The document summarizes recent advances in malaria treatment, including: 1) Newer antimalarial drugs currently in clinical trials such as KAE609, M5717, KAF156, and DSM265 that show promise in treating multidrug resistant malaria. 2) Synthetic compounds like OZ439 and artemisone that are more effective than existing drugs. 3) Investigational drugs like ferroquine and tafenoquine that have longer half-lives and may help treat resistant strains and relapses. 4) Potential combination therapies using methylene blue to reduce transmission while preventing hemolysis in vulnerable patients.

1. RECENT ADVANCES IN
TREATMENT OF MALARIA
Dr. Vikas S. Sharma
Dept. of Pharmacology
GMC Nagpur

2. Overview
◦ Introduction
◦ Currently available antimalarial drugs
◦ Newer antimalarial drugs
◦ Malaria vaccines
◦ Conclusion
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3. Introduction
◦ Protozoal disease caused by infection with parasite of genus plasmodium & transmitted to man by
certain species of infected female Anopheline mosquito
◦ Despite remarkable progress, the global tally of malaria in 2015 was 212 million new cases & 429,000
deaths (WHO African Region - 90% of malaria cases & 92% of malaria deaths in 2015)
◦ Malaria is considered to be endemic in 91 countries in 2016, down from 108 in 2000
◦ Malaria mortality rates are estimated to have declined by 29% globally between 2010 and 2015.
However, progress has been slow inWHO African Region, region that carries heaviest malaria burden
◦ According to the reports, fewer than half of the 91 malaria-affected countries are on track to achieve
the 2020 milestone of a 40% reduction in case incidence & mortality
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4. Life cycle of malarial parasite
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5. Classification
1. 4-Aminoquinolines - Chloroquine (CQ), Amodiaquine (AQ), Piperaquine
2. Quinoline-methanol - Mefloquine
3. Cinchona alkaloid - Quinine, Quinidine
4. Biguanide - Proguanil (Chloroguanide)
5. Diaminopyrimidine - Pyrimethamine
6. 8-Aminoquinoline – Primaquine
7. Sulfonamides and sulfone - Sulfadoxine, Sulfamethopyrazine, Dapsone
8. Antibiotics - Tetracycline, Doxycycline, Clindamycin
9. Sesquiterpine lactones - Artesunate, Artemether, Arteether, Arterolane
10. Amino alcohols - Halofantrine, Lumefantrine
11. Naphthyridine - Pyronaridine
12. Naphthoquinone - Atovaquone
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6. Available drugs are used for
Causal prophylaxis
◦ Target – Pre-erythrocytic phase (in liver)
◦ Primaquine: all species of malaria
◦ Proguanil: primarily for P. falciparum
◦ Atovaquone + Proguanil: P. falciparum by travellers
Suppressive prophylaxis
◦ Target – Erythrocytic phase (Schizontocides)
◦ Exoerythrocytic phase in case of vivax & other relapsing malarias continues, clinical disease does
appear
◦ Chloroquine, Mefloquine & Doxycycline
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7. Available drugs are used for…
Clinical cure
◦ Target – Erythrocytic phase (Schizontocides)
◦ High-efficacy drugs: Artemisinin, chloroquine, amodiaquine, quinine, mefloquine, halofantrine,
halofantrine, lumefantrine and atovaquone
◦ Low-efficacy drugs: Proguanil, pyrimethamine, sulfonamides, tetracyclines and clindamycin
clindamycin
◦ Erythrocytic schizontocides are radical curatives for falciparum, but not for vivax or ovale malaria
Radical cure
◦ Target – Exoerythrocytic stage (hypnozoites)
◦ Drugs that target hypnozoites given together with a clinical curative – total eradication of parasite
◦ Primaquine
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8. Suppressive cure
◦ Target – Hypnozoites
◦ If suppressive prophylaxis is continued for longer period
◦ It is like radical cure but by extended suppressive prophylaxis therapy
◦ Chloroquine
Gametocidal
◦ Target – Male and female gametes of Plasmodia
◦ Primaquine is gametocidal to all species of Plasmodia
◦ Artemisinins have weak lethal action on early-stage but not mature gametes
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Available drugs are used for…

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Available drugs are used for…
P. vivax malaria
◦ Chloroquine + Primaquine
◦ Quinine + Doxycycline or Clindamycin + Primaquine
◦ Artemisinin-based combination therapy + Primaquine
Chloroquine-sensitive P. falciparum malaria
◦ Chloroquine + Primaquine
Chloroquine-resistant uncomplicated P. falciparum malaria
◦ Artesunate-sulfadoxine + pyrimethamine (AS-S/P) Artesunate-mefloquine (AS/MQ)
◦ Artemether-lumefantrine Dihydroartemisinin (DHA)-piperaquine
◦ Artesunate-amodiaquine (AS/AQ) Arterolane-piperaquine

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Available drugs are used for…
Treatment of severe and complicated falciparum malaria
◦ Artesunate i.v./ i.m.
◦ Artemether i.m.
◦ Arteether i.m.
◦ Quinine i.v.

