. Currently, a number of antimalarials are available, however, two of the most widely used drugs, chloroquine and SP are useless in many parts of the world due to drug resistance. The most favored antimalarial on the market for uncomplicated P. falciparum malaria is artemether-lumefantrine, a fixed-dose artemisinin-based combination therapy (ACT) as recommended by the WHO for first line treatment. (10)

The complexity of host response to this infection makes evaluation of drug efficacy difficult. Furthermore, the plasmodia that have entered into the patient blood stream will undergo asexual maturation and another round of multiplication or a number of parasites will have transformed into sexual forms called gametocytes. Because each stage of the parasite life-cycle exhibits distinct biochemical characteristics, one drug may kill one stage of the parasite but have little or no effect on another. Most drugs are inactive against gametocytes. In P. falciparum, gametocytes emerge after 10 days and, once ingested by a mosquito after it has bitten an infected human, can perpetuate transmission. Therefore, initiating treatment early with an effective antimalarial drug can make a significant impact in the transmission rate, at least for P. falciparum infection. Several antimalarial drugs are currently marketed in oral or parenteral (injectable) formulation and to treat or prevent malaria (Table 8).

6.10-17



Table 8: Characteristics of currently available antimalarial drugs.Drug name Indication LimitationsQuinine (QN) cure symptomatic infection,

severe and cerebral malaria1compliance, resistance, safety

Chloroquine (CQ) cure symptomatic infection, IPT2

resistance, safety at high dose

Primaquine prophylaxis for travelers and antirelapsing3 for P.vivax or P. ovale; transmission blocker (gametocytocidal)4

compliance, safety, poor activity on blood schizonts

Sulphadoxine/Pyrimethamine (SP)

cure symptomatic infection, prophylaxis for travelers and IPT

resistance

Amodiaquine (AQ) cure symptomatic infection resistance, safety

Artemisinins cure symptomatic infection, severe and cerebral malaria,(gametocytocidal)4

cost, length of treatment, safety in early pregnancy?

Mefloquine cure symptomatic infection, prophylaxis

resistance, cost, safety

Halofantrine cure symptomatic infection resistance, safety, cost

Arthemeter-lumefantrine

cure symptomatic infection,(gametocytocidal) 4

compliance, cost, resistance, safety in early pregnancy

Chlorproguanil/Dapsone (Lapdap™)

cure symptomatic infection resistance, safety in G6PD deficiency, safety in pregnancy

Proguanil/Atovaquone(Malarone™)

cure symptomatic infection,prophylaxis for travelers

cost, resistance

Piperaquine/Dehydroartemisinin(Artekin™)

cure symptomatic infection(gametocytocidal) 4

potential resistance, availability of GMP material, safety in pregnancy

1 Severe malaria: Outline classification of sever malaria is as follows (33):Group 1: Children t immediate risk of dying who require parenteral antimalarial drugs and supportive therapy(a) Prostrated children (prostration is the inability to sit upright in a child normally able to do so, or to drink in the case of children too young to sit)Three subgroups of increasing severity should be distinguished

i) Prostrate but fully consciousii) Prostrate with impaired consciousness but not in deep comaiii) Coma (inability to localize a painful stimulus

(b) Respiratory distressi) Mild-- sustained nasal flaring and/or mild intercostals indrawing (recession)ii) Severe--the presence of either marked indrawing (recession) of the bony structure of

the lower chest wall or deep (acidotic) breathingGroup 2: Children who, though able to be treated with normal antimalarial drugs require supervised management because of the risk of clinical deterioration but who show none of the features of group 1 (above)(a) Children with a hemoglobin level < 5 g/dL or hematocrit < 15%(b) Children with 2 or more convulsions within a 24 hour periodGroup 3: Children who require parenteral treatment because of persistent vomiting but who lack any specific clinical or laboratory features of groups 1 or 2 (above)2 IPT= Intermittent preventive treatment: drugs administered intermittently to prevent malaria attack in children or complications in pregnant women3 Anti-relapsing: also referred to as radical cure because it kills the hypnozoites or latent liver stage4 Gametocytocidal: sterilization of mature gametocytes but the effect on malaria transmission has not been rigorously evaluated in clinical studies.Results from controlled and uncontrolled clinical trials assessing efficacy of any given drugs are sometimes conflicting but nevertheless it is widely recognized

6.10-18


that prompt intervention with an effective antimalarial reduces morbidity and mortality associated with malaria.(17)

The choice of drugs should depend on a variety of factors such as the pattern of resistance, cost, safety (side-effects), pharmacokinetics, compliance (adherence to treatment regimen) availability and access. The ideal drug for endemic countries should be one that meets all of the following:

active against resistant strains, inexpensive safe to use in pregnancy safe use in children option of oral and parenteral formulation pharmacokinetics (should remain in the body long enough to cure in three

days i.e.: no recrudescence for at least 28 days post-treatment) gametocytocidal active against exo-erythrocytic (liver) stage of plasmodia where P. vivax is

endemic

No such drug exists currently. The situation today is simple but tragic: drugs that are inexpensive no longer work because of widespread resistance and drugs that do work are not affordable by the economic standards of disease-endemic countries.

