Update on new antimalarials


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Update on new antimalarials

  1. 1. An Update on New Anti – Malarials Dept. Name6/2/2012 Privileged and Confidential 1
  2. 2. - Current scenario in Anti - Malarials6/2/2012 Privileged and Confidential 2
  3. 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 vacuole6/2/2012 Privileged and Confidential 3
  4. 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 Proguanil6/2/2012 Privileged and Confidential 4
  5. 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 radical6/2/2012 Privileged and Confidential 5
  6. 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. ******6/2/2012 Privileged and Confidential 6
  7. 7. - New Drugs…Are they required???6/2/2012 Privileged and Confidential 7
  8. 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 20256/2/2012 Privileged and Confidential 8
  9. 9. Treatment failure rates artemether–lumefantrine in the Greater Mekong subregion (2001–2009)6/2/2012 Privileged and Confidential 9
  10. 10. 6/2/2012 Privileged and Confidential 10
  11. 11. Treatment failure rates with artesunate –sulfadoxine –pyrimethamine in selected countries (2001–2008)6/2/2012 Privileged and Confidential 11
  12. 12. 6/2/2012 Privileged and Confidential 12
  13. 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 implementing6/2/2012 Privileged and Confidential 13
  14. 14. 6/2/2012 Privileged and Confidential 14
  15. 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 – II6/2/2012 Privileged and Confidential 15
  16. 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 malaria6/2/2012 Privileged and Confidential 16
  17. 17. Some of the New Drug Targets Privileged and Confidential
  18. 18. - Drugs in Phase – III or completed Phase - III6/2/2012 Privileged and Confidential 18
  19. 19. Arterolane + Piperaquine Synthetic Endoperoxide Pharmacophore Arterolane Hence, availability never a problem!!!! With efficacy against P. falciparum Artesunate6/2/2012 Privileged and Confidential 19
  20. 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.6/2/2012 Privileged and Confidential 20
  21. 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 Population6/2/2012 Privileged and Confidential 21
  22. 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 EMA6/2/2012 Privileged and Confidential 22
  23. 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 pipeline6/2/2012 Privileged and Confidential 23
  24. 24. - Drugs in Phase – I or Phase - II6/2/2012 Privileged and Confidential 24
  25. 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 response6/2/2012 Privileged and Confidential 25
  26. 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…6/2/2012 Privileged and Confidential 26
  27. 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 area6/2/2012 Privileged and Confidential 27
  28. 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 class6/2/2012 Privileged and Confidential 28
  29. 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 20086/2/2012 Privileged and Confidential 29
  30. 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 completed6/2/2012 Privileged and Confidential 30
  31. 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 mixture6/2/2012 Privileged and Confidential 31
  32. 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 - Aventis6/2/2012 Privileged and Confidential 32
  33. 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 completed6/2/2012 Privileged and Confidential 33
  34. 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 phase6/2/2012 Privileged and Confidential 34
  35. 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 deficiency6/2/2012 Privileged and Confidential 35
  36. 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 individuals6/2/2012 Privileged and Confidential 36
  37. 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 Mirincamycin6/2/2012 Privileged and Confidential 37
  38. 38. - Malaria Vaccine6/2/2012 Privileged and Confidential 38
  39. 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. 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 immunostimulants6/2/2012 Privileged and Confidential 40
  41. 41. First Result published in NEJM6/2/2012 Privileged and Confidential 41
  42. 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.abstract6/2/2012 Privileged and Confidential 42
  43. 43. Thank You Fight against Malaria Continues…6/2/2012 Privileged and Confidential 43