Post on 11-Apr-2015
Nuevos fármacosNuevos fármacos
Pere DomingoPere Domingo
Malalties InfecciosesMalalties Infeccioses
Hospital de la Santa Creu i Sant PauHospital de la Santa Creu i Sant Pau
BarcelonaBarcelona
pdomingo@santpau.catpdomingo@santpau.cat
FármacoFármaco CompañíaCompañía FamiliaFamilia Nº abstractNº abstract
OBP-601OBP-601Diagnostic Diagnostic
hybridshybridsITIANITIAN 568568
AZDAZD RFS PharmaRFS Pharma ITIANITIAN 557557
RDEA427RDEA427 Ardea Biosci.Ardea Biosci. ITINANITINAN 569569
IQP-0410IQP-0410 ImQuest Biosci.ImQuest Biosci. ITINANITINAN 551551
QuinolinasQuinolinasBioAlliance BioAlliance
PharmaPharmaIntegrasaIntegrasa 553553
PRO-140PRO-140 ProgenicsProgenicsMab anti-Mab anti-
CCR5CCR5571a571a
CD4-BFFICD4-BFFIRocheRoche
Inh. entrada Inh. entrada
bifuncionalbifuncional551551
FármacoFármaco CompañíaCompañía FamiliaFamilia Nº abstractNº abstract
OBP-601OBP-601Diagnostic Diagnostic
hybridshybridsITIANITIAN 568568
AZDAZD RFS PharmaRFS Pharma ITIANITIAN 557557
RDEA427RDEA427 Ardea Biosci.Ardea Biosci. ITINANITINAN 569569
IQP-0410IQP-0410 ImQuest Biosci.ImQuest Biosci. ITINANITINAN 551551
QuinolinasQuinolinasBioAlliance BioAlliance
PharmaPharmaIntegrasaIntegrasa 553553
PRO-140PRO-140 ProgenicsProgenicsMab anti-Mab anti-
CCR5CCR5571a571a
CD4-BFFICD4-BFFIRocheRoche
Inh. entrada Inh. entrada
bifuncionalbifuncional551551
FármacoFármaco CompañíaCompañía FamiliaFamilia AbstractAbstract
VCH-286VCH-286 ViroChemViroChem CCR5CCR5 550550
MPC-9055MPC-9055 Myriad PharmMyriad PharmInh. Inh.
maduraciónmaduración561, 570561, 570
Inh. RNasa HInh. RNasa H Merck Co.Merck Co. Inh. RNasa HInh. RNasa H 898898
GS-9350GS-9350 GileadGilead PotenciadorPotenciador 4040
SPI-452SPI-452 SequoiaSequoia PotenciadorPotenciador 4141
FármacoFármaco CompañíaCompañía FamiliaFamilia AbstractAbstract
VCH-286VCH-286 ViroChemViroChem CCR5CCR5 550550
MPC-9055MPC-9055 Myriad PharmMyriad PharmInh. Inh.
maduraciónmaduración561, 570561, 570
Inh. RNasa HInh. RNasa H Merck Co.Merck Co. Inh. RNasa HInh. RNasa H 898898
GS-9350GS-9350 GileadGilead PotenciadorPotenciador 4040
SPI-452SPI-452 SequoiaSequoia PotenciadorPotenciador 4141
Análogos deAnálogos de
nucleósidosnucleósidos
OBP-601 (Festinavir)OBP-601 (Festinavir)
• OBP-601 es un nuevo análogo de OBP-601 es un nuevo análogo de nucleósido (AN), derivado de d4Tnucleósido (AN), derivado de d4T
• Potente actividad Potente actividad in vitroin vitro frente a frente a cepas de VIH-1 salvajes y cepas de VIH-1 salvajes y multirresistentesmultirresistentes
• La mutación M184V reduce su La mutación M184V reduce su actividad en 3 a 10 veces.actividad en 3 a 10 veces.
• Tiene menos efecto sobre el ADN Tiene menos efecto sobre el ADN mitocondrial que otros análogos mitocondrial que otros análogos de la timidinade la timidina
• Acción antivírica persiste más Acción antivírica persiste más tiempo tras su retirada del cultivo tiempo tras su retirada del cultivo celularcelular
Paintsil E, et al. CROI. 2009. # 568.Paintsil E, et al. CROI. 2009. # 568.
