Making the most of existing antimalarial medicines: a single dose cure with sulfadoxine–pyrimethamine plus artesunate–pyronaridine

Abstract

Malaria remains a preventable and treatable disease; however, recent efforts to reduce mortality have plateaued. Although artemisinin-based combination therapy demonstrates high efficacy in controlled clinical settings, its real-world effectiveness is often compromised by suboptimal patient adherence. Specifically, the artemether–lumefantrine regimen, administered twice daily over 3 days, has been associated with reduced compliance due to its complexity. Simplified therapeutic regimens that enhance adherence could, therefore, play a critical role in reinvigorating progress toward malaria elimination. Over the past decade, substantial progress has been made in the discovery and development of new chemical entities for malaria treatment, although the most advanced candidate still requires a 3-day dosing regimen. Treatment shortening most likely requires multiple drug combinations. Multi-drug regimens, such as artemether–lumefantrine–amodiaquine appear to be well tolerated, but these are under development to address emerging resistance to lumefantrine and will be unlikely to improve compliance. Sulfadoxine–pyrimethamine was originally developed as a single-dose curative treatment for malaria, and although use was curtailed early due to rapid selection for resistance, it continues to be deployed as a single therapy or in combination with other medicines, in treatment and in prevention. Combining with artemisinin-based combinations would be an option for potential treatment shortening. Of the registered antimalarial treatments, only a few of the artemisinin-based combinations are suitable. Mefloquine is excluded for tolerability concerns, amodiaquine because of its use in seasonal malaria chemoprevention, and lumefantrine and piperaquine due to concerns of emerging resistance. Pyronaridine–artesunate emerges as a promising candidate for association with sulfadoxine–pyrimethamine. A four-drug, single-dose antimalarial regimen would transform compliance, and play a major role in disease elimination. However, to ensure its success it will be important to assess the safety and tolerability of the novel association and understand its efficacy in regions with evolving resistance to sulfadoxine–pyrimethamine. Clinical studies need to assess the risk for selection of strains with novel resistance mechanisms against artesunate or pyronaridine. Importantly, a comprehensive clinical evaluation will generate valuable real-world insights into community acceptance and operational feasibility. This information will be an important foundation for future design of single dose malaria therapies involving new chemical entities.

Background

The 2023 burden of malaria was reported globally to an estimated 263 million cases, and an estimated 597,000 deaths [1]. These estimates suggest an overall increase of 11 million cases from the previous year. Africa continues to carry the heaviest burden of morbidity and mortality, accounting for about 95% of malaria cases and estimated malaria deaths. Plasmodium falciparum is the major parasitic species affecting humans in Africa. The most effective way to manage an uncomplicated case or to avoid progression to severe disease and death is through early diagnosis and prompt and efficacious treatment.

Artemisinin-based combination therapy (ACT), given for 3 days, show efficacy often far above the World Health Organization (WHO) recommended minimum threshold of 95% adequate clinical and parasitological response (ACPR) at day 28 during clinical studies. However, artemisinin-based combinations show lower effectiveness in real-world practice [2, 3], because of many system-specific issues. These include suboptimal intervention access, diagnostic shortcomings, incomplete provider compliance, but most importantly client adherence to the course of therapy. Many studies have shown that compliance rates with the 3-day ACT regimens are highly variable, but as low as 40% [4, 5].

With the development of antimalarial resistance to both artemisinins and many of the partner drugs, there is an urgent need for new therapies with new modes of action [6–8]. The first new approach was the development of synthetic peroxides. Arterolane (OZ277/Rbx11160) was successfully developed as a 3-day medicine, Synriam, in combination with piperaquine and has been widely used in India. Based on this success, the next generation artefenomel (OZ439) was developed as a potential single dose cure in combination with ferroquine. This only achieved 91% efficacy in a phase 2 study, and had significant galenic or formulation issues leading to poor tolerability in small infants [9, 10]. After this, the current most advanced new molecule is a formulation of ganaplacide (KAF156) and lumefantrine, which showed 92–94% efficacy in phase 2 as a single dose [11, 12]. Given the 100% cure rates with 3 days of dosing, this combination has now been tested in phase 3 as a 3-day dosing [13]. However, its potential for treatment shortening by adding a third drug is in early clinical exploration [14]. The other single-dose combinations that are still in early phases include cabamaquine (M5717) + pyronaridine [15], and ZY19489 + ferroquine [16], both of which are exploring both single and multiple dose options. In summary, there are many new combinations which are currently designed to overcome artesunate resistance, and some show potential for treatment shortening, but registration of any new shorter course treatments with new chemical entities will still need several more years.

