1. An Update on New Anti – Malarials
Dept. Name
6/2/2012 Privileged and Confidential 1

2. - Current scenario in Anti - Malarials
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3. Currently used Anti - Malarials
Drug Target of Mode of Adverse Clinical uses
action action effects
Chloroquine Blood-stage Direct heme GI upset, Treatment and
schizonticides binding, Inhibit itching, chemoprophyla
heme dizziness, xis of sensitive
Fe(II)FPIX psoriasis etc. parasites
Polymerase.
Quinine Erythrocyte Same as CQ Tinnitus, Treatment of
schizonticides vertigo, CQ-resistant P.
syncope, falciparum
headache etc.
Mefloquine Blood-stage Formation of Vomiting, Chemoprophyl
schizonticides toxic headache, axix and
substance, insomnia etc. treatment of P.
Swelling of falciparum
food vacuole
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4. Currently used Anti - Malarials
Drug Target of Mode of action Adverse Clinical uses
action effects
Primaquine Tissue-stage Generation of GI upset, Radical cure
schizonticides toxic metabolites, anorexia, and terminal
& Oxygen radicals elevated prophylaxis of
gametocytocid in Plasmodial methemoglo P. Vivax &
es mitochondria binaemia P. Ovale
Halofantrine/ Erythrocytic Inhibit heme GI upset, Treatment of
Pyronaridine schizonticides polymerase, cardiac CQ-resistant P.
Inhibit vacuolar arrest falciparum
degradation
Atovaquone Blood-stage Inhibit GI upset, Treatment and
schizonticides mitochondrial stomatitis chemoprophyla
electron transport xis of P.
falciparum, in
combination
with Proguanil
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5. Currently used Anti - Malarials
Drug Target of Mode of action Adverse Clinical uses
action effects
Pyrimetham Blood-stage Inhibitor of dhfr-ts Headache. Headache.
ine/ schizonticides /dhps, thereby, SJS, Skin SJS, Skin rash
Sulfadoxine inhibit parasitic rash Treatment of
DNA CQ-resistant P.
falciparum (in
combination as
SP)
Proguanil Erythrocytic Inhibit dhfr and GI upset, Chemoprophyla
schizonticides stops pyrimidine nausea, xis (with CQ)
biosynthesis Vomiting
Artemisinin Erythrocytic Formation of iron Neurotoxicity Treatment of
and its schizonticides catalysed free , anorexia, multidrug-
derivatives & radical, Alkylation of dizziness resistant P.
gametocytocid heme, Membrane falciparum
es damage by free
radical
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6. Currently used Anti - Malarials
Drug Target of Mode of action Adverse Clinical uses
action effects
Tetracycline Blood-stage Inhibit Nausea, Treatment and
/Doxycyclin schizonticides mitochondrial vomiting, chemoprophyla
e protein synthesis, diarrhoea xis of P.
block nucleic acid falciparum
synthesis
Note:
dhfr-ts: Dihydrofolate reductase-thymidylate synthase,
dhps: Dihydrofolate pteroate synthase,
SJS: Steven’s Johnson Syndrome.
******
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7. - New Drugs…Are they required???
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8. Need of new Anti - Malarials
Less treatment
options in malaria Demand - Supply
Increasing
Resistance against imbalance
ACTs of Artemisinin
Sulfa
Fat dependent
reactions, SJS New Molecules
bioavailability of
observed with are Warranted
Lumefantrine
Sulfadoxine
Multiple doses of current FDC available in
therapy – Non compliance only some ACTs
Potential
Vaccines in 2025
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9. Treatment failure rates artemether–lumefantrine in
the Greater Mekong subregion (2001–2009)
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10. 6/2/2012 Privileged and Confidential 10

11. Treatment failure rates with
artesunate –sulfadoxine –pyrimethamine in
selected countries (2001–2008)
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12. 6/2/2012 Privileged and Confidential 12

13. (1.) National Medicines Policy and
(2.) Procurement and Forecast of ACTs
Forecast:
124 Million
140 Cumulative 80
number of countries 124
120 adopting ACTs as 1st- 70
Cumulative No. of countries
adopting ACT as 1st-line Rx
Millions of ACT treatment courses
line treatment
60
100
110 50
80 Cumulative
number of countries 40
60 deploying ACTs
30
40 31.3
20
20 10
2.1 5
0.5 0.6
0 0
2001 2002 2003 2004 2005 2006 2007
ACT procured No. countries w ACT 1st line No. countries implementing
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14. 6/2/2012 Privileged and Confidential 14