Antimalarial drug resistance is a major challenge in malaria treatment. Resistance results from gene mutation in the plasmodium and many factors are known to influence the spread of drug resistance. These factors may be genetic (the degree of resistance conferred by a given mutation) or may be linked to the pharmacokinetics (drug concentration profile) and pattern of drug use (quality, availability, distribution) or the immune status of the immunity profile of a community. It is generally accepted that today's widespread resistance to chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) is the result of mass administration and long-term use of these drugs. Chloroquine resistance was first described in the late 50's in S.E. Asia and then in the'70s in Africa and resistance to SP was reported within about 1 year of its introduction. (9) Both drugs have lost clinical effectiveness in Africa where treatment failure rates have reached 80% for CQ in some regions as illustrated in Figures 2 and 3.(17)

Drugs with long elimination phase play a role in resistance development by acting as selective filters, allowing resistant parasite to survive and multiply while the residual drug levels suppress the sensitive parasites. For example, mefloquine and piperaquine have a long elimination phase that could lead to significant selection pressure. Inadequate treatment protocol (dose level administered or duration) or poor quality drug product on the market has also been associated with the development of resistance.

Finally the immunity status of a population contributes to resistance selection as the drug resistant mutants are more likely to emerge from infections involving a large numbers of parasites, which most often occur in non-immune individuals such as children. Therefore, children or non-immune individuals infected with a large numbers of parasites who receive inadequate treatment, (either because of poor quality drug, lack of compliance, vomiting an oral treatment, etc.) are another potential source of resistance.

6.10-19


In order to delay the development and spread of drug resistance, combination therapy has been recommended by the WHO as well as by most malaria experts.(10) Combination therapy consists in administering concomitantly two or more antimalarials, preferably containing artemisinin or one of its derivatives such artesunate, dihydroartemisinin, artemether or arteether (known as ACT or artemisinin-based combination therapy). Artemisinin is derived from a Chinese plant, Artemisia annua, and has been used as an antimalarial in China for over 2000 years. It is today the most potent antimalarial, killing rapidly the biomass of parasites in the blood. However, because of its very short half-life, the drug is eliminated rapidly leaving an opportunity for the residual parasites in the blood or the liver to recrudesce. To be effective as monotherapy, artemisinin must be given at least twice a day for 5 to 7 days. By combining artemisinin with a drug having a longer elimination half-life and a different mechanism of action, the probability for selection of resistant parasite is less and treatment course can be reduced to about 3 days, thus also increasing adherence to treatment. Resistance to artemisinin has not yet been reported but concerns are increasing because of the potential emergence of resistant parasites if it is used massively as monotherapy. Monotherapies can also threaten the efficacy and resistance potential of combination therapies.

6.10-20


Figure 2: Chloroquine Treatment failure in Africa (Source: Africa Malaria Report 2003 WHO 2003) (17)

Figure 3: SP treatment failure in Africa (17)

The other important limitation of artemisinin drugs is the cost. Because it is derived from plant, several laborious steps are necessary to finally develop the end product. The crop must first be planted and then harvested. The artemisinin must then be extracted, purified, synthesized and then formulated into a pill. Co-formulation (two or more drugs in one pill) with the companion drug(s) further adds to the cost of the final finished product. The process takes a total of 18 months, making quick

scale-up a challenge.

Table 9 lists the prices that Médecins Sans Frontières (MSF) pays for these drugs. The quality standards (GMP status) may vary according to suppliers. Coartem, a co-formulation of artemether and lumefantrine, recommended by the WHO, costs US$ 2.40 per treatment course at wholesale and can be marked up

6.10-21


to five times that amount in the private sector. This price is not affordable by much of the population living in disease-endemic countries. For some of the poorest people living with the disease, even a 10-cent dose of chloroquine is already expensive. At US$ 0.10 per course, governments can afford or are able to find external funding to buy chloroquine for the public sector needs. When multiplying the cost of one treatment course with ACT by 200 to 400 million, the estimated number of treatment courses required annually in Africa, it is not surprising that many African countries have not yet switched to ACT drugs such as Coartem. In face of the burden that malaria represents and because ACTs are not deemed affordable at present prices (between US$ 1.00 and 3.00) many countries are changing malaria treatment policies and are buying non-fixed combination of existing drugs such as CQ +SP or AQ plus SP or, if a little more fortunate, they can afford CQ+ and artemisinin, SP + artemisinin or amodiaquine. Many of these non-fixed combinations have not been rigorously tested for safety or efficacy but they are used in the interim, until affordable new drugs become available.