Triple and multidrug combinations as a platform for targeting treatment shortening

There has been a resurgence of interest in triple combinations in recent years: combining artesunate with two long-acting partner drugs, to provide a multiple-stage antimalarial activities (i.e. asexual blood stage, liver stage or sexual stage) and to maintain activity in the presence of partner drug resistance, and thus extend the clinical utility of artemisinin combinations [17–19, 24–26]. Several clinical trials on multidrug antimalarial combinations (MDACT) are underway or have been completed, and give indications for how this platform can be used for treatment shortening [24, 25]. For example, data from studies of artemether–lumefantrine–amodiaquine confirm that an effective combination can be developed that has high efficacy, and good safety and tolerability [28]. A combination of artemether–lumefantrine with atovaquone–proguanil is also being tested clinically [26]. However, not all combinations survive early clinical studies as was shown two decades ago by the failure of chlorproguanil–dapsone–artesunate [27], or more recently, attempts to combine atovaquone–proguanil with amodiaquine were stopped because of reports that atovaquone–proguanil can exacerbate a rare adverse event linked to amodiaquine [29]. This underlines that multidrug combinations are perfectly feasible, and can be well tolerated, but clinical data on combination safety and tolerability is essential.

Exploring single-dose therapy using existing medicines

It is timely to consider whether combinations of existing drugs could shorten malaria treatment and improve compliance and effectiveness. The goal would be a regimen effective against both current and emerging resistant strains [17–19]. Combining four agents with distinct resistance mechanisms may help prevent the development of resistance—an approach long used in tuberculosis therapy empirically [20, 21]. Using approved drugs for such an approach also supports affordability and providing new medicines in the same price range as ACT for procurement agencies, such as the Global Fund [22]. However, single-dose cures pose significant pharmacological challenges [2, 23]. The dose for each ‘long acting’ drug must sustain curative plasma concentrations long enough to clear parasites, achieving curative drug levels for 6–8 days. There is additional complexity in the variability of bioavailability, and limited semi-immunity especially in children [2]. The additional drug loading in using four or more drugs as a single dose may increase adverse reactions like vomiting due to drug loading, risking subtherapeutic exposure.

Chosing sulfadoxine–pyrimethamine as the basis for a treatment shortening multi-drug combination

Sulfadoxine–pyrimethamine (SP) has two active ingredients which target the enzymes, dihydropteroate synthase and dihydrofolate reductase in the folic acid synthesis pathway. It was the first antimalarial combination to cure uncomplicated P. falciparum malaria with a single dose, offering major operational advantages over multi-day regimens like chloroquine or quinine [30]. It was first was introduced in Thailand in 1967 (Fansidar®), but resistance appeared that same year and resistance spread quickly throughout South-East Asia. Resistance remained much lower in Africa: it was first launched in Malawi in 1993, but falling efficacy [31, 32] led to its replacement by ACT in the first decade of the millennium. It remains a WHO- recommended standard of care for treatment in many countries.

The correlation between mutations in the target genes dihydrofolate synthase and dihydropteroate synthase genes and clinical activity is not simple, since SP retains significant clinical activity even in the case of multidrug resistance [33, 34]. Factors such as immunity, drug metabolism, and infection multiplicity clearly influence outcomes. In chemoprevention studies, SP combinations remain active even in the presence of 90% of the quintuple mutation dhps [35]. It also shows high efficacy in chemoprevention, with no impact on efficacy in the presence of the quintuple mutations [35]. The widespread use of SP in chemoprevention is likely to mean that the resistance level is at best stable though, and will remain fixed in the parasite population in Africa [36], in contrast to the re-emergence of chloroquine-susceptible malaria after the removal of drug pressure [37]. Nonetheless, SP shows remarkable tenacity as a drug combination, and some of this tenacity is likely linked to the matched pharmacokinetics of the two drugs and their synergistic action [38].