PK de OBP-601PK de OBP-601
Paintsil E, et al. CROI. 2009. # 568.Paintsil E, et al. CROI. 2009. # 568.
Vida media = 2,3-3,7 horasVida media = 2,3-3,7 horas
No efecto del alimentoNo efecto del alimento
Efectos adversos de festinavirEfectos adversos de festinavir
Paintsil E, et al. CROI. 2009. # 568.Paintsil E, et al. CROI. 2009. # 568.
ConclusionesConclusiones
Paintsil E, et al. CROI. 2009. # 568.Paintsil E, et al. CROI. 2009. # 568.
• Festinavir was safe and well tolerated Festinavir was safe and well tolerated • Festinavir plasma PK demonstrated dose-Festinavir plasma PK demonstrated dose-
proportional relationship across the dose proportional relationship across the dose range studied in healthy menrange studied in healthy men
• At doses ranging from 100 to 900 mg given At doses ranging from 100 to 900 mg given once a day, the plasma concentration of FTV once a day, the plasma concentration of FTV remained above the ICremained above the IC5050 through the dosing through the dosing
period (24 h); QD dosing is anticipatedperiod (24 h); QD dosing is anticipated• Phase 1b to further evaluate safety, tolerability, Phase 1b to further evaluate safety, tolerability,
PK and antiviral activity of FTV is ongoingPK and antiviral activity of FTV is ongoing
AZD y AZD-PDAZD 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.Schinazi RF, et al. CROI. 2009. # 557.
Actividad frente a cepas resitstentesActividad frente a cepas resitstentes
Schinazi RF, et al. CROI. 2009. # 557.Schinazi RF, et al. CROI. 2009. # 557.
ConclusionesConclusiones
Schinazi RF, et al. CROI. 2009. # 557.Schinazi RF, et al. CROI. 2009. # 557.
• AZD and its prodrug can deliver both AZD-TP and AZD and its prodrug can deliver both AZD-TP and
AZG-TP, each of both can inhibit HIV-1 RTAZG-TP, each of both can inhibit HIV-1 RT• The combined delivery of chain-terminating 3’-The combined delivery of chain-terminating 3’-
azidopurine nucleotide analogs with different azidopurine nucleotide analogs with different
incorporation profiles (as A-vs.G-analog) may incorporation profiles (as A-vs.G-analog) may
improve the resistance profile of AZDimprove the resistance profile of AZD• 2,6-diamino purine analogs are predicted to 2,6-diamino purine analogs are predicted to
preferentially pair with Tpreferentially pair with T• The potency and intracellular delivery of AZD-TP The potency and intracellular delivery of AZD-TP
were substantially increased by using the were substantially increased by using the
phosphate prodrugs of AZDphosphate prodrugs of AZD
No Análogos deNo Análogos de
nucleósidosnucleósidos
RDEA427RDEA427
• RDEA-427 es un nuevo no análogo de nucleósido (NAN) RDEA-427 es un nuevo no análogo de nucleósido (NAN) con potente actividad con potente actividad in vitroin vitro (EC (EC5050 de 1 nM) frente a de 1 nM) frente a
cepas salvajes o resistentes a otros NAN de VIH-1.cepas salvajes o resistentes a otros NAN de VIH-1.
• La vida media en humanos es de alrededor de 41 horas, La vida media en humanos es de alrededor de 41 horas, lo que permitirá administrarlo en una dosis diaria.lo que permitirá administrarlo en una dosis diaria.
• Se ha identificado un metabolito con idéntica actividad Se ha identificado un metabolito con idéntica actividad antivírica que RDEA-427 y con una vida media superior antivírica que RDEA-427 y con una vida media superior a 50 horas.a 50 horas.
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
Actividad de RDEA427 frente a Actividad de RDEA427 frente a aislados resistentesaislados resistentes
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
Es activo frente a cepas que contienen las mutaciones K103N, Es activo frente a cepas que contienen las mutaciones K103N, Y181C, Y188L, K101E, y las combinaciones de K103N+Y181C, Y181C, Y188L, K101E, y las combinaciones de K103N+Y181C, Y181C+G190A y K103N+P225H.Y181C+G190A y K103N+P225H.
