1 / 55

Nuevos fármacos

Nuevos fármacos. Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau Barcelona pdomingo@santpau.cat. Análogos de nucleósidos. OBP-601 es un nuevo análogo de nucleósido (AN), derivado de d4T

cedric
Download Presentation

Nuevos fármacos

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Nuevos fármacos Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau Barcelona pdomingo@santpau.cat

  2. Análogos de nucleósidos

  3. OBP-601 es un nuevo análogo de nucleósido (AN), derivado de d4T Potente actividad in vitro frente a cepas de VIH-1 salvajes y multirresistentes La mutación M184V reduce su actividad en 3 a 10 veces. Tiene menos efecto sobre el ADN mitocondrial que otros análogos de la timidina Acción antivírica persiste más tiempo tras su retirada del cultivo celular OBP-601 (Festinavir) Paintsil E, et al. CROI. 2009. # 568.

  4. PK de OBP-601 No efecto del alimento Paintsil E, et al. CROI. 2009. # 568. Vida media = 2,3-3,7 horas

  5. Efectos adversos de festinavir Paintsil E, et al. CROI. 2009. # 568.

  6. Conclusiones • Festinavir was safe and well tolerated • Festinavir plasma PK demonstrated dose-proportional relationship across the dose range studied in healthy men • At doses ranging from 100 to 900 mg given once a day, the plasma concentration of FTV remained above the IC50 through the dosing period (24 h); QD dosing is anticipated • Phase 1b to further evaluate safety, tolerability, PK and antiviral activity of FTV is ongoing Paintsil E, et al. CROI. 2009. # 568.

  7. Análogos de la guanosina 3’-azido-2,6-diamino-2’,3’-dideoxypurine 5’-monophosphate prodrug of AZD (AZD-PD) AZD y AZD-PD Schinazi RF, et al. CROI. 2009. # 557.

  8. Actividad frente a cepas resitstentes Schinazi RF, et al. CROI. 2009. # 557.

  9. Conclusiones • AZD and its prodrug can deliver both AZD-TP and AZG-TP, each of both can inhibit HIV-1 RT • The combined delivery of chain-terminating 3’-azidopurine nucleotide analogs with different incorporation profiles (as A-vs.G-analog) may improve the resistance profile of AZD • 2,6-diamino purine analogs are predicted to preferentially pair with T • The potency and intracellular delivery of AZD-TP were substantially increased by using the phosphate prodrugs of AZD Schinazi RF, et al. CROI. 2009. # 557.

  10. No Análogos de nucleósidos

  11. RDEA-427 es un nuevo no análogo de nucleósido (NAN) con potente actividad in vitro (EC50 de 1 nM) frente a cepas salvajes o resistentes a otros NAN de VIH-1. La vida media en humanos es de alrededor de 41 horas, lo que permitirá administrarlo en una dosis diaria. Se ha identificado un metabolito con idéntica actividad antivírica que RDEA-427 y con una vida media superior a 50 horas. RDEA427 Ong V et al. CROI. 2009. # 569

  12. Actividad de RDEA427 frente a aislados resistentes Es activo frente a cepas que contienen las mutaciones K103N, Y181C, Y188L, K101E, y las combinaciones de K103N+Y181C, Y181C+G190A y K103N+P225H. Ong V et al. CROI. 2009. # 569

  13. Selección in vitro de mutaciones RDEA427 maintained control over K103N HIV-1 in vitro longer than etravirine and TMC278 • Y181C HIV-1 brokethrough RDEA427, etravirine and TMC278 suppression at the same rate Ong V et al. CROI. 2009. # 569

  14. Selección in vitro de mutaciones In K103N virus-infected cells, L100I emerged by passage 30 in the presence of both etravirine and TMC278; the virus had not brokenthrough RDEA427 by P30. RDEA427-treated Y181C virus cultures contained V179T, which shows reduced susceptibility to etravirine. In Y181C virus-infected cells, mutations V179I and P14A were selected by etravirine, and V106I was selected by etravirine and TMC278 by passage 31 Ong V et al. CROI. 2009. # 569

  15. Perfil concentración plasmática-tiempo Ong V et al. CROI. 2009. # 569

  16. Actividad de RDEA427 y 0621154 frente a cepas resistentes a ITINAN The main RDEA427 metabolite observed, 0621154, has an EC50 of 1.1nM against wtHIV-1 and activity equivalent to RDEA427 in NNRTI-resistant viruses Ong V et al. CROI. 2009. # 569

  17. Conclusiones • RDEA427 is active against NNRTI-resistant mutant viruses, including prevalent transmitted viruses and etravirine RAMs. • In vitro selection showed longer suppression of K103N virus by RDEA427 than etravirine and TMC278, suggesting a higher resistance threshold against this virus. • RDEA427 has a half-life of 41 hours after the IV microdose, which would support once daily dosing. • An active metabolite of RDEA427, 0621154, with equivalent activity to RDEA427 in wild-type and NNRTI-resistant viruses, displays a ~50-hour half-life • With its excellent activity against resistant virus, long plasma half-life and lower potential for drug interactions, RDEA427 appears to be a good candidate for further development. Ong V et al. CROI. 2009. # 569

  18. Inhibidores de la integrasa

  19. Las quinolinas, cuyo compuesto líder es QNL111 son una nueva familia de inhibidores de la integrasa Estos compuestos actúan en el paso 3’ y después en el paso de transferencia de la hebra QNL111 fue descubierto y caracterizado a través de una estrategia optimizada de relación estructura-actividad La familia de las quinolinas QNL111 Thibaut L, et al. CROI. 2009. #553