SP has a good safety record: beyond its widespread use in treatment as SP + artesunate; it is used by over 20 million women to protect against infection in pregnancy (IPTp), over 50 million children under 5 years old in Seasonal Malaria Chemoprevention combination, where it shows a median efficacy of 75% [39]. New SP combinations for treatment cannot currently be introduced in areas where SP is used for prophylaxis. However, as vaccines, monoclonal antibodies, and long-acting injectables become more widely adopted, this limitation will diminish [33]. In summary, combining SP with other registered antimalarials could yield a well-tolerated, safe, effective, and deployable single-dose cure—bridging the gap until next-generation therapies arrive.

Selection of a partner drug for sulfadoxine–pyrimethamine in multidrug combinations for the single dose cure and prevention of malaria?

There is limited scope for choosing a partner for SP. The only two other classes of drugs approved for treatment are atovaquone–proguanil and the artemisinin-based combinations. Use of atovaquone–proguanil as a partner drug is limited by the current price (linked to the cost of manufacture, and currently small market), and the relative lack of availability of safety data in African subjects or patients given the commercial focus in prophylaxis for travellers. Artemisinin-based combinations are more attractive as potential partners: artesunate itself has been widely used as a loose combination with SP, confirming the tolerability and safety of the combination, and historically showing high efficacy. The combination is relatively robust clinically, despite the presence of multiple dhfr and dhps mutations. Its showed 100% efficacy in India (as measured by PCR-corrected cure rates at day 28), despite the presence of 27% triple mutants [40], and high efficacy continues to be reported [41]. Even against a background of 56% quintuple mutations in Somalia, it still showed an efficacy of 87.7% [42]. These data underline the need for characterization of the dhfr/dhps resistant mutants in any clinical study, but confirm that SP still retains significant clinical efficacy against multi-resistant strains. It will also be important to characterize the impact of kelch13 mutations, which will clearly impact the speed of resolution of infection and symptoms, although for uncomplicated malaria the link to any change in clinical efficacy is less clear.

Beyond artesunate + SP, there are five other combinations which are recommended by the WHO, based on the partner molecules lumefantrine, amodiaquine, piperaquine, mefloquine and pyronaridine. The combination with an artemisinin-based combination rather than the single aminoquinoline drug is a practical question: of the five drugs, only mefloquine is available as a monotherapy. Each partner drug merits consideration as the potential partner for a four-drug combination with SP and artemisinins. The strengths and weaknesses of the various artemisinin-based combinations are summarized below.

Artemether–lumefantrine (AL): has the disadvantage that in its current formulation requires to be dosed twice daily with food. Although a single daily dose formulation of lumefantrine has been developed by Novartis for ganaplacide–lumefantrine, no-one has so far developed the equivalent once per day dosing for artemether–lumefantrine [11, 12]. The half-life of lumefantrine and its metabolite is approximately 6 days, which is much shorter than the other ACT partner drugs (and their active metabolites). Therefore. it has a lower plasma concentration at days 28 and 42 leading to lower post-treatment prophylaxis than other ACT combination partners [43]. Lumefantrine resistance has been reported both in Uganda and in parasites cultured from a traveller recently returning from Uganda [44, 45]. On the positive side artemether–lumefantrine is the first ACT to be given positive guidance by the WHO for use in first trimester pregnancy: this is an important factor, given over 40 million pregnancies annually in Africa, and the fact that many cannot determine or communicate their pregnancy status.