6.10-22


Table 9: Wholesale prices for Artesunate (semi-synthetic artemisinin derivative) (9)

Drug Range of prices for standard adult dose

Artesunate Asian suppliers:US$0.50 (not yet in production); less for greater quantitiesUS$0.63; 15% discount for greater than 1 million treatmentsUS$1.25 (not yet in production)US$1.26; decreasing to US$1.01 at 3 million treatmentsUS$1.35European suppliers:US$2.68 (2.10 Euros)US$2.42 (1.90 Euros)African suppliers:US$5.36

Coartem US$2.40 for public services of developing countries (tiered pricing; higher for all other buyers)

CV8 (8 tablets) US$1.21 for <1 million treatments; US$0.97 for > 1 million treatments

Artekin II US$1.00 at retail

AS + AQ blister Asian suppliers:US$1.50 (not yet in production)<US$1.91 (1.50 Euros) (not yet in production)European suppliers:US$1.53 (1.2 Euros)US$1.91 (1.5 Euros)US$2.68 (2.10 Euros) for<500,000 treatments; US$1.39 (1.09 Euros) for >500,000 treatments

AS + SP blister (6 tablets) European suppliers:US$2.42 (1.90 Euros) for <500,000 treatments; US$1.24 (0.97 Euros) for >

AQ = AmodiaquineAS = ArtesunateSP = Sulfadoxine-PyrimethamineCV8 = a new combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine

From:: J.M. Kindermans, Médecins Sans Frontières, 2003

Older antimalarials (Table 8) have not been submitted to the battery of safety pharmacology and toxicology testing currently required by international regulatory standards. Almost no post-marketing surveillance (PMS or pharmacovigilance) data have been generated following introduction of CQ, SP or AQ. For newer drugs, safety data are largely derived from studies to assess prophylactic efficacy of these drugs in non-immune travelers (for example, mefloquine or atovaquone/proguanil). Therefore, the true toxicity of these drugs in African populations is poorly understood and documented. Given the clinical

6.10-23


experience gained worldwide, most drugs are considered relatively safe when used under adequate medical surveillance and control. However, in endemic countries, self medication is common place because health service infrastructure is nonexistent or inadequate. Most rural populations, where malaria burden is higher, lack basic health care services. In addition, many health facilities, where they exist, encounter difficulties keeping up with procurement of essential drugs. This coupled with other challenges such as distance to the health care facility are disincentives to the rural populations to call upon health systems for antimalarial treatment. In Africa, between 70 % and 90% of febrile events in children are treated at home in absence of medical diagnosis. Not all febrile events are due to malaria infection but yet many children are exposed repeatedly to potentially toxic drugs. In absence of a reliable health care infrastructure one can assume that pharmacovigilance is equally deficient and the long-term effect of multiple drug exposure on growth and development of children is not known. CQ, the most widely and frequently used drug throughout Africa seems to have the least documented adverse drug reaction risk description. (12)

As mentioned above, the malaria burden is serious in pregnant women (Table 3). In addition to the prompt treatment of a clinical manifestation, the WHO recommends that intermittent preventive treatment (IPT), consisting of two full courses of treatment with an effective antimalarial drug, be made available as part of antenatal care to women in their first or second pregnancies in high transmission areas. (17) Due to the high prevalence of chloroquine (CQ) resistance, sulfadoxine/ pyrimethamine (SP) is the only antimalarial available for use in pregnant women. It has been shown to reduce severe anemia and largely eliminates low birth weight. In addition it was more cost effective than CQ. An effective replacement alternative to SP is needed because the efficacy of this drug is now compromised throughout most of Africa. Other antimalarials are under study to determine whether they are safe and effective for IPT. Recent surveys confirm that at least two-thirds of pregnant women attend antenatal clinic in most African countries at least twice during pregnancy (from second trimester), which provide an opportunity to deliver a prevention drug package. However, visits to antenatal clinics do not necessarily translate into full coverage of IPT as it was observed in Malawi where, a significant increase to 75% coverage was achieved after a well coordinated education campaign about the benefit of IPT during antenatal clinic. (17)

IPT in infancy has also been shown to reduce severe anemia and deaths. In Tanzania, a study showed that clinical malaria was reduced by 60% and severe anemia by 50% in children who received two treatments of SP during their first year of life. (17) Additional studies are underway to evaluate the efficacy and safety of IPT in infancy. However, there are concerns that chemoprophylaxis provided at weekly or fortnightly intervals may be difficult to sustain and where it is possible, it may accelerate the onset of resistance and could impair the development of natural immunity.

VaccinesAlthough vaccines have been one of the most cost effective and easily administered means of controlling infectious diseases, safe and effective malaria vaccine are not yet available and are not expected before another decade. (34)

The development of a malaria vaccine is challenging because the malaria parasites have complex life cycles and thus, distinct development stages, each of

6.10-24


which has multiple antigens that could serve as targets of an immune response. The current approaches to malaria vaccine development can be classified as follows. (35)

1) A pre-erythrocyte that would protect against the infectious form injected by the mosquito (sporozoite) and/or inhibit the development in the liver.

2) An erythrocyte or asexual blood stage vaccine that would inhibit parasite multiplication in the red cells, thus preventing (or decreasing) severe disease during the blood infection.

3) A gametocyte or sexual stage vaccine that would interrupt the cycle of transmission by inhibiting the further development of parasites ingested by the mosquito.