Selección Selección in vitroin vitro de mutaciones de mutaciones
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
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
Selección Selección in vitroin vitro de mutaciones de mutaciones
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
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
Perfil concentración plasmática-Perfil concentración plasmática-tiempotiempo
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
Actividad de RDEA427 y 0621154 Actividad de RDEA427 y 0621154 frente a cepas resistentes a ITINANfrente a cepas resistentes a ITINAN
The main RDEA427 metabolite observed, 0621154, has an ECThe main RDEA427 metabolite observed, 0621154, has an EC5050 of 1.1nM against of 1.1nM against
wtHIV-1 and activity equivalent to RDEA427 in NNRTI-resistant viruseswtHIV-1 and activity equivalent to RDEA427 in NNRTI-resistant viruses
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
ConclusionesConclusiones
Ong V et al. CROI. 2009. # 569 Ong V et al. CROI. 2009. # 569
• RDEA427 is active against NNRTI-resistant mutant viruses, RDEA427 is active against NNRTI-resistant mutant viruses,
including prevalent transmitted viruses and etravirine RAMs.including prevalent transmitted viruses and etravirine RAMs.• In vitroIn vitro selection showed longer suppression of K103N virus selection showed longer suppression of K103N virus
by RDEA427 than etravirine and TMC278, suggesting a higher by RDEA427 than etravirine and TMC278, suggesting a higher
resistance threshold against this virus.resistance threshold against this virus.• RDEA427 has a half-life of 41 hours after the IV microdose, RDEA427 has a half-life of 41 hours after the IV microdose,
which would support once daily dosing.which would support once daily dosing.• An active metabolite of RDEA427, 0621154, with equivalent An active metabolite of RDEA427, 0621154, with equivalent
activity to RDEA427 in wild-type and NNRTI-resistant viruses, activity to RDEA427 in wild-type and NNRTI-resistant viruses,
displays a ~50-hour half-lifedisplays a ~50-hour half-life• With its excellent activity against resistant virus, long plasma With its excellent activity against resistant virus, long plasma
half-life and lower potential for drug interactions, RDEA427 half-life and lower potential for drug interactions, RDEA427
appears to be a good candidate for further development.appears to be a good candidate for further development.
Inhibidores de la Inhibidores de la integrasaintegrasa
La familia de las quinolinasLa familia de las quinolinas
• Las quinolinas, cuyo Las quinolinas, cuyo compuesto líder es compuesto líder es QNL111 son una nueva QNL111 son una nueva familia de inhibidores de familia de inhibidores de la integrasala integrasa
• Estos compuestos Estos compuestos actúan en el paso 3’ y actúan en el paso 3’ y después en el paso de después en el paso de transferencia de la transferencia de la hebrahebra
• QNL111 fue descubierto QNL111 fue descubierto y caracterizado a través y caracterizado a través de una estrategia de una estrategia optimizada de relación optimizada de relación estructura-actividadestructura-actividad
Thibaut L, et al. CROI. 2009. #553Thibaut L, et al. CROI. 2009. #553
QNL111QNL111
Quinolinas en mutantes resistentes Quinolinas en mutantes resistentes a ITIAN/ITINANa ITIAN/ITINAN
Thibaut L, et al. CROI. 2009. #553Thibaut L, et al. CROI. 2009. #553
The color subdivide the resistance fold-change into three levels as follows: green, The color subdivide the resistance fold-change into three levels as follows: green, <3-fold, light brown >10-fold; red, >30-fold;<3-fold, light brown >10-fold; red, >30-fold;Data for Raltegravir (RGV) & quinolines compounds represent the mean of 3 Data for Raltegravir (RGV) & quinolines compounds represent the mean of 3 independent experiments.independent experiments.
Quinolinas en mutantes resistentes Quinolinas en mutantes resistentes a integrasasa integrasas
Thibaut L, et al. CROI. 2009. #553Thibaut L, et al. CROI. 2009. #553
The color subdivide the resistance fold-change into three levels as follows: green, The color subdivide the resistance fold-change into three levels as follows: green, <3-fold, light brown >10-fold; red, >30-fold;<3-fold, light brown >10-fold; red, >30-fold;Data for Raltegravir (RGV) & quinolines compounds represent the mean of 3 Data for Raltegravir (RGV) & quinolines compounds represent the mean of 3 independent experiments.independent experiments.
