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TOOLS FOR ELIMINATION: DRUGS
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Review of progress on the research and development agenda for drugs
Background:
malERA promulgated the concept of Single Encounter Radical Cure and Prophylaxis (SERCaP),
proposing that for eradication to be effective, drug therapy must eliminate the human reservoir of
infection, which would be best achieved in a single patient encounter that resulted in ‘‘eradication’’ of
the parasites in all individuals administered the drug (likely a combination of active pharmaceutical
ingredients). For P. falciparum, the drug therapy would need to eliminate all persistent asexual bloodstage forms, and the long-lived mature-stage P. falciparum gametocytes responsible for transmission.
For P. vivax, the drug therapy would need to be a radical cure that eliminated all persistent asexual
blood-stage forms and the long-lived hypnozoites in the liver. To account for the typical development
and subsequent infectious period of Plasmodium parasites in Anopheline mosquitoes, a prophylaxis
component would also be required to prevent reinfection for at least 1 month after treatment in each
individual treated.
The summary of the original research and development agenda (see cover sheet) provides a convenient
framework for assessing the current overall status, achievements, progress, and gaps in developing
vaccines as tools for elimination. Each of the three topics in the original summary are reviewed
below, including comments submitted by Tools for elimination panelists. This is followed by a more
general assessment of malaria drug development.
KNOWLEDGE GAPS AND RESEARCH PRIORITIES FOR OPTIMIZING CURRENT
DRUGS

Pharmacology studies to optimize dosing regimens
gametocytocidal and anti-relapse efficacy and safety
of
8-aminoquinolines for
Current overall status: Partially addressed [Jittamala, 2015] [Hanboonkunupakarn, 2014]
[Pukrittayakamee, 2014] [Marcsisin, 2014] [Bennett, 2013]
Achievements:
Progress but incomplete:
 PK of primaquine in combination with artemether-lumefantrine (that may inhibit
primaquine metabolism)
 Impact of CYP2D6 on PK dynamics and relevance for gametocytocidal activity
 Safety of primaquine in G6PDd individuals
Gaps:
Detailed narrative and panelists’ comments:
The past five years has seen major progress in the clinical development of tafenoquine
(TQ), a new synthetic 8-aminoquinoline analog of primaquine [Ditusa, 2014; Dow, 2014;
Green, 2014; Li, 2014; Llanos-Cuentas, 2014; Marcsisin, 2014; Melariri, 2015; Miller,
2013; Rajapakse, 2015; Tenero, 2015; Vuong, 2015a; Vuong, 2015b]. Clinical studies so
far, especially the Phase IIb study published in 2014 in Lancet [Llanos-Cuentas, 2014],
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have shown that TQ prevents relapses after clinically and parasitologically confirmed P.
vivax malaria [Rajapakse, 2015]. A dedicated study in healthy volunteers did not find
evidence for cardiotoxic risks for TQ [Green, 2014]. Animal studies show that exposure is
particularly high in liver [Li, 2014]. Recent animal studies suggest that formulation can still
be improved to enhance bioavailability and to reduce risks associated with G6PD
deficiency [Melariri, 2015].
The shorter treatment course is an important practical advantage. Expose-response studies
in Thai patients helped predict that a 800 mg dose would keep >90% of individuals P.
vivax-free for six months [Tenero, 2015]. A large TQ Phase III trial is ongoing based on
these findings. Another study to measure precise PK/PD in volunteers is underway,
registered as JM PROV OPRA trial Reg# ClinicalTrials.gov Identifier: NCT01814683.
One new concern with 8-aminoquinolines TQ and primaquine is the finding that these
drugs must be activity metabolized by CYP2D, and individuals who carry certain genetic
variants of cytochrome may show lower responses [Marcsisin, 2014; Vuong, 2015a;
Vuong, 2015b].