Much research is still needed to discover and develop a safe and effective vaccine but several and studies indicate that it is an achievable goal. The rationale is based on the following observations. (35)

Subjects living in malaria endemic regions naturally acquire protective immunity against clinical diseaseInoculation with attenuated sporozoites can immunize patients against subsequent malaria infection

Immunoglobulin purified from the blood of immune individuals can passively transfer protection against P. falciparum.

Early clinical trials of defined vaccines have shown some degree of efficacy.

Why does the disease burden persist? What can be learnt from past and current research?The reasons for the resurgence of malaria over the past few decades are complex and involve the interplay of environmental, social and political factors.

Technical obstacles such as increasing resistance to insecticides and to drugs, greater exposure to mosquito bites due to primitive housings contributed to the failure of achieving or maintaining control of malaria. The continued problem of the lack of basic health care poses huge challenges in case management of malarial. Further, regional wars, civil unrest, extensive agricultural development projects have worsened the situation by forcing migration of people into highly endemic areas where public health infrastructure is the weakest. Trends in weather pattern such as global warming have been associated with the increase of mosquito population in previously malaria-free areas and El Niño-induced floods is thought to be responsible for local epidemics. Of all the factors cited, most experts agree that the most important is the wide spread resistance to antimalarial drugs in disease endemic areas.

In 1998 the WHO launched the Roll Back Malaria (RBM) initiative to spearhead the global effort to control malaria by acting as a coordinating body in the fight against the disease. The mandate is to half the malaria burden worldwide by 2010 by achieving the following goals:

to provide 60% coverage of children and pregnant women with insecticide treated bednets

to have 60% of malaria cases receive an effective treatment within 24 hours of the onset of symptoms,

6.10-25


to ensure that 60% of pregnant women receive IPT to enable detection of 60% epidemics within two weeks of onset and

implement a response within the next two weeks.

The Commission of Macroeconomics and Health has estimated that an immediate injection of US$ 1 billion per annum was needed to work toward the goals of RBM. Despite improvement in international support and donors expenditures over the past few years, the pledges from donors to date are far below this target. However, even if this financial target is achieved, the morbidity and mortality burden is unlikely to change if antimalarial drugs continue failing due to resistance, poor compliance (effectiveness), safety or high cost. Immediate replacement drugs for CQ and SP include amodiaquine and the fixed combination of chlorproguanil/dapsone (Lapdap ®). However, these drugs already suffer from some cross-resistance with CQ and SP thus, shortening their therapeutic life time and their safety has not yet been fully established in areas where no pharmacovigilance exist. The combination of expensive semi-synthetic artemisinins with older drugs is a short to mid-term solution. SP, the only antimalarial recommended for pregnant women, suffers from widespread resistance. Providing IPT to 60% of pregnant women with a failing drug is not going to change the picture of anemia and low birth weight. Primaquine introduced in the 1940's is still the only existing drug for radical cure (anti-relapse) of vivax malaria. Clearly, new drugs are needed and strategies directed to the discovery and development of safe, effective and affordable drugs must be implemented urgently.

Drug R&D is challenging, requiring scientific and technical skills, and enormous capital. The research-based pharmaceutical industries spend on average US$ 800 million for every new drug when taking into account the high R&D failure rate. The return on investments must be high to justify such spending. Unlike diseases affecting populations of Europe, North America and Japan for which the market system has produced innovative therapies, tropical diseases in developing countries, even considering the millions of sufferers, do not generate the revenue to attract R&D investment for the pharmaceutical industry. In other words, developing countries cannot pay for market-financed innovative therapies. As a result, only 1% of 1,393 new chemical entities (NCE) were approved for tropical diseases over the past 25 years with only four antimalarials registered between 1975 and 1999. (36) Furthermore, these drugs were developed as prophylaxis for travelers or military personnel and therefore are not appropriate and affordable by the population in the disease-endemic areas. Currently most favored ACT are too expensive. Lower prices for ACT may be expected as large-scale demand increases and induces competition among manufacturers. That is also assuming that supply of the drugs can meet such demand, if not, the short term scenario could actually mean that the prices may even increase. Higher demand may also encourage the criminal exploitation of the sick and desperate people by peddlers or less ethical manufacturers of counterfeit or poor quality drugs. (9) This not only endangers patients, it also jeopardizes the use of the registered drugs.

The establishment of the Global Funds to Fight AIDS, Tuberculosis and Malaria as a purchasing fund for procurement of antimalarials may, to some extent, provide a mechanism to justify efforts in R&D. However, the fund is not intended to finance R&D itself.

The discovery and development of the antimalarial drugs registered between 1975 and 1996 was funded largely by the public sector, in particular the

6.10-26


military. The creation of the United Nations Development Programme/World Bank/World Health Organization/ Special Programme for Research and Training in Tropical Diseases (WHO/TDR) in 1975 facilitated the establishment of a partnership approach to drug discovery and development between public sector organizations and companies for those diseases lacking the market incentive. Mefloquine and halofantrine were discovered, developed and registered as a result of collaboration between the Walter Reed US Army Institute of Research (WRAIR), WHO/TDR and the private pharmaceutical companies.(37)

This approach evolved rapidly and led to the creation of organizations such as the Medicines for Malaria Venture (MMV, http://www.mmv.org), a not-for-profit organization using a public-private partnerships (PPP) approach to discover, develop, and deliver new antimalarials as "global public goods". This was made possible by recent increase in funding opportunities through national governments, philanthropic organizations or private industry. The establishment of the Bill & Melinda Gates Foundation with its mission of supporting such innovative approaches for product development for neglected diseases has made a tremendous impact in the capabilities of these PPPs.