11. Limitations of conventional antimalarial drugs
◦ Drug resistance – require Multi-DrugTherapy
◦ Adverse effects
◦ Multiple doses
◦ Majority of antimalarial drugs have a bitter taste
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12. Antimalarial drugs
under various
stages of clinical trial
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14. Based on phenotypic assay
KAE609
◦ Spiroindolone, KAE609, a potential Na+-ATPase 4 ion channel (PfATP4) inhibitor
◦ 7 times more potent than artesunate & 40 times more potent than 4-aminoquinolines
◦ Results of Phase II clinical trial – clearance t1/2 of 0.9 h for P. falciparum & 0.95 h for P. vivax.
◦ Furthermore, the mean terminal t1/2 for elimination was 20.8 h – OD oral dosing regimen
◦ In vitro studies showed activity against artemisinin-resistant K13 mutant parasite and prevents
recrudescence of dihydeoartemisinin (DHA)-arrested ring at minimal concentration
◦ Thus, a broad range of antimalarial action & useful for treatment of multidrug-resistant P.
malaria.
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15. Based on phenotypic assay…
M 5717 (DDD107498) – Phase I completed
◦ Novel phenotypic molecule that specifically acts against liver-stage P. falciparum malaria
◦ In vitro assays against different P. falciparum laboratory strains, such as artemisinin-resistant
chloroquine-, amodiaquine- and mefloquine-resistant strains, revealed a low micromolar range
the parasite
◦ May be effective against multidrug resistant Plasmodium strains (Dd2 and 7G8).
◦ Excellent oral bioavailability & a longer plasma t1/2, which is preferable for single-dose treatment
◦ These results suggest that, it can achieve complete parasitic clearance in blood stage by rapid
for more than 48 h.
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16. KAF156 (imidazolopiperazine)
◦ Promising chemoprevention molecule, a cyclic amine resistance locus inhibitor
(PfCARL)
◦ In vitro, it is active against uncomplicated P. falciparum & P. vivax strains in liver,
asexual erythrocytic, & transmission stages
◦ Phase II proof-of-concept trial was conducted among Vietnamese & Thai patients,
treated with 400 mg/day for three days & a single 800 mg dose
◦ In 21 Patients who received a single 800 mg dose, 67% of patients cleared
which is comparable to other antimalarial medications
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Based on phenotypic assay…

17. DSM265
◦ Dihydroorotate dehydrogenase (DHODH) inhibitor acting against the liver stage
◦ Proving to be promising as a one-dose (400 mg) malaria cure in a Phase I trial,
an encouraging safety profile
◦ Currently in Phase II
◦ Its activity against uncomplicated P. falciparum and P. vivax parasites is being
assessed in adult patients using a single dose treatment (400 mg)
◦ Although it showed robust results in Phase I trials, further studies are needed
predict its safety for use in pregnant women
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Based on phenotypic assay…

18. Malaria and pregnancy:
◦ It is not recommended to use ACTs during the first trimester due to side effects observed in
preclinical models
◦ Currently, sulfadoxine-pyrimethamine is used in pregnant women as an intermittent preventive
treatment to reduce infections and improve pregnancy outcomes
◦ Cotrimoxazole prophylaxis for prevention of malaria in pregnancy & co-infection with malaria and
HIV in women were completed in 2013, but results have not yet been published
◦ Mefloquine has shown significant benefits but may cause nausea and neuropsychiatric side
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Based on phenotypic assay…