Rapid and robust point-of-care glucose-6-phosphate dehydrogenase (G6PD) test to
improve safety of 8-aminoquinoline use
Current overall status: Partially addressed [Roca-Feltrer, 2014]
Achievements:
Progress but incomplete: A quantitative G6PD DX is underdevelopment (PATH)
Gaps:
 Necessity of G6PD testing for single low dose primaquine in different settings. Is it
needed or is it safe regardless of G6PD status if given at single low dose?
 Comparative efficacy of primaquine, tafenoquine and methylene blue
 Relevance of genotypically G6PDd but phenotypically G6PDn individuals: are they at
risk? [Eziefula, 2014b]
Detailed narrative and panelists’ comments:
A reliable, point-of-care test for G6PD-deficient patients is among the three priorities listed
by UNITAID [UNITAID, February 2015]. With the development of tafenoquine, and with
primaquine still the only approved treatment with efficacy against liver-stage Plasmodium
vivax (hypnozoites), developing a reliable assay to identify G6PD-deficient patients is
urgent. The problem with genetic approaches is that so far, more than 440 G6PD gene
variations have been identified that can cause enzyme activity deficiencies of varying
severity, depending on the mutation and on the individual person.
Access Bio has made commercially available two point-of-care tests for G6PD deficiency
[Adu-Gyasi, 2015; Kim, 2011]:
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1. The CareStart™ G6PD RDT, a qualitative test based on the lateral flow platform.
There is now growing data regarding the performance of this test under controlled
conditions. More data is required in operational conditions.
2. The CareStart™ G6PD Biosensor, which is a quantitative test which measures units
of G6PD activity. The technology employs a tetrazolium dye that changes to
purple-colored formazan in the presence of G6PD enzymes.
Additionally, in November, PATH announced a collaboration with GSK to develop a
G6PD diagnostic using a US$9.13 million grant from the Bill & Melinda Gates Foundation
(www.path.org).
These tests will help support implementation of treatment using primaquine and also
tafenoquine, an investigational 8-aminoquinoline-based drug that is currently under
development by GSK and Medicines for Malaria Venture.

Tests that can detect resistance to artemisinins and ACT partner drugs
Current overall status: Partially solved for artemisinin component; potentially solved for
piperaquine resistance (not published) [Huang, 2015] [Tun, 2015] [Mok, 2014] [Straimer,
2014]
Achievements: There is a marker for Artemisinin resistance
Progress but incomplete:
 Partially solved for artemisinin component
 Potentially solved for piperaquine resistance (not published)
Gaps:
 What is the relevance of K13 mutants outside Asia?
Detailed narrative:
Progress in this area involves both understanding the genetics that allows resistance, and in
vitro assays that reflect the diminished Plasmodium responses. In mainland SE Asia slow
rates of P. falciparum parasite clearance following treatment with artesunate are now
known to be associated with mutations in the PF3D7 Kelch propeller domain [Ariey, 2014;
Ashley, 2014]; seventeen kelch mutations have been identified so far [Carter, 2015;
Escobar, 2015; Isozumi, 2015; Straimer, 2014; Tun, 2015]. The practical problem is that in
these patients there is a clear change in the kinetics of parasite killing, but not a clear effect
on the IC50 for artesunate [Dondorp, 2010; Noedl, 2013]. Analysis of the parasites has
suggested that the cause of this insensitivity is in the early ring stages of the parasite; a
newly developed in vitro ring-stage survival assay (RSA) was found to correlate with
response rates in patients [Witkowski, 2013]. Both approaches (parasite genetics/RSA) are
helpful in clinical trial settings as proxies to help decide if experimental treatments work
against artemisinin-resistant parasites, but they are too cumbersome to be used as
diagnostic to guide optimal treatment.
Resistance against piperaquine (PQ), also in the Greater Mekong Subregion, is another
growing concern and when used in ACT it is not always clear which partner drug fails
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[Chaorattanakawee, 2015; Leang, 2015]. In vitro studies with parasites from this area show
that PQ resistance is on the rise, associated with Pfmdr1 copy number variation, whereas
mefloquine (MQ) sensitivity improved [Chaorattanakawee, 2015]. Unfortunately, again,
PQ resistance is difficult to measure in vitro, the curves look atypical (‘long tails’) and may
be better represented by their IC90s.
Lumefantrine resistance has been similarly difficult to tackle [Hamed, 2015].
The interplay between drug resistance and fitness in malaria parasites is increasingly
understood [Rosenthal, 2013]; this is highly relevant for optimized, regional drug rotation
and drug discovery strategies. Another major finding is that of the role of PfS47, which
conveys protection against immune responses from insect vectors, particularly Anopheles
gambiae, the most efficient African vector [Molina-Cruz, 2014; Molina-Cruz, 2013]; the
relevance is that recombination between this locus and those that confer drug resistance
facilitates spread of resistant Plasmodium into Africa.