To date sixteen PPPs have been established specifically for product development (PD-PPP) in diseases otherwise neglected by the private sector. Like MMV, these PPPs use the private sector approaches to face research and development challenges, and use the portfolio management approach to pursue their goal of fulfilling a public health rather than commercial need by developing a product specifically for use in developing countries. These sixteen PPP represent more than 1.1 billion in committed funding which includes funding received as well as funding that is pledged in the future. Structure, focus, size and management of these PD-PPP have been subject of an in-depth review: Public-Private Partnerships for Neglected Diseases Opportunities to Address Pharmaceutical Gaps for Neglected Diseases (Chapter 8.1).

The large pharmaceutical companies are also increasingly becoming involved in the search of new therapeutic tools for neglected diseases, which facilitates the establishment of drug development partnerships. For instances, GSK has established Diseases of the Developing World Initiative; Sanofi has established Malaria Impact Initiative and Novartis has established the Novartis Institute for Tropical Diseases. Pfizer is currently sponsoring clinical trials to assess the safety and efficacy of the combination of azithromycin and chloroquine for uncomplicated malaria.

In only four years of operation MMV is managing the largest-ever portfolio of malaria drug research, with 21 projects which will be discussed in further details below. More important than the total number of projects, is the fact that the portfolio includes eight completely new classes of drugs, illustrating the opportunity for innovation that PPPs has to offer. Such advances result from MMV's collaborations with 40 public and private institutions around the world. Partnerships operate within a well established contractual framework: pharmaceutical, biotec and research institute partners contribute their know-how, staff, infrastructure and facilities to individual projects, while MMV and its Expert Scientific Advisory Committee manage the portfolio as a whole.

There is much hope that efforts resulting from innovative-discovery will continue to feed the antimalarial pipeline as exciting scientific breakthroughs have occurred in our knowledge of the biology, immunology and molecular genetics of malaria. The P. falciparum genomic information can be exploited to yield new

6.10-27

http://www.mmv.org/


therapeutic targets, as well as antigens for potential vaccines. The potential offered by the improved understanding of the biochemistry pathways of the plasmodia is illustrated in Table 10 below. A comprehensive review of recent advances in target selection and validation and, screening methods of antimalarial drug candidate has been published recently by Fidock et al. (38)

These innovation opportunities need not only to be seized but also transitioned into a malaria specific drug development program to ensure that the new drug candidates translate into treatments fulfilling the ongoing unmet medical needs in malaria.

6.10-28


Table 10: Targets for antimalarial chemotherapy (Source: Fidock et al, 2004) (38) Reproduced with permission from Nature Reviews (www.nature.com/reviews) Drug Discovery (Vol 3, No. 6, pp 509-520)copyright (2004) Macmillan Magazines Ltd.

Target location

Pathway/mechanism

Target molecule Examples of therapies References

Existing therapies New compounds

Cytosol Folate metabolism

Glycolisis

Protein synthesisGlutathione metabolismSignal transductionUnknown

Dihydrofolate reductaseDihydropteroate synthaseThymiclylate synthaseLactate dehydrogenasePeptide deformylaseHeat-shock protein 90Glutathione reductaseProtein KinasesCa2+ - ATPase

Pyrimathamine, proguanilSulphadoxine, dapsone

Artemisinins

Chlorproguanil

5-fluorootateGossypol derivativesActinoninGeldanamycinEnzyme inhibitorsOxindole derivatives

82,83

84858687888990

ParasiteMembrane

Phospholipid synthesisMembrane transport

Choline transporterUnique channelsHexose transporter Quinolines

G25

Dinucleoside dimmersHexos derrivatives

71

91

92

Food vacuole Haem polymerizationHaemoglobin hydrolysis

Free-radical generation

HaemozoinPlasmepsinsFalcipainsUnknown

Chloroquine

Artemisinins

New quinolinesProtease inhibitorsProtease inhibitorsNew peroxides

93,9495,9697,9899,100

Mitochondrion

Electron transport

Cytochrome c xidoreductase

Atovaquone 101

Apicoplast Protein synthesisDNA synthesisTranscriptionType II fatty acid bio-synthesisIsoprenoid synthesisProtein farnesylation

Apicoplast ribosomeDNA gyraseRNA polymeraseFabHFabI/PIENRDOXP reductoisomeraseFarnesyl transferase

Tetracycline, clindamycinQuinolonesRifampin Thiolactomycin

TriclosanFosmidomycinPeptidomimetics

102

2932,33,1033025,104

Extracellular Erythrocyte invasion

Subtilisin serine proteases

Protease inhibitors

97,105

DOXP, 1-deoxy-p-zylulose 5-phosphate; PIENR, Plasmodium falciparum enoyl-ACP reductase

6.10-29


What is the current pipeline?For the purpose of this analysis, projects have been classified under two main categories:

Development: includes all projects for which compound has been selected for full scale regulatory pre-clinical or clinical development programme.