19. Synthetic medicinal compounds
◦ Synthetic artemisinin-like endoperoxides & their derivatives have been proven to be more effective
than chloroquine
OZ439 (artefenomel)
◦ Next generation synthetic endoperoxide ozonide, longer half-life (30 h) and a MIC of more than one
week, after a single dose
◦ First highly active ozonide against Plasmodium
◦ Different doses of artefenomel (200–1200 mg) were tested in a Phase IIA exploratory, open-label trial
& revealed promising safety and efficacy profiles among SEAsian adults with uncomplicated P.
falciparum & P. vivax malaria
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20. ◦ Due to the longer elimination t1/2 of 46–62 h, a single dose of OZ439 alone or in combination with
piperaquine can eliminate 98.0 % of P. falciparum and 99.6 % of P. vivax within 36 h.
◦ Artefenomel has demonstrated a higher parasitic clearance within the first 24 h in P. vivax patients as
compared to P. falciparum patients (30–36 h)
◦ Gametocyte clearance was 100 % in patients who were administered 1200 mg of artefenomel within
48 h
◦ Currently being evaluated with piperaquine in Phase IIB trials.
Synthetic medicinal compounds…
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21. Artemisone
◦ Semi-synthetic second-generation artemisinin derivative
◦ More effective than artesunate against P. falciparum and multidrug resistant strains
◦ Dose-escalating Phase I trials: Rapidly effective, as it achieves peak plasma concentrations
min following oral administration
◦ Phase II interventional study testing artemisone for treating uncomplicated P. falciparum
has been withdrawn for unknown reasons
Synthetic medicinal compounds…
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22. Aminoquinoline scaffolds
Ferroquine (Currently in Phase II)
◦ Ameliorated blood-schizonticidal 4-aminoquinoline
◦ Along with artefenomel, it is a more effective parasite-killing compound against Plasmodium
when compared to artesunate
◦ Greatest advantage: 30-h t1/2, which is highly superior to that of other artemisinin derivatives
◦ Ferroquine-artesunate dose-ranging Phase II trial on P. falciparum-infected adults & children
97 % PCR-confirmed cure rates after treatment with 2 mg/kg ferroquine combined with 4 mg/kg
artesunate
Cure rate was reduced to 79 % when ferroquine monotherapy 4 mg/kg/day for 3-days regimen
was used
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23. Tafenoquine
◦ Patients with a G6PD deficiency are common in malaria-endemic countries & are at high risk of
hemolysis due to treatment with antimalarial drugs
◦ It is an 8-aminoquinoline derivative & has a similar mode of action to primaquine against
hypnozoites, gametocytes, and liver stages
◦ More potent during blood stages due its longer half-life (14 days) as compared to primaquine.
Nevertheless, slower parasitic clearance was observed with monotherapy.
◦ Therefore, combing tafenoquine with other partner drugs may ideally benefit G6PD-deficient
patients
◦ In a Phase IIb dose-ranging trial, different doses of tafenoquine alone (50, 100, 300, or 600 mg)
combination with 15 mg primaquine for 14 days were tested, with a fixed dose of chloroquine for
days
Aminoquinoline scaffolds…
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24. ◦ A single dose of tafenoquine (300 mg) co-administered with chloroquine – prevent relapse in 89.2 %
of people as compared to chloroquine alone (51.7 %) during first 6 months of follow-up
◦ Phase IIb dose-ranging trial (DETECTIVE study) conducted on P. vivax patients for radical cure
showed that single-dose tafenoquine (300 mg) combined to chloroquine is more efficacious in
preventing relapses as compared to chloroquine alone, with a similar safety profile
◦ Two new Phase III studies:
DETECTIVE study – to evaluate the efficacy, safety, and tolerability of tafenoquine co-administered
with chloroquine as a radical cure for P. vivax malaria
GATHER study – to assess the incidence of hemolysis & efficacy and safety of tafenoquine over
primaquine
Aminoquinoline scaffolds…
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25. Biomolecular approaches
Methylene blue (Phase I trial in combination with primaquine)
◦ Methylene blue combined with chloroquine - prevent hemolysis in G6PD-deficient adult patients
◦ Different doses of methylene blue with chloroquine for 3 days - 90 % recovery rates in
falciparum malaria
◦ In 2011, treatment with artesunate-amodiaquine-methylene blue was studied in children aged
6 & 50 months with uncomplicated P. falciparum malaria
◦ This combination showed poor efficacy (71 %) when compared to the control group (artesunate-
amodiaquine; 85 %)
◦ After comparing a fixed dose 15 mg/kg of methylene blue co-administered with artesunate or
amodiaquine versus artesunate-amodiaquine for 3 days, decreased gametocytes (from 100 to 36
were reported within 7 days of treatment
◦ Interestingly, pronounced effect on gametocyte clearance indicates that methylene blue is a new
promising drug component to reduce P. falciparum transmission.
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26. Antibiotics
Fosmidomycin
◦ Derived from Streptomyces lavendulae bacterial isolates
◦ Inhibits non-mevalonate pathway (DXP reductoisomerase), essential for the synthesis of
parasite isoprenoids
◦ T1/2 of only two hours and acts rapidly upon oral administration
◦ One study indicated complete parasitic clearance on day 7 following administration of
(1200 mg QID) in adult patients with uncomplicated P. falciparum malaria
On day 28, recrudescence was observed in 7/9 patients, indicating monotherapy failure
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27. Antibiotics…
◦ Fosmidomycin co-administered with clindamycin has been proven to be effective in adults & older
children with acute uncomplicated P. falciparum malaria
◦ Two additional short half-life combinations (fosmidomycin with artesunate) were evaluated in 50
children aged between 6 & 12 years. Five different fosmidomycin-artesunate regimens achieved
complete cure rates within three days of administration, and no resistant alleles were detected after 7 &
28 days
However, no evidence of prolonged protection by this combination was provided
◦ Overall, studies indicated that fosmidomycin is only effective for short-term treatment
◦ Phase IIA open-label efficacy trial focusing on fosmidomycin and piperaquine for treating patients with
uncomplicated P. falciparum malaria, aged between 1 and 60 years & with a body weight between 5 &
90 kg – currently ongoing
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28. Under-trial antimalarial drugs
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Tafenoquine
(-)
(-)
KAE609
(-)
(-)
M5717
DSM265
(-)
KAF156
(-)
Artefenomel
Methylene blue
Ferroquine