Determine gametocytocidal and anti-relapse activity of current drugs and those in the
pipeline
Including:
a. Drugs to act across stages in simple dosing regimens
b. Assays to measure transmission blocking activity
c. Increased capacity for human challenge studies for early go/no go decisions on drug
candidates
Current overall status: Great progress in terms of assays, drugs and human challenge studies
for transmission-blocking activity
Achievements: The blood stage challenge model for PK/PD work is established; there are better
models for P vivax, e.g. humanized mouse; higher through-put assays for gametocytes have
been developed (McCarthy, QIMR); Assays to measure transmission blocking activity
[Bolscher, 2015] [Ruecker, 2014] [Stone, 2014] [M. Delves, 2012]; New compounds [Phillips,
2015] [Baragaña, 2015] [McNamara, 2013]; Human challenge studies: Solved for drugs
against blood stage parasites and pre-erythrocytic activity [Marquart, 2015]
Progress but incomplete:
 Human challenge studies to assess transmission-blocking effects
Gaps:
 Human challenge studies to assess anti-hypnozoite activity
 Relationship between in vitro assays on transmission blocking potential and
transmission reduction in vivo
 Relevance of differential effect of drugs on male/female gametocytes and transmission
in natural conditions
Detailed narrative:
With the availability of new gametocyte assays a number of studies have tested whether
existing antimalarials target gametocytes, and the general finding is that they do not
[Douglas, 2013; Peatey, 2012]; moreover there are differences in drug sensitivities between
male and female gametocytes [M. J. Delves, 2013]. These lack of responses are especially
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problematic as gametocytes that escape chemotherapy may then spread resistance. For P.
vivax, gametocyte carriage mirrors asexual-stage infection densities, thus “Prevention of
relapses, particularly in those with high asexual parasitemia, is likely the most important
strategy for interrupting P. vivax transmission” [Douglas, 2013]
.
KNOWLEDGE GAPS AND RESEARCH PRIORITIES FOR DEVELOPING NEW DRUGS
FOR MALARIA ERADICATION
Desired products

Drugs that prevent transmission by killing or preventing development of gametocytes, or
blocking sporozoite development in the mosquito
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
There has been progress in the development of new phenotypic screens involving
gametocytes [Dantzler, 2015; Douglas, 2013; Duffy, 2013; Wu, 2015]. Some of these are
now automated and suitable for medium/high-throughput screening [Lelievre, 2012].
Recently such assays identified gametocidal candidates [Lelievre, 2012] some coming from
the MMV Malaria Box [Lucantoni, 2013], a set of drug-like test compounds freely made
available to researchers by MMV [Aleman Resto, 2014; Bessoff, 2014; Bowman, 2014;
Boyom, 2014; Fong, 2015; Hain, 2014; Ingram-Sieber, 2014; Kaiser, 2015; Lucantoni,
2013; Paiardini, 2015; Spangenberg, 2013].
The availability of new assays (cited above), in vivo detection procedures [Wampfler,
2013] and a growing awareness of the problem [Gardiner, 2015; Nilsson, 2015; Wampfler,
2013] facilitates testing new drugs in development for gametocidal activity. A screen with
the MMV Malaria Box identified 64 gametocytocidal compounds with 50% inhibitory
concentrations (IC50s) below 2.5
[Lucantoni, 2013]. Just recently, a 13,500 compound
library was screened against P. falciparum stage V gametocytes identified a number of hits
active in the standard membrane feeding assay [Almela, 2015].
Recently described DDD107498 is a multi-stage inhibitor [Baragaña, 2015] that would fall
in the category of antimalarials that kill all relevant parasite stages.
A single dose of primaquine is effective in blocking transmission of Plasmodium
falciparum but there have been concerns over using this drug as a component of treatment
of clinical cases or as a component of the anti-malarial regimen used in mass drug
programmes, because of the risk in G6PD-deficient subjects and there was some
uncertainty over what dose to use. Progress has been made in determining the dosage to be
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used for killing P. falciparum gametocytes and the safety of these low doses [Graves,
2015]. An important trial in Uganda showed that a dose of 04.mg/kg was as effective as the
WHO recommended dose of 0.75 mg/kg [Eziefula, 2014a], and other trials of low dose
regimens are in progress. However, as the Cochrane review [Graves, 2015] points out,
there is still no direct evidence that addition of primaquine to the treatment regimen for
clinical cases of P. falciparum malaria reduces malaria transmission at the community level
and this needs to be evaluated.
Elimination of P. vivax is likely to be more difficult than elimination of P. falciparum in
areas where both infections are prevalent because of the occurrence of relapses in the
former infection. Effective treatment of P. vivax hypnozoites requires much larger dose of
primaquine than needed for interruption of transmission of P. falciparum, increasing the
risk of adverse reactions in G6PD-positive subjects.
Tafenoquine, given a single treatment, offers a potential alternative to primaquine which
would be easier to administer although still able to cause haemolysis in G6PD-deficient
subjects. Some progress has been made in defining the optimum dosage and safety of
tafenoquine [Rajapakse, 2015] but development of this drug has been disappointingly slow;
the first trial was reported 16 years ago, and it appears that this has not been given the
priority that it should have been accorded.
The ability of ivermectin to kill mosquitoes has been known for some time and increased
attention to malaria elimination has led to increased interest in the potential of ivermectin
as a useful tool in malaria elimination programmes. It has been demonstrated clearly that
the drug reduces the lifespan of anopheline mosquitoes and can, therefore, be expected to
have a transmission-blocking impact [Ouédraogo, 2015], but the drug is only present in the
blood for a few days after treatment so it is uncertain how effective it would be in largescale implementation programmes. A promising approach to overcoming this problem is
the development of long-acting formulations [Chaccour, 2015], an approach that needs
safety and efficacy evaluation in man. Should an adverse reaction occur with a long-acting
formulation this could be potentially very dangerous, unless an antidote was available.
A number of new anti-malarials with a unique mode of action are in the MMV portfolio,
and there is now a recognition that investigation of transmission-blocking properties should
be a key part of the evaluation of any new class of anti-malarials. Progress has been made
in the development of in vitro and animal models that allow this to be done and this is a
commendable development. The potential transmission-blocking activity of any new class
of antimalarials needs to be seen as an important part of its early evaluation.