Discovery: includes all projects for which compound has not yet been selected

Development ProjectsDrug name(s) Sponsoring Organizations Status

Rectal artesunate WHO/TDR Pre-registration

Chloroquine- Pfizer Phase II/IIIAzythromycin

Artemether-lumefantrine MMV- Novartis-(WHO-TDR) Line extension Pediatric Coartem

Chlorproguanil-dapsone- MMV- GSK- WHO/TDR, Phase IIArtesunate (ACT)

Improved pentamidine MMV- Immtech International Phase IIDB289 Univ. North Carolina

Mefloquine- DNDi, TROPIVAL (France), Phase I/IIArtesunate (co-package) Far Manginhos, Brazil

Amodiaquine- DNDi, TROPIVAL (France) Phase I/IIArtesunate (co-package) Far Manginhos, Brazil

Synthetic Peroxide MMV- Ranbaxy (India) Phase I/IIOZ277/RBX11160

Pyronaridine-artesunate MMV- Shin Poong Ltd. (Korea) Phase I/II

Intravenous artesunate MMV- WRAIR (USA) IND

Dihydroartemisinin MMV- Holleykin (China) Pre-clinical GLPpiperaquine (Artekin) Sigma-Tau (Italy), Oxford University

Clinical GCP

Artemifone MMV- Bayer (Germany) Phase I/II

8-aminoquinoline MMV- Univ. Mississippi Pre-INDNPC1161B NIH

4-aminoquinoline MMV- GSK- Univ. Liverpool (UK) TransitionIsoquine

4-aminoquinoline AQ-13 Tulane Univesity- NIH Phase II

CQ-Methylene Blue MSD-Univ. Heidelberg Phase II

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Discovery Projects

Project name(s) Sponsoring Organizations Status

Dicationic molecules MMV- Univ. North Carolina Lead optimizationGeorgia State Univ.Swiss Tropical Institute

4 (1H)-pyridones MMV-GSK (Spain) Pre-clinical

Novel tetracyclines MMV-Paratek (USA) Lead identification

Protein farnesyl- MMV-Univ. Washington- Lead optimizationTransferase (Pf-PFT) Yale University

Manzamine alkaloids MMV-Univ. Mississippi- Lead optimizationUniv. Maryland-

Gadjah Mada Univ. (Indonesia)

Dihydrofolate reductase MMV-Biotec (Thailand)- Lead identification

London School of Hygiene andTropical Medicine (UK)-Monash University (Australia)

Falcipain MMV-Univ. San Francisco- Lead identificationGSK (Spain)

Fatty acid biosynthesis (FAS II)MMV-Texas A&M-Albert Einstein Lead identificationJacobus Pharma

Glycerhaldehyde-3- MMV-Swiss Tropical Ins,- ExploratoryPhosphate dehydrogenase Hoffman-LaRoche(GAPDH)

Fatty acid MMV-GSK (Spain) ExploratoryBiosynthesis (FAB I)

Peptide deformylase MMV-GSK (Spain) Exploratory

In addition to this portfolio, one should mention the significant efforts of research and development deployed by the Walter Reed Army Research Institute of Research (WRAIR), through the United States Army Medical Research and Material Command (USAMRMC) in the search of new antimalarials. (9) Several families of compounds in various stages of pre-clinical development include:

Pyrroloquinazolines 3rd generation antifolates Imidazolinedione derivatives Tryptanthrins New macrolides and ketolides Chalcones Methylene Blue Mefloquine analogs Tafenoquine

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Many of these compounds were selected on the basis of their prophylactic potential as they are intended for soldiers on mission in malaria endemic countries. The desired drug profile needed to treat uncomplicated or severe malaria in developing countries is very specific to these populations and will be discussed in further detail below.

For the non-initiated to the complexity and risk associated with innovative drug discovery and development, the current antimalarial portfolio may appear like a Roman feast and thus, one could question the rationale for the quest of new drugs. While the innovation is paramount this does not simply mean new drugs. The challenge is not so much about developing newer drugs but developing better drugs, those that will be custom-made for the most neglected, namely children and pregnant women. In addition, it is not expected that these projects will all succeed. R&D is high-risk, with more failures than successes. Hence, a sustainable pipeline of drug research is necessary in order to yield effective, affordable and appropriate antimalarials.