15. Some of the New Drug Targets
1) Dihydroorotate dehydrogenase (DHODH): The parasite and
mammalian forms differ considerably. Potent and selective
compounds have been developed
2) Adenosine deaminase inhibitors:
3) Inhibitors designed to be active against the transition state of purine
nucleoside phosphorylase have been shown to be active against P.
falciparum . Compounds are safe and ready to test on humans
4) Apicoplast – an organelle selectively present in Plasmodium
Metabolic pathways in apicoplast are potential targets
e.g. Fosmidomycin targeting 1-deoxy-d-xylulose 5-phosphate pathway.
In Phase – II
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16. Some of the New Drug Targets
5) Protease targets: Are potential but selective parasite selectivity is
an issue
e.g. cysteine proteases - falcipain57 and the serine protease inhibitors -
PfSUB1 were difficult to develop as drug candidates because of
selectivity issues.
6) Choline channel blocker - Albitiazolium bromide. Important
because IV/IM possible and hence can be useful against severe
malaria. In Phase II
7) Imidazolopiperazine: In Nov 2011, new class discovered active
against both liver and blood stages of parasite
- Hence, useful to prevent and treat malaria
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17. Some of the New Drug Targets
Privileged and Confidential

18. - Drugs in Phase – III or
completed Phase - III
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19. Arterolane + Piperaquine
Synthetic
Endoperoxide
Pharmacophore
Arterolane
Hence, availability
never a problem!!!!
With efficacy against
P. falciparum
Artesunate
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20. Arterolane + Piperaquine
• First New Chemical Entity (NCE) of India (Arterolane)
• Phase – III trials completed for uncomplicated P. falciparum while
that for P. vivax are on - going
• Developed in line with WHOs recommendation of Anti – Malarial
drugs
• Fixed Dose Combination (FDC) with only 3 tablets (1 OD *3 days)
Regimen
• No fat dependent bioavailability issues life Lumefantrine
• Will be launched soon in India by Ranbaxy Laboratories Ltd.
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21. Dihydroartemisinin + Piperaquine
Dihydroartemisinin
Piperaquine
• Dihydroartemisinin is derived from natural source
• Combined with long acting drug Piperaquine
• Has been used extensively in China and Cambodia
• Approved by EMA recently and WHO recommended FDC
• Approved by 21 countries world wide
• Trials are still on - going in Indian Population
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22. Artesunate + Pyronaridine
Artesunate
Pyronaridine
• Developed by Korean company Shin Poong and MMV jointly
• Completed Phase III trials and proved to be non inferior to
Artemether + Lumefatrine
• FDC with only 3 tablets (1 OD *3 days) regimen like
Arterolane + Piperaquine
• For approval with EMA
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23. Azithromycin + Chloroquine
Azithromycin
Chloroquine
• Safe and well tolerated in pregnant women: hence a potential combination for use in
early pregnancy
• Passing the WHO approved criteria of 95%efficacy with respect to patient being free
of parasite recrudescence on day 28
• FDC for prophylactic use during pregnancy for which 4 tablets are to be taken
• Clinical signs of synergy between two molecules seen
• Most advanced non ACT based regimen currently in pipeline
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24. - Drugs in Phase – I or
Phase - II
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25. Drugs in Phase I of II Clinical Trials
• 7 in Phase II and 8 in Phase I
• Focus is not no efficacy at these stages but how
novel or useful the molecule is going to be?
• Should be able to be used by varied population
• Dramatic life saving response
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26. Artemisone (Artemifone)
• Semisynthetic derivative of Artemisinin with
additional thiomorpholino group in 10 – position
• Proved effective in Phase –II
• Project was dropped as there was no dramatic
advantage compared to parent drug. However…
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27. Artemisone (Artemifone)
• In Nov 2009, NEJM reported the first clinical
trial confirming Artemisinin resistance in
Thai – Cambodia region
• Median Parasite Clearance Time (PCT)
increased to 84h compared to 48h
• Artemisone was hence thought of if it had
continue to show PCT <48h, as it is
structurally different than artemisinin
• Proof of concept study has been planned to
see this advantage in artemisinin resistant
area
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28. Novel 4 - Aminoquinolines
• Commonly used 4 – aminoquinolines are
Basic Ring
1) Chloroquine
2) Amodiaquine
• Newer 4 – aminoquinolines in development are
N – ter – butyl -
Ferroquine AQ - 13
isoquine
Can be advantageous if…
• Cross resistance is less
• Dose is reduced than currently used 4 – aminoquinolines
• Better safety profile than current drugs in the class
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29. Ferroquine
Ferrocene moiety
• Developed at University of Lille
• Has a Ferrocene moiety (Iron sandwiched between two organic rings) which
contributes to the physico - chemical properties of Ferroquine