Drugs that cure liver stages of vivax (and ovale) malaria; Assays to measure activity
against liver stages
Current overall status:
Achievements:
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Progress but incomplete:
Gaps: Need a non-8-aminoquinoline to treat Pv relapse
Detailed narrative:
For addressing the parasites’ liver stages with antimalarials, the Aotus monkey model has
been long used [Voller, 1969; Voller, 1968], but significant progress has been made in
novel human liver models [Kaushansky, 2014], with newly developed assays [Borrmann,
2011; da Cruz, 2012; Derbyshire, 2012; Meister, 2011; Prudencio, 2011; Rodrigues, 2015;
Stanway, 2013; X. Zou, 2013], helped by in vitro culture of human liver cells [March,
2013] and mini-livers in culture or animals [Takebe, 2013].
Subsequently, animal models need to be set up for antimalarials that target the liver stages,
preferably in rodents [Mikolajczak, 2015; Morosan, 2006; Sacci, 2006; Siu, 2015;
Vaughan, 2012], or in non-human primates [Joyner, 2015]. Developments of only few
compounds for this indication have been reported [Zeeman, 2014; B. Zou, 2014].

Ideally, drugs that can be administered in a single encounter at infrequent intervals, and
that result in radical cure of all parasite stages
Current overall status: Significant progress
Achievements:
Progress but incomplete: Single encounter drugs are under development
Gaps: Still need more NCEs as many compounds will fail over time
Detailed narrative:
This area has seen significant progress, with the development of new, potent molecules
with significantly improved half-life compared to artemisinins, such as OZ439 [Charman,
2011; Darpo, 2015; Lau, 2015; Moehrle, 2013; Wang, 2013]. Other example for this
approach is the spiroindolone KAE609 (also known as cipargamin) [Rottmann, 2010;
Yeung, 2010], which hits a new target ATPase 4 ion channel PfATP4 [Spillman, 2013];
KAF156 [Diagana, 2015; Held, 2015; Kuhen, 2014a; Leong, 2014b], and DDD107498
[Baragaña, 2015], which targets PfeEF2 (protein synthesis) in all Plasmodium stages.
These molecules hold the promise of significantly expanding the pharmacophores and span
of targets exploited in antimalarials. The background and status of these and additional
SERCaP candidates was recently reviewed [Wells, 2015].

Sustained or pulsed release formulations
Current overall status: No activity was reported in this area
Gaps:
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
Exceptionally safe schizonticidal drugs for curing asymptomatic falciparum infection
Current overall status: Some promising leads
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
Some promising leads are, or will soon progress into the clinic: KAE609
[Lakshminarayana, 2014; Leong, 2014a; Stein, 2015; White, 2014; Zhang, 2015], DSM265
[McCarthy, 2014a; Phillips, 2015], OZ439 [Darpo, 2015; Lau, 2015; Moehrle, 2013;
Wang, 2013] and KAF156 [Kuhen, 2014b].
Fundamental research questions aimed towards developing desired drugs

Fundamental studies of liver and sexual stage biology (in both host and mosquito)
Current overall status:
Achievements:
Progress but incomplete:
Gaps: Completely humanized mouse
Detailed narrative:

Mechanisms of resistance and pharmacological strategies to deter resistance
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
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Significant progress has been made in understanding the molecular basis of drug resistance
(see section on testing for resistance).

