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Presentaci

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Title: Presentaci n de PowerPoint Author: Albert Tuldra Last modified by: Hospital Universitari Germans Trias i Pujol Created Date: 1/21/2008 9:47:20 AM – PowerPoint PPT presentation

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Title: Presentaci


1
Nuevos fármacos
Pere Domingo Malalties Infeccioses Hospital de la
Santa Creu i Sant Pau Barcelona pdomingo_at_santpau.c
at
2
Fármaco Compañía Familia Nº abstract
OBP-601 Diagnostic hybrids ITIAN 568
AZD RFS Pharma ITIAN 557
RDEA427 Ardea Biosci. ITINAN 569
IQP-0410 ImQuest Biosci. ITINAN 551
Quinolinas BioAlliance Pharma Integrasa 553
PRO-140 Progenics Mab anti-CCR5 571a
CD4-BFFI Roche Inh. entrada bifuncional 551
3
Fármaco Compañía Familia Nº abstract
OBP-601 Diagnostic hybrids ITIAN 568
AZD RFS Pharma ITIAN 557
RDEA427 Ardea Biosci. ITINAN 569
IQP-0410 ImQuest Biosci. ITINAN 551
Quinolinas BioAlliance Pharma Integrasa 553
PRO-140 Progenics Mab anti-CCR5 571a
CD4-BFFI Roche Inh. entrada bifuncional 551
4
Fármaco Compañía Familia Abstract
VCH-286 ViroChem CCR5 550
MPC-9055 Myriad Pharm Inh. maduración 561, 570
Inh. RNasa H Merck Co. Inh. RNasa H 898
GS-9350 Gilead Potenciador 40
SPI-452 Sequoia Potenciador 41
5
Fármaco Compañía Familia Abstract
VCH-286 ViroChem CCR5 550
MPC-9055 Myriad Pharm Inh. maduración 561, 570
Inh. RNasa H Merck Co. Inh. RNasa H 898
GS-9350 Gilead Potenciador 40
SPI-452 Sequoia Potenciador 41
6
  • Análogos de
  • nucleósidos

7
OBP-601 (Festinavir)
  • 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

Paintsil E, et al. CROI. 2009. 568.
8
PK de OBP-601
No efecto del alimento
Paintsil E, et al. CROI. 2009. 568.
Vida media 2,3-3,7 horas
9
Efectos adversos de festinavir
Paintsil E, et al. CROI. 2009. 568.
10
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.
11
AZD y AZD-PD
  • Análogos de la guanosina
  • 3-azido-2,6-diamino-2,3-dideoxypurine
  • 5-monophosphate prodrug of AZD (AZD-PD)

Schinazi RF, et al. CROI. 2009. 557.
12
Actividad de AZD y AZD-PD
Schinazi RF, et al. CROI. 2009. 557.
13
Actividad frente a cepas resitstentes
Schinazi RF, et al. CROI. 2009. 557.
14
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.
15
  • No Análogos de
  • nucleósidos

16
RDEA427
  • 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.

Ong V et al. CROI. 2009. 569
17
Actividad de RDEA427 frente a aislados resistentes
Es activo frente a cepas que contienen las
mutaciones K103N, Y181C, Y188L, K101E, y las
combinaciones de K103NY181C, Y181CG190A y
K103NP225H.
Ong V et al. CROI. 2009. 569
18
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
19
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
20
Perfil concentración plasmática-tiempo
Ong V et al. CROI. 2009. 569
21
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
22
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
23
  • Inhibidores de la integrasa

24
La familia de las quinolinas
  • 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

QNL111
Thibaut L, et al. CROI. 2009. 553
25
Quinolinas en mutantes resistentes a ITIAN/ITINAN
The color subdivide the resistance fold-change
into three levels as follows green, lt3-fold,
light brown gt10-fold red, gt30-fold Data for
Raltegravir (RGV) quinolines compounds
represent the mean of 3 independent experiments.
Thibaut L, et al. CROI. 2009. 553
26
Quinolinas en mutantes resistentes a integrasas
The color subdivide the resistance fold-change
into three levels as follows green, lt3-fold,
light brown gt10-fold red, gt30-fold Data for
Raltegravir (RGV) quinolines compounds
represent the mean of 3 independent experiments.
Thibaut L, et al. CROI. 2009. 553
27
Quinolinas y mutacionesR a RAL
Thibaut L, et al. CROI. 2009. 553
28
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 NRTIs and NNRTIs
    mutations do not impact on quinolines antiviral
    activities
  • Furthermore, quinolines remain still active
    against INSTIs mutants suggesting a different
    mechanism of action

Thibaut L, et al. CROI. 2009. 553
29
  • Antagonistas de CCR5

30
PRO-140
  • 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

Thompson M, et al. CROI. 2009. Abstract 571a
31
Diseño estudio fase IIa
Thompson M, et al. CROI. 2009. Abstract 571a
32
Características basales
Thompson M, et al. CROI. 2009. Abstract 571a
33
Respuesta antiviral
Thompson M, et al. CROI. 2009. Abstract 571a
34
Cambio en el ARN del VIH-1 desde el basal
Thompson M, et al. CROI. 2009. Abstract 571a
35
Tasa de respuesta antiviral
Definida como al menos un episodio de reducción
1 log10 o lt 400 copias/ml tras la primera dosis
del fámaco
Thompson M, et al. CROI. 2009. Abstract 571a
36
Efectos adversos más frecuentes
Thompson M, et al. CROI. 2009. Abstract 571a
37
EAs asociados con PRO-140
Thompson M, et al. CROI. 2009. Abstract 571a
38
Conclusiones
  • 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.

Thompson M, et al. CROI. 2009. Abstract 571a
39
  • Inhibidores de la entrada

40
Inhibidor de la entrada bifuncional
  • 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.

Jekle A, et al. CROI. 2009. 551.
41
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.
42
Actividad frente a cepas resistentes a MVC
  • 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.

Jekle A, et al. CROI. 2009. 551.
43
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.
44
  • Inhibidores de la maduración

45
MPC-9055
  • 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.

Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
46
Actividad antiviral MPC-9055
  • 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

Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
47
Actividad frente a cepas resistentes
Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
48
Conclusiones
  • 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

Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
49
Medianas de perfil de concentración-tiempo
Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
50
Efectos adversos
Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
51
EAs de laboratorio
Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
52
Conclusiones
  • MPC-9055 had a favorable safety profile following
    single, oral dose administration in healthy
    volunteers
  • Most adverse events were mild with the most
    common being nausea, diarrhea, and
    lightheadedness
  • Food increased MPC-9055 exposure nearly 2-fold
  • Plasma concentrations increased in a less than
    dose proportional manner

Baichwal V, et al. CROI. 2009. 561. Beelen A,
et al. CROI. 2009. 570
53
  • Potenciadores farmacocinéticos

54
GS-9350
Mathias A, et al. CROI. 2009. 40
55
SPI-452
Gulnik S, et al. CROI. 2009. 41
56
Jacques Cartier (1491-1557)
57
  • Success is the ability to go from one failure to
    another with no loss of enthusiasm
  • Winston S. Churchill
  • (1874-1965)
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