Antimalarial compounds: from bench to bedside
UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland
* Author for correspondence (e-mail: olliarop{at}who.int)
Accepted 8 August 2003
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Summary |
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Current efforts focus, on the one hand, on research into novel compounds with mechanisms of action that are different to the traditionally used drugs, and, on the other hand, on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and expensive ventures. Whilst very few new antimalarial drugs were developed in the last quarter of the 20th century (only four of the nearly 1400 drugs registered worldwide during 1975-1999), various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial pipeline is relatively healthy. Projects are underway at different stages of drug development, from pre-development to registration. However, there is relatively little novelty, as current development projects still rely upon the traditional quinoline, antifolate and, in particular, artemisinin compounds. New structures are expected from the more upstream discovery efforts but it will take time before they become drugs.
Therefore, whilst waiting for the drugs of tomorrow, there is a pressing need for immediately available, effective and affordable drugs that will have long life spans. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance.
Most research work has focussed on the use of artesunate combined with currently used standard drugs, namely mefloquine, amodiaquine, sulfadoxine/pyrimethamine and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and are dependent on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. Malaria control programmes need efficacious drugs that can be used with ease by the populations of endemic countries.
This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.
Key words: artemisinin, drug development, malaria
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Current challenges in malaria chemotherapy |
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From a public health perspective, drug resistance is a critical factor that
undermines malaria control. Plasmodium falciparum resistance to CQ
and S/P is widespread. There are also foci of MQ, halofantrine and AQ
resistance (Wongsrichanalai et al.,
2002). The clinical consequences of such resistance are well
described in terms of increased morbidity and mortality, especially amongst
young African children (Greenwood et al.,
1987
; Murphy et al., 2001). In certain areas, notably Indonesia
and parts of Oceania, CQ-resistant Plasmodium vivax is an emerging
problem (Baird et al.,
1995
).
One factor in the emergence of drug-resistant P. falciparum has
been the over-reliance on the two principal classes of antimalarial drugs;
namely, the quinoline (e.g. CQ) and antifolate (S/P) drugs for treating
falciparum malaria. Experience has shown that S/P is very vulnerable to
resistance (Watkins and Mosobo,
1993; Plowe,
2003
). In Thailand, S/P had an effective life span of just five
years (White, 1992
). S/P
resistance is also a worrying development in East Africa (Oguto et al., 2000;
Legros et al., 2002
). Because
CQ and S/P are inexpensive, they have been used and recommended even in the
face of poor efficacy. Another important consideration is access to good
diagnosis and treatment. Poverty and the inability to travel to a local clinic
often result in the purchase of sub-therapeutic doses of CQ in many parts of
rural Africa and treatment in the home
(Marsh et al., 1999
). Drug use
that leads to low drug concentrations lingering in the blood is a powerful
selective pressure for the development of resistant parasites
(White, 1992
). Overcoming or
reducing resistance requires the adoption of several strategies; central to
these is the use of effective chemotherapy for those who need it.
In order for this objective to be reached, we will indeed need new
molecules with novel structures and targets to circumvent resistance
(Rosenthal, 2003). But we also
need to develop and implement strategies to protect drugs against resistance.
Resistance to single-drug therapies will inevitably occur. Drug combinations,
which have been standard practice for viral and bacterial diseases, are now
being adopted for malaria as well.
The artemisinin derivatives in combination with standard antimalarials are
now being promoted as the best therapeutic option for treating drug-resistant
malaria and retarding the development of resistance
(White et al., 1999;
White, 1999
;
World Health Organization,
2001
). The artemisinin derivatives are currently the most rapidly
acting and potent antimalarial drugs
(White, 1997
). These
pharmacodynamic effects are due to their rapid absorption and activity against
many stages of the malaria life cycle, from young asexual forms (rings) to
early sexual forms (gametocytes; Kumar and
Zheng, 1990
). Their half-lives are short (<1 h for AS), which
protects them from resistance. They reduce gametocyte carriage and infectivity
and have been the main reason why transmission has been reduced on the
Thai-Myanmar border (Targett et al.,
2001
; Price et al.,
1996
; Nosten et al.,
2000
). Tolerability of these drugs is excellent (White, 1998).
Data on their safety during pregnancy are limited but encouraging
(McGready et al., 2001
). They
are not generally recommended for use during the first trimester unless better
alternatives are unavailable or unsuitable.
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The global antimalarial pipeline |
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Two considerations emerge. First, there are few affordable treatments for
malaria today, especially to treat uncomplicated paediatric malaria in Africa.