In vitro culture of P. vivax to understand parasite biology
Current overall status:
Achievements:
Progress but incomplete:
Gaps: More work needed on establishing hyponozoites in culture
Detailed narrative:
This area was reviewed in 2013 [Zeeman, 2013]. Long-term in vitro cultures of blood-stage
parasites were so far feasible only for Plasmodium falciparum and P. knowlesi. Just
recently an improved culture system was described for vivax [Roobsoong, 2015], boosted
by the enhanced production of human reticulocytes [Noulin, 2014] although parasite
densities remain low.
Tools and capacities

Increased capacity for clinical pharmacology research including
pharmacokinetics/pharmacodynamics studies in populations targeted for malaria
elimination
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
Some advances evidenced by published work in this area [Bergstrand, 2014; Hodel, 2014;
Kay, 2013; Patel, 2015; Reuter, 2015; Zaloumis, 2012].

Increased capacity for human challenge studies for early go/no go decisions on drug
candidates
Current overall status:
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Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
There is growing capacity and utilization of the controlled human malaria infection
(CHMI) model; new antimalarial drug candidates are now almost systematically tested in
Plasmodium-infected volunteers [Engwerda, 2012; Marquart, 2015; McCarthy, 2013;
McCarthy, 2011; McCarthy, 2014a; McCarthy, 2014b; Stanisic, 2015] in order to acquire
precise PK/PD parameters in immuno-naïve individuals (corresponding to the status of
vulnerable children). Importantly these results can be compared against established drugs
such as piperaquine and mefloquine, tested in the same model, guiding optimal dosing and
significantly accelerating clinical development.

Assays to measure transmission-blocking activity
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
(See above: Determine gametocytocidal and anti-relapse activity of current drugs and those
in the pipeline)

Assays to measure activity against liver stages
(See above: Drugs that cure liver stages of vivax (and ovale) malaria)

In vitro culture of P. vivax and other non-falciparum species for drug screening
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
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Detailed narrative:
(See above sections for P. vivax; no reports on a screening assay, or progress on other nonfalciparum species [Zeeman, 2013])

Genomic and proteomic approaches to identify transmission-blocking and liver-stage
activity
Current overall status: No activity was reported in this area
Gaps:
KNOWLEDGE GAPS AND RESEARCH PRIORITIES FOR DRUG TREATMENT AND
PREVENTION STRATEGIES FOR ERADICATION

Field studies to evaluate new drugs and approaches in a variety of epidemiological
settings
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:

Robust and highly sensitive malaria diagnostics for malaria infection and especially for
carriage of infectious gametocytes
Current overall status: Partially solved: [Britton, 2015] [Hopkins, 2013] [Hofmann, 2015]
[Taylor, 2014] [Lin Ouedraogo, 2015] [Slater, 2015, in press]
Achievements:
Progress but incomplete: Markers for infectious gametocytes. Sensitivity is okay, specificity is
not good.
Gaps: Comparative sensitivity different diagnostics
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Detailed narrative:
Progress has been made in Pfs25 PCR and NASBA [Koepfli, 2015; Mwingira, 2014;
Walker, 2015; Wampfler, 2013]; see also diagnostics section.

Measures to monitor and improve adherence and safety
Current overall status:
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
The expanded use of child-friendly, dispersible Coartem can be listed here, with 250
million treatments of this life-saving medicine had been delivered to 50 malaria-endemic
countries by November 2014 (www.mmv.org; [Ebstie, 2015; Manyando, 2015; Ogolla,
2013; Tiono, 2015]).