  20. Quinolinas en mutantes resistentes a ITIAN/ITINAN The color subdivide the resistance fold-change into three levels as follows: green, <3-fold, light brown >10-fold; red, >30-fold; Data for Raltegravir (RGV) & quinolines compounds represent the mean of 3 independent experiments. Thibaut L, et al. CROI. 2009. #553

  21. Quinolinas en mutantes resistentes a integrasas The color subdivide the resistance fold-change into three levels as follows: green, <3-fold, light brown >10-fold; red, >30-fold; Data for Raltegravir (RGV) & quinolines compounds represent the mean of 3 independent experiments. Thibaut L, et al. CROI. 2009. #553

  22. Quinolinas y mutacionesR a RAL Thibaut L, et al. CROI. 2009. #553

  23. Conclusiones • Quinolines family and QNL111 as a lead, are new potent HIV integrase inhibitors • In vitro assays demonstrate a specific activity of quinolines during the 3’ processing step of integration and consequently an inhibition of the strand transfer step • The data highlight that NRTI’s and NNRTI’s mutations do not impact on quinolines antiviral activities • Furthermore, quinolines remain still active against INSTI’s mutants suggesting a different mechanism of action Thibaut L, et al. CROI. 2009. #553

  24. Antagonistas de CCR5

  25. PRO-140 es un anticuerpo monoclonal CCR5 humanizado que inhibe de forma potente las cepas de VIH-1 con tropismo CCR5 in vitro. En su desarrollo ha demostrado una buena tolerabilidad y una actividad potente y duradera tras una única dosis intravenosa PRO-140 Thompson M, et al. CROI. 2009. Abstract 571a

  26. Diseño estudio fase IIa Thompson M, et al. CROI. 2009. Abstract 571a

  27. Características basales Thompson M, et al. CROI. 2009. Abstract 571a

  28. Respuesta antiviral Thompson M, et al. CROI. 2009. Abstract 571a

  29. Cambio en el ARN del VIH-1 desde el basal Thompson M, et al. CROI. 2009. Abstract 571a

  30. Tasa de respuesta antiviral* *Definida como al menos un episodio de reducción ≥ 1 log10 o < 400 copias/ml tras la primera dosis del fámaco Thompson M, et al. CROI. 2009. Abstract 571a

  31. Efectos adversos más frecuentes Thompson M, et al. CROI. 2009. Abstract 571a

  32. EAs asociados con PRO-140 Thompson M, et al. CROI. 2009. Abstract 571a

  33. SC PRO 140 demonstrated potent and prolonged antiretroviral activity without significant local or systemic toxicity. The findings support further exploration of infrequent subcutaneously dosing with PRO 140 as a long-acting approach to HIV-1 therapy. Conclusiones Thompson M, et al. CROI. 2009. Abstract 571a

  34. Inhibidores de la entrada

  35. El inhibidor de la entrada bifuncional CD4-BFFI se ha obtenido al unir el inhibidor de la fusión de segunda generación T-651 con el anticuerpo monoclonal anti-CD4 mAb-6314 CD4-BFFI ha demostrado actividad antivírica potente in vitro frente a aislados con tropismo X4, R5 y dual El mecanismo de acción es a través de su unión con el receptor CD4+, un hecho que es indispensable para que ejerza su actividad antivírica. Inhibidor de la entrada bifuncional Jekle A, et al. CROI. 2009. # 551.

  36. Actividad antivírica CD4-BFFI La actividad antivírica de CD4-BFFI es 70 veces superior a la del inhibidor de la fusión T-651 y 50 veces superior a la de una mezcla equimolar de las dos moléculas progenitoras (T-651 y mAb-6314). Jekle A, et al. CROI. 2009. # 551.

  37. Mantiene su potente actividad antivírica frente a cepas resistentes a los inhibidores de fusión T-20 y T-1144, al MVC y al anticuerpo monoclonal anti-CCR5 mAb-3952. Actividad frente a cepas resistentes a MVC Jekle A, et al. CROI. 2009. # 551.

  38. Conclusiones • CD4-BFFI is a novel, bifunctional HIV entry inhibitor with high and broad antiviral activity • CD4-BFFI is active against HIV-1 strains independent of their co-receptor usage • CD4-BFFI retains antiviral activity against entry-inhibitor resistant HIV-1 variants • Binding of CD4-BFFI through its anti-CD4 Mab moiety surface is required for its antiviral activity • CD4-BFFI is stable in vivo and has favorable pharmacological properties Jekle A, et al. CROI. 2009. # 551.

  39. Inhibidores de la maduración

  40. MPC-9055 es un potente inhibidor de la maduración del VIH-1, al inhibir el procesamiento del Gag e impedir el paso de la proteína de la cápside viral de p25 a p24. MPC-9055 Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

  41. A concentraciones nanomolares (IC50: 7 nM), es activo frente a cepas de los grupos M, N y O, subtipos A a G, con tropismo X4, R5 y dual, salvajes o mutirresistentes Actividad antiviral MPC-9055 Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

  42. Actividad frente a cepas resistentes Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

  43. MPC-9055 potently inhibits HIV replication in vitro Broad range of activity against clinical isolates including drug resistant strains Inhibits virus maturation by blocking Gag cleavage at the CA-SP1 site Mechanism of action is distinct from current HIV therapies In clinical development Conclusiones Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

  44. Medianas de perfil de concentración-tiempo Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

  45. Efectos adversos Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

  46. EAs de laboratorio Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570

More Related