• {Artesunate + Ferroquine} is in Phase – II trial
• Dose ranging study comparing it with Artesunate + Amodiaquine was
conducted in 2008
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30. Isoquine & AQ - 13
Mechanism of Amodiaquine toxicity
• Isoquine do not generate quinine – imine that are suspected to cause side
effects of amodiaquine when used repeatedly for prophylaxis
• At Phase – I stage of drug development
• AQ – 13 is simplified 4 – amino quinoline with advantage of less dose, hence
less bio-burden and cost. Phase – I study completed
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31. (+) Mefloquine
Mefloquine
One of the diasterioisomer is responsible for commonly
seen CNS side effects and Gastrointestinal
intolerance of Mefloquine
• (+) erythro Mefloquine is under trial and can be potential to reduce
the side effects associated with Mefloquine
• Also the cost of production is similar to that of Mefloquine racemic
mixture
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32. Ozonides
• Three (3) ozonide are there under development
1) CDRI 97/98 a simple trioxolane developed by Central
Drug Research Institute, India (Phase – I started)
2) OZ439 next generation ozonide by University of
Nebraska, Phase – I started in April 09
3) Trioxaquine – fusion between 4 – aminoquinoline and a
trioxane developed by Sanofi - Aventis
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33. Fosmidomycin and 4 - Pyridone
Pyruvate and glyceraldehyde 3-phosphate
DOXP synthase
Fosmidomycin
1-Deoxy-D-xylulose 5-phosphate
• In combination with Clindamycin it has shown good action against
Plasmodium falciparum
• Project is in Phase – II of drug development
• Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial
mitochondrial electron transport chain targeting Cytochrome bc1 (complex III)
• Effective against Atovoquone resistant strains
• Phase – I completed
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34. Methylene Blue (MB)
• Activity of dyes against malarial parasite seen >80 years
ago
• Phase – II studies of MB + Chloroquine are published
but failed to meet the WHO criteria of 95%efficacy
• Disadvantage: a) It interacts with large number of
various targets in body
b) Blue coloration of urine
• However, MB + Amodiaquine / Artesunate trials is under
recruitment phase
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35. Tafenoquine
• A Novel 8-aminoquinoline
• Since last 60 yrs primaquine is the most commonly used
drug of this class for radical cure in P. vivax
• Disadvantage of primaquine is that it is 14 day long therapy
and hence compliance is always an issue
Tafenoquine
• Tafenoquine was produced in 1980s
• However, Tafenoquine might be developed as shorter course
of therapy and has a better therapeutic window
• But, it also showed signs of haemolysis due to G6PD
deficiency
6/2/2012 Privileged and Confidential 35

36. HUMALMAB
This project is aimed at development of Human monoclonal antibodies
as tools for malaria research and therapy and was started in 1st January
2007.
Overall objective: To generate human monoclonal antibodies (HumAbs)
with specificity for P. falciparum antigens of importance in acquired
protection to P. falciparum-induced malaria.
Specific objective:
 To generate HumAbs with specificity for antigens exposed on the
surface of infected erythrocytes
 To generate HumAbs with specificity for variants of the PfMSP1
antigen
 To test the reactivity and specificity of the developed HumAbs with
respect to P. Falciparum isolates obtained from infected individuals
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37. Other drug classes for radical cure
1) Tinidazole – a nitroimidazole
- Is metabolized in liver and has shown some effect against
dormant hypnozoites in primate model
Tinidazole
- Clinical trials are going in Thailand
2) Mirincamycin
- Efficacy shown in pre – clinical studies
- Showed activity against hypnozoites in primate models
Mirincamycin
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38. - Malaria Vaccine
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39. Malaria Vaccine – Urgent need
 A safe, effective, and affordable malaria vaccine would create a powerful public
health benefit by closing the gap left by other interventions like insecticide bed nets
etc
 Challenges: scientific unknowns, inadequate funding, too little cooperation among
scientists and among funding agencies, limited private-sector involvement, mixed
levels of interest from developing countries, and as yet uncertain mechanisms for
procuring and distributing a successful vaccine
 To meet these challenges the global malaria vaccine community came together to
establish a shared vision and goals and to identify the activities that could address
some of the above-mentioned challenges in Aug 2006
Result was: Malaria Vaccine Technology Roadmap
Strategic Goal Landmark
By 2025, develop and license a By 2015, develop and license a first-
malaria vaccine that has a protective generation malaria vaccine that has a
efficacy of more than 80% against protective efficacy of more than 50%
clinical disease 3 and lasts longer than against severe disease and death and
four years lasts longer than one year.
6/2/2012 Privileged and Confidential 39