How must drug treatment and prevention strategies change as elimination proceeds?
Current overall status: Not enough progress.
Achievements:
Progress but incomplete:
Gaps:
Detailed narrative:
When to switch from MDA to MSAT is unclear. A recent WHO meeting gave a good
summary of the current evidence for MSAT and MDA for elimination purposes
[Okell, 2014; Slater, 2015, in press]

Strategies to deter resistance
Current overall status:
Achievements:
Progress but incomplete:
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Gaps:
Detailed narrative:
General assessment of malaria drug development
The clinical landscape
Artemisinin combination therapies (ACTs) continue to represent the mainstay of malaria treatment
[41-45]. Over the past five years a number of new tablet strengths and formulations have been
approved (Table 2), including child-friendly dispersible tablets (Coartem). The increase in number of
WHO-prequalified generics exerts a strong pressure on pricing [25, 46], improving access. For
instance, the procurement price of AL (Artemether + Lumefantrine) dropped between 2012 and 2013
from US$ 1.59 (US$ 0.01–2.33) to US$ 1.40 (US$ 1.17–2.15), and the median price of 3x2 ASAQ
(Amodiaquine + Artesunate) has declined since first becoming prequalified in October 2008, from
US$ 1.09 (US$ 0.69–1.09) in 2008 to US$ 0.94 in 2013 [41]. These price reductions likely also
contribute to the recently observed decrease in counterfeit antimalarials that are offered to patients
[47-51].
In the near future even more price pressure is to be expected with the recently tightened coordination
between the Global Fund and the President's Malaria Initiative (PMI) in forecasting ACT demand for
suppliers and long-term, guaranteed procurement volumes. Supply and pricing of artemisinins has
been notoriously volatile in the past. Prices fell from 2011, but this could result in less
planting/harvesting of Artemisia annua crop, and shortages in 2016-2017. The good news is that a
semi-synthetic process has been developed (through a collaboration between Sanofi and the U. of
Berkeley, US) that starts from dihydroartemisinic acid (DHAA) and uses microbial fermentation [52]
to produce artemisinin, with the first deliveries as ACTs in 2014; this process has a shorter lead time
and is non-seasonal.
Nevertheless ACTs, being intrinsically difficult to synthesize, remain more expensive than alternative
antimalarials (e.g. US$ 2.02, compared to US$ 0.51 for SP (Pyrimethamine + Sulfadoxine) or US$
0.65 for CQ (chloroquine; data from Uganda, [41]).
Where will the new leads come from?
The (re-)discovery of artemisinins has arguably prevented millions of deaths over the past decades.
Moreover its introduction has reduced the use of older antimalarials, thus slowing the spread of
resistance against these drugs and extending their useful lifetime. Third, artemisinins have triggered
the opening of a whole new chemical landscape around peroxides. In retrospect it obvious that this
class of chemicals would never have been part of synthetic chemical collections. This tremendous
success story (and others) have spurred great interest in ‘ethnobotanic’ knowledge for malaria [53] and
other diseases [54]. However the difficulties with tapping into the natural reservoir are many:
traditional knowledge is rapidly lost in the absence of written records, the production (content) of plant
secondary metabolites is notoriously unreliable (eg are produced seasonally, or when under attack of
specific pathogens only), problems in identifying the correct plant species/variety and extract
preparation; concerns over ‘biopiracy’ and practitioner’s reliance on placebo-effects (i.e. no real
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efficacy. The active ingredient must be isolated, a doomed effort if activity results from a complex
mixture. Only a single natural product is listed in Table 4; The U. of Geneva, Switzerland has been
developing Argemone mexicana extracts [55], which showed efficacy in a trial in Mali [56]. A large
number of papers describe ethnobotanic efforts to find new antimalarials (e.g. [57-61] among many
others), but none of these have led to results that could be further exploited for widespread use. In
spite of the odds, given the tremendous payoff of fresh chemical starting points from natural products
this quest must nevertheless continue.
New candidate drugs, new targets
A reduction in costs for phenotyping screening has produced a crop of new molecules, with new
targets, that are now entering the clinic ([9]; Table 3). This harvest also required the public availability
of high-quality chemical libraries originating from large pharma companies, Novartis [62] and
GlaxoSmithKline [63], and the hospital-based drug discovery group at St. Jude Children's Research
Hospital in Memphis Tennessee [64]. These large collections, totaling 6 million compounds, were
screened, initially in-house [65], and later at The Eskitis Institute, Brisbane [66]; most of these
activities took place within a precompetitive model (deferring IP ownership). What is particularly
exciting is that these molecules were (later) found to have new targets [67]: PfATP4 (Na+-ATPase 4)