Given the devastating impact of multi-drug resistance, delivering artemisinin-fixed combination therapies in the immediate future is a priority in line with the WHO-RBM's objectives. This is why the portfolio includes many new ACT or new formulations of existing drugs, such as: pediatric formulation of Coartem (lumefantrine- artemether) and rectal and intravenous formulations of artesunate. Likewise the following fixed and non-fixed ACT may be viewed as the low hanging fruits as they are combinations of older drugs with known safety and efficacy profiles. All are currently in various phases of clinical trials and for the most advanced products, approval of a marketing application by at least one internationally recognized regulatory authority is contemplated as early as 2006 or 2007. Their success will depend not only on the evidence of safety and efficacy but also stability (shelf-life), availability (access) and cost.

artesunate with chlorproguanil-dapsone (CDA), mefloqine-artesunate (non-fixed) amodiaquine-artesunae (non-fixed) artesunate: pyronaridine DHA:piperaquine (Artekin)

DB289, an improved pentamidine-like molecule showed good activity in a proof of concept study and is now undergoing further biopharmaceutical studies to determine whether the total daily dose can be increased in order to shorten the treatment course to 3 days. There is much hope that the synthetic peroxide (OZ277/RBX11160) will provide an alternative to the costly semi-synthetic artemisinin derivatives. A large phase I study is currently taking place in the UK and data to date justify progression to a proof of concept in malaria patients within the next few months. In line with current WHO recommendations discouraging the use of drug in monotherapy for the treatment of acute uncomplicated malaria, these drugs, as well as all other new drugs in MMV's portfolio, will be developed as fixed dose combination therapy unless there is a strong rationale or new recommendations arguing against this approach. There are currently two exceptions: rectal and intravenous formulations of artesunate, which are intended for severe malaria in situations where drugs cannot be administered orally and a drop of the parasite biomass must be achieved rapidly and can be followed with a definitive therapy.

There are a number of additional challenges to developing fixed-dose combination. Additional pre-clinical studies are required to preclude

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antagonistic effects, or safety concerns. This means further pharmacology and toxicology studies prior to progressing to clinical trials. Pharmaceutical development may be challenged by chemical incompatibility. Safety and efficacy trials must be preceded by well thought drug-interaction and dose-finding studies.

Significant funding will be required to bring these ACT and other new drugs on the market. MMV estimates that US$ 30 to 50 million will be needed annually to bring its products to registration. The newly established European Developing Countries Clinical Trials Partnership (EDCTP), committed to building clinical research capacity in developing countries, may bring significant support to MMV. Indeed, it is hoped that funding from EDCTP will be used to develop clinical trial site infrastructure and resources necessary to conduct research to international standards. Developing this capacity in developing countries is an absolute prerequisite to MMV’s success in conducting phase II-III studies to GCP standard acceptable by the competent regulatory authorities worldwide. However, for continued justification of EDCTP's existence, one must ensure that there are sufficient new chemical entities to be tested.

Opportunities for research and what are the gaps between current research and potential research issues In a recent communication, Lester M. Crawford, Acting Food and Drug Administration (FDA) Commissioner noted that while historically 14% of drugs that entered phase I clinical trial eventually obtained approval, now 8% of these drugs make it to the market. Filings of standard new molecular entities have also fallen by over 50% in less than 10 years, going from 34 in 1995 to 12 in 2003. This has pushed the cost of developing a single drug from US$1.1 billion in 1995 to 1.7 billion in 1997.(39) The reasons for the growing attrition rate are not clear but they certainly include the increasing complexity of the regulatory requirements as well as the several changes occurring in the pharmaceutical industry businesses. In response to the growing cost and complexity of drug development the FDA launched a program called Critical Paths to investigate strategies for improving the drug development process to reduce attrition.(39)

Drug candidates fail to achieve registration for several reasons in addition to those that are purely business decision. Toxicity is responsible for 21 % of failures, lack of activity or efficacy accounts for 29 % and oral bioavailability and formulation issues are responsible for 39 %. The steps that occur between discovery of a biological target and a drug candidate for development are crucial, requiring a multidisciplinary approach from medicinal chemistry, pharmacology, toxicology, pharmacokinetics as it was illustrated in a comprehensive review by Nwaka and Ridley.(37)

To optimize the drug selection process, MMV has defined a target product profile as follows:

Efficacy against drug resistant strains Cure within three days (once a day dosing regimen) Low propensity to generate rapid resistance Safe in small children (< 6 mos.) Safe in pregnancy Appropriate formulations and packaging Low cost of goods

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Drugs are also evaluated based on their potential to be used for the following indications:

Intermittent treatment in pregnancy and infancy Treatments suitable for emergency situations e.g. single dose treatment

for refugee camps P. vivax malaria (including radical cure) Severe malaria Prophylaxis

To reach this goal, the drug discovery process must rely on a prospective multidimensional lead optimization integrating antimalarial, physicochemical, metabolism, pharmacokinetic and toxicity. For instance, OZ277/RBX11160 was selected using a "selection matrix" based on the target characteristics and yield a compound with several advantages over those of semi-synthetic artemisinins.(40,41) Progression of OZ277 to development candidate took approximately three years and the compound is currently in phase I study, which is an encouraging result for the partnership approach (http://www.mmv.org).

However it is not known at this time whether this product or other products at this stage of development will be safe in small children or pregnant women as there is no predictive model that can be included in the "selection matrix" package.