Artesunate-amodiaquine (ASAQ): amodiaquine was originally linked to hepatotoxicity and agranulocytosis, leading to a black box warning by the US FDA. Widespread use as artesunate-amodiaquine has not confirmed this risk in African patients, and the main adverse events for the fixed dose combination ASAQ are QTc prolongation and a rare extrapyramidal syndrome. Concerns about amodiaquine resistance exist in West Africa, although these seem to have stabilized or even reversed with the delivery of fixed dose artesunate-amodiaquine since 2008.

DHA–piperaquine (DP): has been widely deployed, and piperaquine resistant parasites have been linked to clinical failure in South East Asia, and potentially in Africa [46, 47]. It has a considerable QTc effect, similar to chloroquine. It is given without food, but has a threefold food effect, meaning that if patients inadvertently take food, the plasma levels are threefold higher, leading to a QTc prolongation, which has raised some cardiac safety concerns for its use in mass drug administration [48]. The formulation of DHA–piperaquine requires that the two drugs be kept physically separate, and this has led to a significant cost differential between DP and earlier artemisinin-based combinations, such as AL and ASAQ.

Mefloquine–artesunate (ASMQ): showed poor tolerability when administered at high doses [49], and is significantly more expensive than other partner compounds. Resistance to mefloquine was reported in South East Asia leading to a switch to DHA–piperaquine. Mefloquine has been associated with an increased risk of mother to child transmission of HIV [50], and has a black box warning from the US FDA related to neuropsychiatric events. The relatively limited use means that ASMQ is typically the most expensive fixed dose ACT.

Artesunate–pyronaridine (AP): is the newest of the artemisinin-based combinations, given a positive scientific opinion by the European Medicines Agency in 2012 as a 3-day treatment for uncomplicated malaria and incorporated into the WHO treatment guidelines in 2023. Pyronaridine has the advantage of the absence of a major effect of food intake on bioavailability, and a long post-treatment protection effect. No resistance mutations have been identified in clinical studies [51], and despite extensive incubations, no resistance mutations have been reported from in vitro studies [52]. Pyronaridine has no significant effect on QTc prolongation (predicted to be less than 10 ms) [53]. It was originally associated with enhanced liver enzyme levels in repeat dose phase 1 volunteer studies, but more extensive studies in patients showed artesunate-pyronaridine and artemether–lumefantrine have similar hepatic safety when used repeatedly in participants with uncomplicated malaria [54]. That safety profile was further confirmed in a large real-world cohort even monitoring trial of more than 8500 malaria episodes [55]. Pyronaridine appears to be well tolerated in pregnancy. No teratogenic effects were observed in animals preclinically, and no increase in adverse pregnancy outcomes of teratogenic effects in 52 pregnancy outcomes from first trimester exposure [56], and with more data becoming available from ongoing interventional studies [57], and 839 pregnancies in second and third trimester (PYRAPREG consortium, http://www.pyrapreg.org) [58] and, therefore, is recommended by the European Medicines Agency in cases where artemether–lumefantrine or quinine–clindamycin are not available (EMA SmPC, Pyramax). A single dose of AP has been shown to clear infection in subjects with asymptomatic P. falciparum infection [59], with the caveat that the mean age was 16.6 years, suggesting they had acquired a certain immunity to malaria, and the geometric mean parasite density was low (550/µl). From a resistance perspective, then no stable pyronaridine resistance mutants have been selected and characterized in the laboratory, and pyronaridine is fully active against clinical isolates showing resistance to the other ACT partners.

Based on these data, the best candidate for a partner to SP for a single-dose cure with a multidrug combination therapy would be AP, based on its long half-life, good safety and tolerability record especially the emerging data in early pregnancy, lack of a food effect, and lack of detected resistance. This concept is currently evaluated in a proof of concept pilot study in Gabon assessing the efficacy, safety, and tolerability of the combination in children and adults with uncomplicated malaria (1-D-CURE trial, PACTR202405571736678).

Cost of medicine and local manufacturing

Sulfadoxine-pyrimethamine (SPAP) as a potential single dose cure is attractive from a cost perspective. Based on current pricing through the Global Fund Process, a single adult dose of SPAP could be priced around $0.95 for an adult [60], which is only slightly higher than a 3 day adult course of AL at $0.60. In addition, the cost of new medicines drops substantially post-launch: artemether–lumefantrine for example is priced fourfold lower than public health launch cost of $2.40 in 2001. If similar savings could be made for artesunate–pyronaridine, a price of $0.45 per adult could be achievable, making it extremely interesting compared to 3 days of ACT.

