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Chagas Disease Discovery (1909 – 2009)

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Chagas Disease Discovery (1909 – 2009) Presented by DNDi at ASTMH 2009 Drugs for Neglected Diseases Iniciative & Universidade Federal de Ouro Preto, Brazil Combination of Benznidazole and Nifurtimox plus Posaconazole enhances activity against Trypanosoma cruzi in experimental Chagas disease Maria Terezinha Bahia, André Talvani, Shing Chang, Isabela Ribeiro Neglected populations Future New Chemical Entities ‐ Target Product Profile Old drugs with new Chemotherapy strategies Specific anti‐ T. cruzi treatment Improvements in Case Management –Heart Disease Present (2009) Vector control/eradication programmes Description of main clinical manifestations Trypanosoma cruzi identification Past (1909) Chagas disease discovery (1909 – 2009) 1 Presented by DNDi at ASTMH 2009 Evaluating combination treatment… Combination with registered compounds (Benznidazole/Nifurtimox) Aims: (i) improvement of efficacy (ii) improvement of safety and tolerability (iii) reduction of the dose and duration of the therapeutic regimen (iv) Potential impact on resistance development to each individual compounds from the combinations Starting point: Evaluation of combination therapy Nifurtimox/Benznidazole + Azole compounds « Reduction in time, costs and risks » Current available drugs • Benznidazole and Nifurtimox: nitroheterocyclic drugs • Parasiticidal activity: conversion of reactive intermediates within the parasite that generate superoxide, which causes oxidative damage to components of the parasite • Compounds activated within the parasite, probably by a Type 1 Mitochondrial Nitroreductase enzyme Wilkinson et al. PNAS 2008; 105:5022‐7 Paulino et al. Mini Rev Med Chem. 2005 2 Presented by DNDi at ASTMH 2009 Trypanosoma cruzi Ergosterol Biosynthesis Pathway Azole class of compounds: Posaconazole, Ravuconazole E.G. Hankins et al. / Molecular & Biochemical Parasitology 144 (2005) 68–75 Combination of nitroheterocyclic compounds Benznidazole and Nifurtimox plus Posaconazole Swiss mice inoculated with 5.0 x 103 blood trypomastigotes of T. cruzi Y strain Treatment initiated 4 days post‐infection with confirmed parasitaemia 7 consecutive days with each single drug by gavage Therapeutic dose (n=6) Y strain Half of the therapeutic dose (n=6) Y strain One forth of the therapeutic dose (n=6) Y strain 3 Presented by DNDi at ASTMH 2009 Mice infected with Y strain of Trypanosoma cruzi treated with different doses of Benznidazole, Nifurtimox and Posaconazole Dose Parasitemia suppression Parasitemia Parasitemia peak x (dose+SD) reactivation (day) 103 * Benznidazole 100mg 1.33+0.52 5 10.0 (17th) 50 mg 1.83+0.75 1 84.6 (16th) 25 mg ND ‐ 246.6 (8th) Nifurtimox 50 mg 1.0+0.0 5 8.3 (16th) 25 mg ND ‐ 30.6 (8th) 12.5 mg ND ‐ 396.6 (8th) Posaconazole Ps 20 mg 1.33+0..51 12 11.3 (24th) Ps 10 mg 1.5+0.54 11 49.3 (25th) Ps 5.0 mg 1.17+0.41 11 318.6 (26th) No treated control group Control ‐ ‐900.6 (8th) Nifurtimox Maximum parasitemia levels of the Y strain 7 aabc 6 infected mice treated with different 5 4 doses of Benznidazole, Nifurtimox and 3 Posaconazole 2 Log -Log Parasitemia 1 0 Nfx 50 mg Nfx 25 mg Nfx 12.5 mg Benznidazole Posaconazole a ab b a ab b 7 7 6 6 5 5 4 4 3 3 2 2 Log -Log Parasitemia 1 -Log Parasitemia 1 0 0 Bz - 