Artemisinin derivatives have been taxed for a long period of time with neurotoxicological safety concerns based on animal studies. Many thousands of patients, adults and children, have taken these drugs over the past few decades and today there is no serious evidence of neurotoxic effects. They are generally considered safe except in the first trimester of pregnancy. This is again based on animal studies that showed fetal resorption, fetotoxicity and possibly teratogenicity under very specific conditions.(42) Whilst there is nothing to suggest this is true for humans, the drug is not recommended for use in early pregnancy and, current advice is that artemisinin containing drugs should only be used in later pregnancy when there is no other treatment available. There is limited safety data in pregnant women based on relatively small studies done in Southeast Asia and trials are in progress in African women in their second and their trimester of pregnancy. Trials during first trimester would be considered unethical and no sponsors would assume such a liability risk even though no one really knows the risk. It will take a very long time to find out if artemisinins cause harmful effects to fetus or women during the first few days/weeks of pregnancy. It is the clinical experience from women treated with artemisinin and who are unaware of their pregnancy that will determine whether it is safe or not. With the tools that are available to scientists today, there should exist a better way to predict drug safety in pregnancy. For antimalarials as it is the case for most drugs, a definitive assessment of risk for use during pregnancy (fertility outcomes, effect on labor and delivery, fetal development, birth defects and other fetal toxicities) is not available at the time of product approval.

The same issues apply to safety in children and infant. Recent regulations make it not only possible, but mandatory, to involve children in clinical trials of investigational drugs, and draft guidelines on juvenile toxicity studies have been issued to make this possible. The limitations of animal data in reproductive toxicology studies hold true for the juvenile animal studies. Furthermore, these studies rely on cumbersome, costly assessment methods with no assurance that they will be predictive of potential adverse outcomes in humans.

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http://www.mmv.org/


There are not yet adequate, cost-efficient, pre-clinical study models that can be used in a drug selection matrix to determine whether a drug can be safe in pregnancy or small children. These assessments can only be done during late stage development. Given that malaria is most devastating in these populations, it is imperative that pharmaceutical industries, regulators and academic scientists work on the development and validation of new experimental methods to evaluate product safety earlier in the development process. Research directed toward improving a drug development toolkit, containing methods using animal, cells-culture, biomarkers and computer-based predictive models to screen drug candidates for safety is warranted to meet increasing challenge of drug development.

Conclusions and Recommendations□ P. falciparum malaria kills over one million people and causes up to 500 million cases annually, affecting mainly young children and pregnant women. Vivax malaria is responsible for 70-80 million cases per year accounting for 50% of all malaria cases, mostly outside Africa.

□ The economic consequences are enormous in Africa, with an estimated US$ 12 billion per year in lost GDP and a loss of 45 million years of productive life due to deaths and disability. Households spend up to 30% of their income on malaria related expenses.

□ The number of imported malaria cases is increasing Europe and deaths occur due to a lack of recognition of the disease and sometimes because of poor medical management.

□ There is no safe and effective vaccine to date and those currently in development are not expected to provide long-term nor complete protection.

□ Malaria is curable and preventable. The principal control strategies include case management by rapid diagnosis and effective treatment and, personal protection with bed nets.

□ Effective drugs exist. Drugs such as CQ and SP and have proven to be useful in the control of malaria but wide spread resistance make these drugs useless in much of the disease-endemic areas. Newer artemisinin-based combination therapies are effective but are too expensive for the people and governments in developing countries. CQ costs approximately US$ 0.10 per course while ACT cost 10 to 20 times more. New affordable, safe and effective drugs are urgently needed to roll back malaria.

□ Adequate coverage of mosquito bed nets have been shown to reduce child deaths by 20%. However they are not yet widely used due to cost and lack and the difficulty to sustain an adequate coverage.

□ At least US$ 1 billion is needed annually to implement these control strategies. Pledges from donors and government organizations are far below this target. □ Today, it costs nearly US$ 800 million to discover and develop new drugs due to the high attrition rate and stringent regulatory requirements.

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□ The pharmaceutical industry has largely been disengaged from innovative drug R&D in tropical diseases due to the lack of market incentive.

□ In the meantime, basic science made important advances in areas such as genetic and molecular biology allowing better understanding of the parasite biology and identification of drug target.

□ Innovation in basic science has not translated into new drugs because a funding gap exists between basic science and research geared toward discovery and development of new drugs.

□ The creation of Public-Private-Partnerships (PPP) such as the Medicines for Malaria Venture (MMV) provide a new cost-effective approach to innovative drug discovery and development. In a few years of operation, MMV has built the largest-ever antimalarial portfolio with a total expenditure of about US$60 million. Expenditures will increase significantly as the drugs reach clinical trial phases. Collaboration with the EDCTP may help support the cost of clinical studies (phase II-III studies) and thus facilitate rapid registration.

□ MMV estimates that at least US$ 30 to 50 million will be required annually to maintain a sustainable portfolio in which new and better drugs can be developed that are appropriate for people living in the disease-endemic areas.

□ Academic scientists, industry and regulators need to team up to translate the innovation from basic research into applied sciences which will lead to the development of more cost efficient experimental models for drug discovery and development. Increased funding of innovative approaches toward applied sciences for drug R&D is an obligatory prerequisite for the development of new medicines that will meet the global public health needs.

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