Beyond the simple question of price, in the current funding climate there is also the question of local manufacturing. National Malaria Control Programmes will become increasingly dependent on the use of national and local funds to procure medicines, and locally manufactured medicines will become increasingly important. SP is already manufactured in Africa to the international manufacturing ICH GMP standards, and approved for WHO prequalification. Artesunate–pyronaridine is currently only being manufactured by Shin Poong in South Korea, and there are now projects to support its manufacturing in Africa.

Ethical implications of implementing a single encounter cure for malaria with existing antimalarial drugs

The expected benefits of single dose therapy include improved compliance, with higher effectiveness, but also decreased costs, both important for malaria elimination. A single dose cure could dramatically improve access to medicines in remote areas, and a key question will be ensuring equitable distribution, where local manufacturing will be key. Whilst the safety and tolerability of the two two-drug combinations are understood, the potential for rare, but unexpected new adverse events must be managed by a stepwise increase in the number of cases treated to gain robust evidence of safety and tolerability. Probably the most important ethical question will be to manage the development to ensure that the maximum knowledge about the potential for new resistance selection is obtained, in particular resistance against pyronaridine. Establishing the efficacy and effectiveness of SPAP especially in areas where the more severe quintuple mutation SP resistance is not particularly widespread will be an important first step. SPAP will help to refine the target product profile for a single dose cure, and serve as a benchmark for future treatment shortening regimens, to focus on providing evidence for better efficacy, tolerability and cost-effectiveness.

Conclusion

Despite good progress in the early part of the century, the malaria burden has recently plateaued or increased. One of the reasons for this is that although the clinical efficacy of antimalarials remains high, real-life effectiveness is clearly lower, driven by incomplete compliance to a 3-day treatment. Although there are many new drugs in development, in the short term there is a critical opportunity to optimize the use of existing drugs to simplify malaria treatment and improved compliance. The existing drugs have the advantage that their safety profiles are well understood, including data on key populations such as small infants and pregnant women. The existing drugs tend to be more cost effective than new drugs, and many are being manufactured in Africa. More effective case management of malaria cannot be postponed until the next generation of new chemical entities will become available; there is a need now, as shown by the stalling progress of malaria elimination. Sulfadoxine–pyrimethamine forms a good basis for a new multi-drug regimen, given that it targets two mechanisms of action which are different from the artemisinin-based combinations. It will be important to investigate to what extent SP in multi-drug combinations is compromised by new resistance mutations, and to determine whether these are significant enough to put the clinical target of 95% ACPR at day 28 beyond reach. Other gaps that need to be addressed in the development of SPAP, include the absence of modelled pharmacokinetic/pharmacodynamic parameters for single-dose administration across age groups; and to obtain more clinical safety data on the SPAP combination. These are questions that can only be answered by clinical data, and this is where the hypothesis needs to be tested. If the control of malaria is to get back on track, there is no time to lose.

Abbreviations

ACPR

Adequate clinical and parasitological response

ACT

Artemisinin-based combination therapy

AL

Artemether–lumefantrine

AP

Artesunate–pyronaridine

ASAQ

Artesunate–amodiquine

DP

Dihydroartemisinin–piperaquine

IPTp

Intermittent preventive treatment in pregnancy

MDACT

Multidrug antimalarial combination therapy

SP

Sulfadoxine–pyrimethamine

SPAP

Sulfadoxine–pyrimethamine plus artesunate–pyronaridine

WHO

World Health Organization

Author contributions

GMN, MR, RZM and PGK drafted a first version of the article. BL, QB, PA, OMA, AD, TW, and FN substantially revised and expanded subsequent drafts. All authors reviewed and approved the final version.

Funding

Open Access funding enabled and organized by Projekt DEAL. The authors declare no funding for the work on this article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.