is targeted by KAE609 [68-72] and SJ557733 [64, 73]; PfPI4K (Phosphatidylinositol‑4 kinase) is
targeted by MMV390048 ([74]; today all clinically validated targets). Finally, PfEF2 (Elongation
factor 2) is targeted by DDD107498 [75]. Moreover, optimization of DSM265 [76, 77] and P218 [78]
was greatly helped by comparing inhibitory activity against their Plasmodium targets
(PfDHODH/Dihydroorotate dehydrogenase resp. PfDHFR/Dihydrofolate reductase) with the human
orthologs.
Nearly all phenotypic screens search for TCP1 (SERCaP, Single Encounter Radical Cure and
Prophylaxis) compounds, fueled by improved culture conditions and mouse models [79]. New,
innovative assays amenable to high-throughput screening are urgently required to address antimalarial
for the ‘neglected’ product profiles: chemoprevention, targeting the liver schizonts; blocking
transmission and relapse prevention. New assays are being developed that address the parasites’ liver
stages [62, 80-86], helped by in vitro culture of human liver cells [87] and mini-livers in culture or
animals [88]. Subsequently, animal models need to be set up for antimalarials that target the liver
stages, preferably in rodents [89-93], or in non-human primates [94].
Another important area for the development of phenotypic screens involves gametocytes, to prevent
transmission [95-98]. Recently novel assays were set up and identified gametocidal candidates [99]
some coming from the MMV Malaria Box [100], a set of drug-like test compounds freely made
available to researchers by MMV [65, 100-109]. This area is especially important since many
antimalarials in use do not target gametocytes [96, 99, 110]; moreover there are differences in drug
sensitivities between male and female cells [111]. This is especially problematic as gametocytes that
escape chemotherapy may enhance the spread of resistance.
Clinical Development
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Experimentally induced (volunteer) malaria models have emerged as a particularly cost-effective
model to rapidly acquire pharmacokinetic (PK) and pharmacodynamic (PD) properties of these
candidates, accelerating dose-finding and rational drug partner choice, as well as vaccine testing [112117]. In parallel, target compound profiles (TCPs) and target product profiles (TPPs) have been
described for various type of antimalarials [118]. A single drug that specifically targets P. vivax,
tafenoquine, has now progressed into Phase III. It is an 8-aminoquine, like primaquine, but with vastly
improved in vivo half-life. It has the same liability as its predecessor, however, in presenting a safety
risk for G6PD-deficient patients, and improved diagnostic tests for G6PD would greatly increase the
drug’s potential (see Diagnostics section).
Among ACTs there is still an unmet need for the most vulnerable patents: pregnant women and
children. Additional studies are needed to establish the safety of ACTs including the first trimester.
Additional studies are also required for pediatric use: dosing, safety and adapted formulation. Only a
few ACTs have been specifically formulated for pediatric use (Coartem and ASAQ). A pediatric
formulation based on DHA PPQ is in Phase IIb/III trials. There is no taste-masked formulation of
AQ+SP that would allow Seasonal Malaria Chemoprevention (SMC) in children.
For severe malaria the best available treatment today is injectable artesunate, which several studies
have shown is superior over injectable quinine [119], however uptake is slow. An alternative
formulation for intrarectal use is in the final stage of development.
With the termination of Azithromycin-CQ (AZCQ), which was in development in Phase III, there are
few prospective treatments that fit the IPTp profile (Intermittent preventive treatment in pregnancy).
One candidate is Co-trimoxazole, currently in Phase II. Concerns are that it requires daily
administration and, when co-administered with SP, may have specific safety concerns in HIV-positive
patients. They other ‘neglected’ category is IPTi (Intermittent preventive treatment in infants); there
are no drugs in development, however DHA/PPQ (Dihydroxy-artemisinin/piperaquine) is being
proposed for this purpose.
Regulatory approval for antimalarials is significantly obstructed and delayed by the lack of
harmonized guidelines. In a positive development the East Africa Medicines Regulatory
Harmonization Programme (EAC-MRH), which aims to harmonize medicines regulation systems and
procedures in accordance with national and international policies and standards, is now operational
and launched a request for proposals (RFP) for harmonized registration in December 2014.
All new antimalarials are to be developed as combination; the days when chloroquine was added to
table salt [120] and lost as useful antimalarial to resistance are gone. However, developing
combination treatments, even though increasingly common for other diseases as well (tuberculosis,
HIV/AIDS and cancer), is highly problematic with the requirement from SRA (stringent regulatory
agencies) that dose-dependent contributions are to be demonstrated for each partner drug. The
problems are that a factorial trial design to formally demonstrate this in patients results in many
