update on new antimalarials

Privileged and Confidential

Dept. Name04/11/2023

An Update on New Anti – Malarials

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Privileged and Confidential04/11/2023

- Current scenario in Anti - Malarials

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Privileged and Confidential04/11/2023 3

Drug Target of action

Mode of action

Adverse effects

Clinical uses

Chloroquine Blood-stage schizonticides

Direct heme binding, Inhibit

heme Fe(II)FPIX

Polymerase.

GI upset, itching,

dizziness, psoriasis etc.

Treatment and chemoprophylaxis of sensitive

parasites

Quinine Erythrocyte schizonticides

Same as CQ Tinnitus, vertigo,

syncope, headache etc.

Treatment of CQ-resistant P.

falciparum

Mefloquine Blood-stageschizonticides

Formation of toxic

substance, Swelling of

food vacuole

Vomiting, headache,

insomnia etc.

Chemoprophylaxix and

treatment of P. falciparum

Currently used Anti - Malarials



Mode of action Adverse effects

Clinical uses

Primaquine Tissue-stage schizonticides

& gametocytocid

es

Generation of toxic metabolites, Oxygen radicals

in Plasmodial mitochondria

GI upset, anorexia, elevated

methemoglobinaemia

Radical cure and terminal

prophylaxis of P. Vivax &P. Ovale

Halofantrine/ Pyronaridine

Erythrocytic schizonticides

Inhibit heme polymerase,

Inhibit vacuolar degradation

GI upset, cardiac arrest

Treatment of CQ-resistant P.

falciparum

Atovaquone Blood-stage schizonticides

Inhibit mitochondrial

electron transport

GI upset, stomatitis

Treatment and chemoprophyla

xis of P. falciparum, in combination

with Proguanil





Clinical uses

Pyrimethamine/

Sulfadoxine

Blood-stage schizonticides

Inhibitor of dhfr-ts /dhps, thereby, inhibit parasitic

DNA

Headache. SJS, Skin

rash

Headache. SJS, Skin rash Treatment of

CQ-resistant P. falciparum (in

combination as SP)

Proguanil Erythrocytic schizonticides

Inhibit dhfr and stops pyrimidine

biosynthesis

GI upset, nausea, Vomiting

Chemoprophylaxis (with CQ)

Artemisinin and its

derivatives

Erythrocytic schizonticides

& gametocytocid

es

Formation of iron catalysed free

radical, Alkylation of heme, Membrane damage by free

radical

Neurotoxicity, anorexia, dizziness

Treatment of multidrug- resistant P. falciparum





Clinical uses

Tetracycline/

Doxycycline

Blood-stage schizonticides

Inhibit mitochondrial protein synthesis, block nucleic acid

synthesis

Nausea, vomiting, diarrhoea

Treatment and chemoprophyla

xis of P. falciparum

Note: dhfr-ts: Dihydrofolate reductase-thymidylate synthase, dhps: Dihydrofolate pteroate synthase, SJS: Steven’s Johnson Syndrome. ******



- New Drugs…Are they required???

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Need of new Anti - Malarials

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Increasing Resistance against

ACTs

Less treatment options in malaria Demand - Supply

imbalanceof Artemisinin

Multiple doses of current therapy – Non compliance

FDC available in only some

ACTs

Sulfa reactions, SJS observed

with Sulfadoxine

Fat dependent bioavailability of

Lumefantrine

New Molecules are Warranted

Potential Vaccines in 2025


Treatment failure rates artemether–lumefantrine in the Greater Mekong subregion (2001–2009)


Treatment failure rates with artesunate –sulfadoxine –pyrimethamine in

selected countries (2001–2008)


(1.) National Medicines Policy and(2.) Procurement and Forecast of ACTs

124

110

2.10.5 0.65

31.3

0

20

40

60

80

100

120

140

2001 2002 2003 2004 2005 2006 2007

0

10

20

30

40

50

60

70

80

ACT procured No. countries w ACT 1st line No. countries implementing

Mill

ions

of A

CT tr

eatm

ent c

ours

es

Cum

ulati

ve N

o. o

f cou

ntrie

s a

dopti

ng A

CT a

s 1s

t-lin

e Rx

Cumulative number of countries adopting ACTs as 1st-line treatment

Cumulative number of countriesdeploying ACTs

Forecast: 124 Million


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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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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Privileged and Confidential



- Drugs in Phase – III or

completed Phase - III

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Arterolane + Piperaquine

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Endoperoxide Pharmacophore

Arterolane

Artesunate

Hence, availability never a problem!!!!

With efficacy against P. falciparum

Synthetic



• 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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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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Dihydroartemisinin

Piperaquine


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


• For approval with EMA

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Artesunate

Pyronaridine


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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Azithromycin

Chloroquine


- Drugs in Phase – I or

Phase - II

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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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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…


Artemisone (Artemifone)

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• 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


Novel 4 - Aminoquinolines

FerroquineN – ter – butyl -

isoquineAQ - 13

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

• Commonly used 4 – aminoquinolines are

1) Chloroquine2) Amodiaquine

Basic Ring

• Newer 4 – aminoquinolines in development are


Ferroquine

• 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

Ferrocene moiety


Isoquine & AQ - 13Mechanism 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


(+) 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

Mefloquine


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


Fosmidomycin and 4 - Pyridone

Pyruvate and glyceraldehyde 3-phosphate

1-Deoxy-D-xylulose 5-phosphate

DOXP synthase

• In combination with Clindamycin it has shown good action against Plasmodium falciparum

• Project is in Phase – II of drug development

Fosmidomycin

• 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

http://en.wikipedia.org/wiki/Pyruvate

http://en.wikipedia.org/wiki/Glyceraldehyde_3-phosphate

http://en.wikipedia.org/wiki/Glyceraldehyde_3-phosphate

http://en.wikipedia.org/wiki/1-Deoxy-D-xylulose_5-phosphate


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


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 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

Tafenoquine


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

HUMALMAB


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

- Clinical trials are going in Thailand

2) Mirincamycin

- Efficacy shown in pre – clinical studies

- Showed activity against hypnozoites in primate models

Tinidazole

Mirincamycin


- Malaria Vaccine

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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 GoalBy 2025, develop and license a

malaria vaccine that has a protective efficacy of more than 80% against

clinical disease 3 and lasts longer than four years

LandmarkBy 2015, develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50%

against severe disease and death and lasts longer than one year.


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/AS01E1) AS02: proprietary oil-in-water emulsion formulated with MPL® and Stimulon® QS21 immunostimulants2)AS01: liposome formulation with MPL® and QS21 immunostimulants


First Result published in NEJM


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:815.http://www.sciencemag.org/content/334/6061/1372.abstract


Thank You

Fight against Malaria Continues…

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