In practice, the vast majority of cases in the world today (which occur in
Africa) are treated with drugs that are cheap but by and large ineffective (CQ
or S/P). Second, the current R&D model, which (with few exceptions) is
largely based on public sector basic research and discovery of products to be
then developed by the private sector, has been ineffective in providing
innovative antimalarial drugs. Only four of the nearly 1400 drugs registered
worldwide during 1975-1999 (Trouiller et
al., 2002) were antimalarials. The truly innovative products,
artemisinin and its derivatives, were discovered in China but their
distribution is still limited because their developments do not meet
international criteria. It is worth noting here that the rules and criteria
regulating drug development have changed significantly in the recent past.
Stricter criteria are being applied today than in the past, particularly with
the adoption of the guidelines of the International Conference for
Harmonisation [ICH; refer to the official web site
(http://www.ich.org/)
for details]. As a consequence, developing a new drug is now more expensive
and takes longer. This, along with the low solvability of the markets that
these drugs are intended for, explains in part the low output of new
antimalarial drugs by the Western, research-based pharmaceutical industry. The
world's drug market is highly skewed; more than 80% of the US$ 337 billion
market in 1999 was in the USA, Europe and Japan, which account for less than
20% of the world's population.
Other factors concur. Traditionally, Western countries have promoted antimalarial drug research during the colonial era, and in case of war in endemic countries (e.g. MQ during the Vietnam war). Today, neither condition exist, and the traveller market alone does not suffice. However, the future is looking brighter. A number of drugs and drug combinations are in various stages of development (Table 1). The majority of these drugs will be used for treating uncomplicated falciparum malaria. Funding for these projects is from a variety of sources from the private and public sectors. A brief description of each drug is presented below, limited to drugs intended for the treatment of uncomplicated falciparum malaria. The majority are combinations of existing antimalarial drugs with an artemisinin derivative. Here, we will detail developments in this area.
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Chlorproguanil-dapsone (LapDap), a non-artemisinin-containing fixed-dose
antifolate combination similar to S/P developed jointly by GlaxoSmithKline
(GSK) and WHO/TDR (Tropical Disease Research), is undergoing regulatory
scrutiny in the UK (Lang and Greenwood,
2003). The two separate entities have been in use for several
years. They were combined in order to obtain an antifolate combination with
shorter residence time in the body than S/P and hence a lower probability of
selecting resistant parasites. The drug compares well with S/P
(Sulo et al., 2002
) in
controlled studies in East Africa and was effective in patients who failed on
S/P (Mutabingwa et al., 2001
).
However, there is some debate regarding its optimal role in treating
falciparum malaria in Africa because it shares similar genetic mechanisms of
resistance as S/P and its life span may be short if used widely. This might
compromise the eventual use of LapDap itself and when combined with AS
[chlorproguanil-dapsone-artesunate (CDA)]. CDA is at an early phase of
development, with funding by Medicines for Malaria Venture (MMV), GSK and
WHO/TDR, having completed pre-clinical toxicological studies. Phase I clinical
trials have yet to start.
Coartemether (Riamet®, Coartem®) is a fixed-dose combination of
artemether (a rapidly acting, short-lived antimalarial) and lumefantrine (a
long-resident drug also referred to as benflumetol). The registered
indications and branding for this drug cover treatment, including standby
treatment, of uncomplicated malarial episodes caused by pure or mixed
Plasmodium falciparum infections. The combination is expected to
confer mutual protection against resistance and prevent recrudescence after
artemether therapy. The components of this combination were originally studied
and developed in China by the Academy of Military Medical Sciences (AMMS),
Beijing and Kunming Pharmaceutical Factory (KPF), Kunming. The combination
product has been registered in China since 1992 but underwent further
development when Novartis signed a collaborative agreement in 1994 with AMMS,
KPF and CITITEC, the technology arm of the China International Trust and
Investment Corporation (CITIC). Studies for international registration started
in 1995. The drug was registered in Switzerland in 1999 and has since received
marketing authorisation in several endemic and non-endemic countries.
Coartemether is marketed under a dual-branding, dual-pricing strategy.
Riamet® (six doses over either 3 days or 5 days) is available in
developed, non-endemic countries as a standby treatment for travellers at a
price comparable with the latest antimalarial introductions. Coartem® is
registered and marketed in malaria-endemic countries as either a four- or
six-dose treatment of uncomplicated falciparum malaria at prices comparable
with locally available products. Recently, an agreement was reached between
Novartis and WHO for the drug to be made available to the public sector of
developing countries at a preferential price. Many clinical trials have been
conducted both with the original Chinese combination product and the
subsequent product for international registration, mostly with the four-dose
regimen. Recently, a Cochrane review
(Omari et al., 2003)
identified eight randomized, controlled trials comparing coartemether with
standard treatment for uncomplicated falciparum malaria (2117 participants).