treatment arms, increasing costs and time; second, the main benefit of using combinations (the
prevention the origin and spread of resistance) cannot realistically be demonstrated in the timescale of
a trial. Finally, existing treatments are extremely efficient; ARTs typically effect parasite reduction
rates (measured over 48h) of 103-105 for artemisinins [121] with an overall cure rate of >95%. In this
context, demonstrating superiority over existing treatments and/or separating out the contribution of
ART and a partner drug would require large trial arms. Another aspect of innovative antimalarial
Page | 16
development concerns formulations with extended stability in hot, humid climates (preventing loss of
medicines due to irregular supply lines and demand/supply fluctuations), and a treatment that is
administered once vs a three-day treatment. These considerations are typically not taken into account
when assessing the value (approving) NCEs for affluent markets, but the innovations listed above save
lives in rural, tropical areas. For three-day treatments the reality on the ground is that parents or
patients will sell part of the treatment, or keep tablets to be given to relatives with fever later. For
example, a recent study that compared directly observed therapy (DOT) with self-administered therapy
(SAT) for primaquine at the Thai-Myanmar border found the former was about four-fold more
effective [122]. A recent study in Kenya reported 42-58% adherence to ACTs [123]. A key asset of a
SERCaP is that it can be administered as DOT right after diagnosis.
Improving the pharmacoeconomics of antimalarial drug discovery; generating the ‘pull’
Malaria is a disease with ‘market failure’ and attracting sponsors and corporate investors with pharma
expertise for projects with a negative NPV is a daily struggle, whose success mostly relies on CEOs’
personal engagements, and for as long as they keep their position. The GAIN Act for anti-infectives
[124] was implemented to incentivize development of new anti-infectives, and has successfully helped
drive innovation in this field, making new therapies to combat resistance available to patients.
Similarly, the 21st Century Cures Act [125, 126], which is currently in development, aims to increase
access to medications intended to treat disease states currently lacking a cure. The introduction of the
priority review voucher (PRV) to incentivize neglected diseases is a major game changer in attracting
industrial interest. The market value of PVRs is difficult to estimate, and was initially assessed at
$321M [127]. Sale value is however critically dependent on (highly fluctuating) demand, and vouchers
are not quite being traded at this price level but there is a sharply upward trend, with the recent (May
2015) sale of a PVR by Rethrophin to Sanofi for $245M (Table 3)
The introduction of these incentives is of paramount importance for an Organization like MMV
(Medicines for Malaria Venture), which typically seeks to involve a large Pharma partner when one of
its pipeline products moves into Phase III, to shoulder the costs and risks (in addition to providing
expertise).
However, the PVR scheme is not perfect as they reward (essentially) NCEs but not other life-saving
innovations. As a NEJM editorial in 2008 says [128]: “..an effective novel antimalarial drug that
degrades in the heat and must be taken six times a day would earn its sponsor a voucher, but no
voucher would be granted for a follow-on formulation that might be more useful in resource-poor
settings”. More recently, a much-cited PloS blog (tinyurl.com/paaf3t5) was highly critical on patient
access for a drug whose approval triggered awarding the latest Voucher. To an extent, this criticism is
based on the same argument.
What did malERA say about What has been tackled
key R&D questions
Page | 17
What remains unanswered
and
still
relevant?/new
research questions
Knowledge gaps optimizing
- PQ PK
- More data available on PQ PK
- G6PD tests
[Hanboonkunupakarn, 2014]
- Tests for As resistance
- G6PD see Diagnostics
- Gametocyticidal activity of - Progress on As resistance
current drugs
molec dx Mbengue Nature 2015
- Tafenoquine work progressing
Knowledge gaps new drugs
[Llanos-Cuentas, 2014]
- Trans blocking
- See MMV portfolio [Burrows,
- Liver stage killers
2014]
- SERCAP
- Sustained formulations
- CHMI model
- Very safe schizonticides
- Trans blocking assays for field
[Bousema, 2013]
Gaps New tools/capacities
- Roobsoong PV in vitro
o Human challenge
o Trans blocking assay
- Additional data on MSAT
o In vitro cx PV
- Early data on MDA GMS
Drug elim erad strategies
- PQ PK in different
populations (SSA)
- G6PD – see dx
- More data on As resistance
distribution
globally;
correlation with clin data
- TFQ safety; role in
transmission
reduction
strategies
- OZ439 trials (SERCAP?)
- NITD609
- TCP3a and 3b
- Refine CHMI model
- Refine field assays Trans
blocking
- Need to improve PV cx
methods
- Hypno models
- More studies on MDA of
fMDA, safety, methods to
address operational barriers,
and impact
- Optimal use in different epi
studies and with what VC
strategies
Resistance
deterrence
strategies need eval
Page | 18
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