100 mg Bz - 50 mg Bz - 25 mg Ps - 20 mg Ps - 10 mg Ps - 5 mg 4 Presented by DNDi at ASTMH 2009 Nifurtimox 100 Survival rates of the Y strain infected 80 mice treated with different doses of 60 Benznidazole, Nifurtimox and 40 Survival % Survival Posaconazole 20 0 0 5 10 15 20 25 30 Days after infection Nfx - 50 mg Nfx - 25 mg Nfx - 12.5 mg IC Benznidazole Posaconazole 100 100 80 80 60 60 40 40 Survival % Survival % Survival 20 20 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Days after infection Days after infection Bz - 50 mg Bz - 100 mg Bz - 25 mg IC Ps 20 mg Ps 10 mg Ps 5.0 mg IC Drug Combination experiments Drug combinations: Benznidazole (Bz) plus Posaconazole (Ps) 25 and 50 mg/kg.day of Bz + 5 and 10 mg mg/kg/day of Ps Nifurtimox (Nfx) plus Posaconazole (Ps) 12.5 and 25 mg/kg.day of Nfx + 5 and 10 mg mg/kg.day of Ps 5 Presented by DNDi at ASTMH 2009 Benznidazole plus Posaconazole treatment Treatment Parasitemia Parasitemia Parasitemia Survival rate (%) scheme suppression reactivation peak (n=6) (dose+SD) (day) Bz/Ps 1.4+0.55 10 21.600 (22nd) 100% (50/10mg) Bz/Ps (50/5mg) 1.33+0.52 10 60.000 (22nd) 100% Bz/Ps 1.67+0.52 10 40.166 100% (25/10mg) (26th) Bz/Ps (25/5mg) 1.16+0.41 7 11.133 100% (27th) Bz 100mg 1.33+0.52 5 10.000 100% (17th) Ps 20 mg 1.33+0..51 12 11.333 100% (24th) Benznidazole plus Posaconazole treatment Parasitaemia 6 5 4 3 2 Log - Parasitemia 1 0 g g g g g g m m m m m m 0 0 0 5 0 5 0 2 1 s 1 s 1 - s s - P P s P / P / z / / P g g B g g m m m m 0 5 0 5 5 2 5 z 2 z z B z B B B Maximum parasitemia – log parasite/0.1 mL of blood 6 Presented by DNDi at ASTMH 2009 Nifurtimox plus Posaconazole treatment Treatment Parasitemia Parasitemia Parasitemia Survival rate scheme suppression reactivation peak (%) (n=6) (dose+SD) (day) Nfx /Ps 1.5+0.55 11 63.333 100% (25/10mg) (27th) Nfx /Ps 1.33+0.52 11 27.333 100% (25/5mg) (27th) Nfx /Ps 1.0+0.0 10 68.666 84% (12.5/10mg) (27th) Nfx /Ps 1.16+0.41 9 68.666 100% (12.5/5mg) (27th) Ps 20 mg 1.33+0.51 12 11.333 100% (24th) Nfx 50 mg 1.0+0.0 5 8.333 100% (16th) Nifurtimox plus Posaconazole treatment Parasitaemia 6 5 4 3 2 Log-Parasitemia 1 0 g mg m 0 mg - 2 10 mg Ps Nfx - 50 mg g + Ps 5 + Ps g + Ps 5 m g m m 25 2.5 x 1 f x Nfx 25 mg + Ps N10 mg 12.5 f fx N N Maximum parasitemia – log parasite/0.1 mL of blood 7 Presented by DNDi at ASTMH 2009 Drug combination experiments Conclusions and future directions 9The combination of Ps and Bz or Nfx was significantly more efficacious against T. cruzi than the same dose of each drugs alone. 9Need for confirmation of findings in experimental models with prolonged exposure and immunosuppression for assessment of cure 9 Alternative combination regimens for Chagas disease should be further investigated “A one‐shot inexpensive, nontoxic drug to be used in individual cases as well as for preventing Chagas disease transmission is still a vague dream.” Brener Z: Chemotherapy of Trypanosoma cruzi infection” Advances in Pharmacology and Chemotherapy, 13: 2‐40, 1975. Prof. Z Brener (1928-2002) 8 Presented by DNDi at ASTMH 2009 Collaborators: Post-graduated students: Isabel Mayer DNDi: F. Alves Livia Figueiredo B. Bourdin Ivo Caldas R. Don Sergio Caldas E. Torreele Graduated students: Andre Gravel Alvaro Neto Tassiane Martins Technicians: Vivian Figueiredo Hidelmagna Silva Maira Azevedo 9.
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