Quinolinas y mutacionesQuinolinas y mutacionesRR a RAL a RAL
Thibaut L, et al. CROI. 2009. #553Thibaut L, et al. CROI. 2009. #553
ConclusionesConclusiones
Thibaut L, et al. CROI. 2009. #553Thibaut L, et al. CROI. 2009. #553
• Quinolines family and QNL111 as a lead, are new potent Quinolines family and QNL111 as a lead, are new potent HIV integrase inhibitorsHIV integrase inhibitors
• In vitroIn vitro assays demonstrate a specific activity of assays demonstrate a specific activity of quinolines during the 3’ processing step of integration quinolines during the 3’ processing step of integration and consequently an inhibition of the strand transfer and consequently an inhibition of the strand transfer stepstep
• The data highlight that NRTI’s and NNRTI’s mutations The data highlight that NRTI’s and NNRTI’s mutations do not impact on quinolines antiviral activitiesdo not impact on quinolines antiviral activities
• Furthermore, quinolines remain still active against Furthermore, quinolines remain still active against INSTI’s mutants suggesting a different mechanism of INSTI’s mutants suggesting a different mechanism of actionaction
Antagonistas de CCR5Antagonistas de CCR5
PRO-140PRO-140
• PRO-140 es un anticuerpo monoclonal PRO-140 es un anticuerpo monoclonal CCR5 humanizado que inhibe de forma CCR5 humanizado que inhibe de forma potente las cepas de VIH-1 con potente las cepas de VIH-1 con tropismo CCR5 tropismo CCR5 in vitroin vitro. En su . En su desarrollo ha demostrado una buena desarrollo ha demostrado una buena tolerabilidad y una actividad potente y tolerabilidad y una actividad potente y duradera tras una única dosis duradera tras una única dosis intravenosaintravenosa
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Diseño estudio fase IIaDiseño estudio fase IIa
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Características basalesCaracterísticas basales
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Respuesta antiviralRespuesta antiviral
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Cambio en el ARN del VIH-1 Cambio en el ARN del VIH-1 desde el basaldesde el basal
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Tasa de respuesta antiviral*Tasa de respuesta antiviral*
*Definida como al menos un episodio de reducción *Definida como al menos un episodio de reducción ≥ 1 log≥ 1 log1010 o < 400 o < 400
copias/ml tras la primera dosis del fámacocopias/ml tras la primera dosis del fámaco Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Efectos adversos más frecuentesEfectos adversos más frecuentes
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
EAs asociados con PRO-140EAs asociados con PRO-140
Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
ConclusionesConclusiones
SC PRO 140 demonstrated potent and SC PRO 140 demonstrated potent and
prolonged antiretroviral activity without prolonged antiretroviral activity without
significant local or systemic toxicity. The significant local or systemic toxicity. The
findings support further exploration of findings support further exploration of
infrequent subcutaneously dosing with infrequent subcutaneously dosing with
PRO 140 as a long-acting approach to PRO 140 as a long-acting approach to
HIV-1 therapy. HIV-1 therapy. Thompson M, et al. CROI. 2009. Abstract 571aThompson M, et al. CROI. 2009. Abstract 571a
Inhibidores de la Inhibidores de la entradaentrada
Inhibidor de la entrada Inhibidor de la entrada bifuncionalbifuncional
• El inhibidor de la entrada bifuncional El inhibidor de la entrada bifuncional
CD4-BFFI se ha obtenido al unir el CD4-BFFI se ha obtenido al unir el
inhibidor de la fusión de segunda inhibidor de la fusión de segunda
generación T-651 con el anticuerpo generación T-651 con el anticuerpo
monoclonal anti-CD4 mAb-6314monoclonal anti-CD4 mAb-6314
• CD4-BFFI ha demostrado actividad CD4-BFFI ha demostrado actividad
antivírica potente antivírica potente in vitroin vitro frente a frente a
aislados con tropismo X4, R5 y dualaislados con tropismo X4, R5 y dual
• El mecanismo de acción es a través de su El mecanismo de acción es a través de su
unión con el receptor CD4+, un hecho unión con el receptor CD4+, un hecho
que es indispensable para que ejerza su que es indispensable para que ejerza su
actividad antivírica.actividad antivírica.Jekle A, et al. CROI. 2009. # 551.Jekle A, et al. CROI. 2009. # 551.