29. Global malaria vaccine pipeline
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30. Malaria vaccine
◦ Despite many decades of intense research & development effort, there is no commercially available malaria
vaccine
◦ RTS,S/AS01 – most advanced vaccine candidate against P. falciparum. Recombinant protein-based malaria
vaccine is Mosquirix, a combination of 25 % fusion protein RTS and 75 % wild-type HbsAg antigen
◦ July 2015, European MedicinesAgency issued a positive scientific opinion on vaccine’s risk-benefit balance
◦ WHO has adopted these recommendations & is strongly supportive of the need to proceed with the pilots as
next step for the world’s first malaria vaccine
◦ Phase IV pharmacovigilance study – to determine incidence of protocol specificAESI, other AE leading to
hospitalisation or death and of meningitis, in infants and children of sub-Saharan African countries, prior to
implementation of RTS,S/AS01E candidate vaccine – in a follow-on study
◦ Phase 3b – measles / yellow fever co-administration
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31. Conclusions
◦ The development of new drugs for malaria presents a challenging situation
◦ Traditional medicines have provided few drugs, but to combat malaria, new drugs are urgently needed.
◦ These new drugs must ideally possess minimal toxicity, rapid efficacy, and low cost
◦ Natural products, semisynthetic drugs, and synthetic compounds offer vast opportunity
for the drug development process.
◦ Further, assessment and clinical evaluation of RTS,S/AS01 for malaria vaccination offers new hope
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32. Conclusions…
◦ Effective compounds should be developed before global emergence of resistance to artemisinin
derivatives & 4-aminoquinoline
◦ Molecules such as ferroquine should be combined with a potential partner drug to enhance efficacy
◦ Additional challenges in preventing the relapse of malaria episodes include hemolysis in patients with a
G6PD deficiency, treatment for drug-resistant strains, paediatric dosing, serious drug-drug
interactions, transmission blocking, radical cure, & relapse prevention
◦ Potentially targeting mitochondrial electron-transport chain of P. falciparum & protein inhibition in
blood- & liver-stage parasites could be ideal for future drug development.
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33. References
◦ Goodman & Gilman’sThe Pharmacological Basis of Therapeutics 12th Edition
◦ Rang & Dales’s Pharmacology 7th Edition
◦ Bertram G. Katzung & Anthony J.Trevor’s Basic & Clinical Pharmacology 13th Edition
◦ Biamontea MA,Wannerb J, Le Roch KG. Recent advances in malaria drug discovery. Bioorg Med Chem Lett.
2013 May 15; 23(10): 2829–2843
◦ Bhagavathula et al. Alternatives to currently used antimalarial drugs: in search of a magic bullet. Infectious
Diseases of Poverty (2016) 5:103
◦ S Chiranjeev, Awasthi SK. Recent Advances in Antimalarial Drug Discovery — Challenges and Opportunities.
Chapter 3 An Overview ofTropical Diseases 39-59
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34. Thank you
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