40. Closest Vaccine - RTS,S/AS01
 Name: GlaxoSmithKline Biologicals (GSK) RTS,S AS01/AS02
 Development stage: Phase 3 trial
 Main partner: GlaxoSmithKline Biologicals
 Additional partners: Malaria Clinical Trials Alliance; 11 African clinical trial sites
 Platform: The RTS,S antigen, produced in S. cerevisiae, consists of the two proteins
RTS and S that intracellularly and spontaneously assemble into mixed polymeric
particulate structures that are each estimated to contain, on average, 100
polypeptides
 Antigen: RTS,S consists of sequences of the circumsporozoite protein and the
hepatitis B surface antigen (HBsAg)
 Adjuvant: AS02D/AS01E
1) AS02: proprietary oil-in-water emulsion formulated with MPL® and Stimulon® QS21
immunostimulants
2)AS01: liposome formulation with MPL® and QS21 immunostimulants
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41. First Result published in NEJM
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42. References
1. World Health Organization. World Malaria Report 2008. <http://malaria.who.
2. int/wmr2008/malaria2008.pdf> (2008).
3. Bassat, Q. et al. Dihydroartemisinin-piperaquine versus artemether lumefantrine for treating non complicated malaria in African
children: a randomized open label phase III non inferiority trial in five African countries. PLoS Med.
4. Ramharter, M. et al. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in
pediatric patients in Gabon. J. Infect. Dis. 198, 911–919 (2008).
5. Dunne, M.W. et al. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute
uncomplicated Plasmodium falciparum malaria in India. J. Infect. Dis. 191, 1582–1588 (2005).
6. Haynes, R.K. et al. Artemisone—a highly active antimalarial drug of the artemisinin class. Angew. Chem. Int. Ed. Engl.
45, 2082–2088 (2006).
7. Biot, C., Glorian, G., Maciejewski, L.A. & Brocard, J.S. Synthesis and antimalarial activity in vitro and in vivo of a new
ferrocene-chloroquine analogue. J. Med. Chem. 40, 3715–3718 (1997).
8. O’Neill, P.M. et al. Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials.
J. Med. Chem. 46, 4933–4945 (2003).
9. Mzayek, F. et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy
volunteers. PLoS Clin. Trials 2, e6 (2007).
10. Wiesner, J., Borrmann, S. & Jomaa, H. Fosmidomycin for the treatment of malaria. Parasitol. Res. 90 (suppl. 2), S71–S76
(2003).
11. Zoungrana, A. et al. Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated
falciparum malaria: a randomized controlled trial from Burkina Faso. PLoS One 3, e1630 (2008).
12. Yeates, C.L. et al. Synthesis and structure–activity relationships of 4-pyridones as potential antimalarials. J. Med. Chem.
51, 2845–2852 (2008).
13. Walsh, D.S. et al. Randomized dose-ranging study of the safety and efficacy of WR 238605 (Tafenoquine) in the prevention of
relapse of Plasmodium vivax malaria in Thailand. J. Infect. Dis. 180, 1282–1287 (1999).
14. Timothy N. C. Wells*, Pedro L. Alonso‡ and Winston E. Gutteridge, New medicines to improve control and contribute to the
eradication of malaria. Natures review drug discovery, Nov 09, Vol:8
15. http://www.sciencemag.org/content/334/6061/1372.abstract
6/2/2012 Privileged and Confidential 42

43. Thank You
Fight against Malaria Continues…
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