The meta-analysis concluded that the four-dose coartemether regimen was
superior to CQ and equivalent to S/P in areas of CQ resistance but inferior to
MQ and MQ-AS in areas of multidrug resistance. The six-dose regimen was
equivalent to MQ-AS but was reported to be better tolerated
(Vugt et al., 1999
;
van Vugt et al., 2000
). Work
between Novartis and WHO has led to a more user-friendly packaging of the
six-dose treatment for improved adherence, which is now being field tested.
Paediatric formulation is also being developed.
The combination of DHA and PPQ was developed in China (ArtekinTM) and
is registered in China and Cambodia. It has been evaluated extensively in
clinical trials in Thailand, Vietnam, Cambodia and China
(Denis et al., 2002). Efficacy
has been high and tolerability uniformly excellent in all trials in these
multidrug-resistant areas including Hai Nan, China, where PPQ-resistance was
common after extensive use of mass prophylaxis. Initially, the coformulation
also included PPQ and trimethoprim (CV8). This product is still part of
national policy in Vietnam. PPQ is an orally active bisquinoline discovered by
Rhône-Poulenc in the early 1960s and developed for clinical use in China
in 1973. PPQ is approximately equivalent to CQ against sensitive parasites and
is significantly more effective than CQ against resistant P.
falciparum. PPQ replaced CQ as the recommended treatment for falciparum
malaria in China in 1978. Overall, 194,140 kg of PPQ phosphate, equivalent to
140 000 000 adult doses, were used for mass prophylaxis and treatment.
Surveillance at the time found no adverse events other than rare cases of a
rash. DHA is the active metabolite of AS and artemether. It has equivalent
clinical efficacy to the more widely used AS. A development programme has been
developed between Holleykin and Guangzhou University (China), The University
of Oxford, MMV and WHO/TDR to support the international registration of the
drug.
AS-AQ and AS-S/P have completed clinical trials in Africa (see below). AS-MQ has been widely used in Thailand and other parts of Southeast Asia as a non-fixed combination, where it proved highly effective in areas of MQ resistance. AS-AQ and AS-MQ will be further developed as fixed-dose combinations and will undergo all the pertinent pre-clinical and clinical studies before registration. A blister pack of AS-S/P has been developed using age-based dosing and is being used in clinical trials in Africa. The two new fixed-dose combinations (AS-AQ and AS-MQ) are currently being developed by a number of partners in Brazil, Malaysia, Thailand and France. MSF and WHO/TDR are the coordinating bodies, and funding has been obtained from the European Commission. This development will cover the full spectrum from formulation pharmaceutics to Phase 3 clinical trials. This work is being conducted to meet the necessary standards for drug registration.
Several other drugs and drug combinations are in an early phase of
development. AS-PRN builds on the rationale of using an artemisinin derivative
with a longer-acting partner drug. PRN is a Mannich base antimalarial compound
that has been synthesized and developed in China, where it obtained marketing
authorization for the treatment of malaria in the 1980s. It has proven
efficacy against drug-resistant falciparum malaria in Africa
(Ringwald et al., 1996). The
efficacy in Thailand of polybioavailable formulation against
multidrug-resistant malaria was less than 90%
(Looareesuwan et al., 1996
). In
the same setting, a better formulation was >95% effective (S. Looareesuwan,
V. Navaratnam and P. L. Olliaro, unpublished).
Work is being planned for drugs that are chemical alterations of well-established antimalarial drugs. Artemisone is a metabolically stable semi-synthetic derivative of artemisinin that is being developed by Bayer & MMV. Several trioxanes obtained by total synthesis are now available and are being assessed for further development by MMV. Isoquine is an isomeric derivative of AQ that should not generate the toxic quinone-imine metabolites that are thought to have a role in the hepatic and neutrophil toxicities. The development of this drug is also being coordinated by MMV. Short-chain CQ analogues with better efficacy on CQ-resistant isolates are being researched at Tulane University.
A novel compound, fosmidomycin, has recently been tested in small numbers
of patients. Fosmidomycin inhibits 1-deoxy-D-xylulose 5-phosphate
reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid
biosynthesis, which is absent in humans but present in many pathogens and
plants. Fosmidomycin was well tolerated and produced modest cure rates
(Lell et al., 2003;
Missinou et al., 2002
).
However, it is a drug worthy of more trials and could be used in combination
with other antimalarials.
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Clinical trials of AS-based combinations in Africa |
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The criterion for using a particular drug at a given site was that its efficacy was not less than 75%. CQ was used in West Africa, and the other two drugs in several countries across Africa. Two trials were conducted in Latin America, using AQ in Colombia (trial ongoing) and S/P in Peru. This report focuses on the African studies. The institutions involved are listed in Table 2. These were randomised, double-blind, placebo controlled trials that were conducted under Good Clinical Practices (GCP). Common clinical protocols and an analytical plan were used; the latter was designed so that an individual patient data (IPD) meta-analysis could be done. Collectively, they represent the largest series of antimalarial drug trials ever conducted. There were 11 sites in eight African countries (Table 2).