Actividad antivírica CD4-BFFIActividad antivírica CD4-BFFI
La actividad antivírica La actividad antivírica
de CD4-BFFI es 70 de CD4-BFFI es 70
veces superior a la del veces superior a la del
inhibidor de la fusión T-inhibidor de la fusión T-
651 y 50 veces superior 651 y 50 veces superior
a la de una mezcla a la de una mezcla
equimolar de las dos equimolar de las dos
moléculas progenitoras moléculas progenitoras
(T-651 y mAb-6314).(T-651 y mAb-6314).Jekle A, et al. CROI. 2009. # 551.Jekle A, et al. CROI. 2009. # 551.
Actividad frente a cepas Actividad frente a cepas resistentes a MVCresistentes 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.Jekle A, et al. CROI. 2009. # 551.
ConclusionesConclusiones
Jekle A, et al. CROI. 2009. # 551.Jekle A, et al. CROI. 2009. # 551.
• CD4-BFFI is a novel, bifunctional HIV entry inhibitor CD4-BFFI is a novel, bifunctional HIV entry inhibitor with high and broad antiviral activitywith high and broad antiviral activity
• CD4-BFFI is active against HIV-1 strains independent of CD4-BFFI is active against HIV-1 strains independent of their co-receptor usagetheir co-receptor usage
• CD4-BFFI retains antiviral activity against entry-CD4-BFFI retains antiviral activity against entry-inhibitor resistant HIV-1 variantsinhibitor resistant HIV-1 variants
• Binding of CD4-BFFI through its anti-CD4 Mab moiety Binding of CD4-BFFI through its anti-CD4 Mab moiety surface is required for its antiviral activitysurface is required for its antiviral activity
• CD4-BFFI is stable CD4-BFFI is stable in vivoin vivo and has favorable and has favorable pharmacological propertiespharmacological properties
Inhibidores de la Inhibidores de la maduraciónmaduración
MPC-9055MPC-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. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
Actividad antiviral MPC-9055Actividad 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. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
Actividad frente a cepas resistentesActividad frente a cepas resistentes
Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
ConclusionesConclusiones
• MPC-9055 potently inhibits HIV MPC-9055 potently inhibits HIV replication replication in vitroin vitro
• Broad range of activity against clinical Broad range of activity against clinical isolates including drug resistant strainsisolates including drug resistant strains
• Inhibits virus maturation by blocking Inhibits virus maturation by blocking Gag cleavage at the CA-SP1 siteGag cleavage at the CA-SP1 site
• Mechanism of action is distinct from Mechanism of action is distinct from current HIV therapiescurrent HIV therapies
• In clinical development In clinical development Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
Medianas de perfil de Medianas de perfil de concentración-tiempoconcentración-tiempo
Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
Efectos adversosEfectos adversos
Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570CROI. 2009. # 570
EAs de laboratorioEAs de laboratorio
Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
ConclusionesConclusiones
• MPC-9055 had a favorable safety profile MPC-9055 had a favorable safety profile following single, oral dose administration in following single, oral dose administration in healthy volunteershealthy volunteers
• Most adverse events were mild with the most Most adverse events were mild with the most common being nausea, diarrhea, and common being nausea, diarrhea, and lightheadednesslightheadedness
• Food increased MPC-9055 exposure nearly 2-Food increased MPC-9055 exposure nearly 2-foldfold
• Plasma concentrations increased in a less Plasma concentrations increased in a less than dose proportional mannerthan dose proportional manner
Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570Baichwal V, et al. CROI. 2009. # 561. Beelen A, et al. CROI. 2009. # 570
Potenciadores Potenciadores farmacocinéticosfarmacocinéticos
GS-9350GS-9350
Mathias A, et al. CROI. 2009. # 40Mathias A, et al. CROI. 2009. # 40
SPI-452SPI-452
Gulnik S, et al. CROI. 2009. # 41Gulnik S, et al. CROI. 2009. # 41
Jacques CartierJacques Cartier(1491-1557)(1491-1557)