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All the S/P studies had three arms: S/P alone and two dosing regimens of AS. The CQ and AQ studies used three days of AS (Table 3). The dose of AS was 4 mg kg-1 day-1 for three days or one day (S/P studies only). The results of one day of AS are not reported here. AS/placebo was provided by Sanofi-Synthélabo/Guilin, AQ by Warner-Lambert/Parke-Davis (now Pfizer) and S/P by the International Dispensary Association.
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The primary efficacy end points were the parasitological cure rates at days 14 and 28. Secondary efficacy parameters were the rates of parasite and fever clearances and gametocyte carriage rates. Molecular genotyping was used to distinguish between recrudescent and fresh infections; these results were used to correct the day 28 cure rates (missing PCR data were excluded). PCR and drug analyses were conducted for the genetic mutations of drug resistance and population pharmacokinetics, respectively. These results will be reported elsewhere.
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Results |
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Primary outcomes
AQ studies
The addition of AS to AQ resulted in an increased cure rate in Gabon and
Kenya but not in Senegal on days 14 and 28
(Table 3; Adjuik et al., 2002).
S/P studies
In The Gambia, cure rates were similar on day 14 but were higher by day 28
(von Seidlen et al., 2000). In
Uganda, Malawi and Kenya, the background failure rates of S/P alone were high.
Cure rates were increased significantly by the addition of AS.
CQ studies
CQ cure rates were low in all three countries. AS improved significantly
the cure rates in Burkina-Faso and São Tomé but not in
Côte d'Ivoire.
Secondary outcomes
Parasite clearance rates were significantly faster in all trials except
Côte d'Ivoire with both three days and, in the S/P studies, one day of
AS compared with the standard drug alone
(Fig. 1). Fever clearance rates
were consistently faster in the S/P studies but not always in the CQ and AQ
studies. Gametocyte carriage was reduced significantly in the S/P
(Fig. 2) and CQ studies by the
AS regimens, but the effect of AS in the AQ studies was inconsistent.
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Tolerability of the combinations and the standard drugs was good in all studies (full details to be published elsewhere). Generally, there was no increase in the proportion of patients reporting adverse events in the AS arms compared with the single agents. Remarkable side effects in the AQ and AQ-AS arms were mild itching in nine patients (1%) and drug-induced vomiting in 11 patients (1.2%). In the S/P study in Kenya, 16 (2.7%) children developed mild, papular rashes. Serious adverse events (SAE) were few and mostly due to signs of severe malaria, e.g. convulsions, anaemia and coma. One child with AQ-induced vomiting was admitted to hospital. There were five deaths, all unrelated to study drugs. Haematology results showed that the mean haemoglobin increased by day 28 and was generally similar between the combination and standard drug arms. In the AQ study, there was a decline in the mean neutrophil counts, reaching a nadir on day 21 and rising thereafter. Nine (6%) of 153 children developed neutropenia (neutrophil count <1000), one of whom was parasitaemic. The clinical significance of this neutropenia is unclear. All children were afebrile and asymptomatic. Biochemistry results were unremarkable. Mean creatinine and liver enzyme values were stable. Raised liver enzymes present on day 0 resolved during follow-up.
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Towards the development of optimal age-based dosing of fixed-dose combinations |
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Conclusions |
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Artemisinin-based combinations hold the promise of overcoming drug-resistant malaria: AS-MQ, ArtekinTM and the six-dose coartemether are effective in areas of multidrug resistance. There are prospects, at least for the latter two, to be used in Africa as well. The clinical trials conducted in African children, a key target group, showed that combining AS with a standard drug resulted in a significant improvement of cure rates over those of the standard drugs. However, the absolute day 28 cure rates for falciparum malaria in some studies was still relatively low because of the high degree of resistance to the standard drug. Tolerability was similar for both the combination arms and the standard drugs. Gametocyte carriage was reduced, most notably in the S/P arms. On a large scale, this might reduce malaria transmission over the long term.
Fixed-dose combinations are generally agreed to be better than unfixed doses for patient adherence. Blister packs of fixed-dose AS-based combinations have been designed for clinical trials in Africa. Information from these trials will be of value to malaria control programmes. Further research is required to assess more fully the efficacy, safety and long-term public health impact of artemisinin-based combinations.
Compliance with international standards of production and research is paramount if these products are to be registered and adapted widely. Cost of treatment has been brought up, time and again, as a limitation to the adoption of these combinations in resource-constrained settings. Their costs today are in the range of US$1-2.4 for an adult treatment. So, they are significantly more expensive than CQ or SP. However, both emerging data and modelling studies show that the adoption of combinations as first-line therapies will lead to overall net savings for both individuals and health systems. Moreover, cost-of-goods is decreasing with increasing demand of active principles.
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Note added in press |
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