ES2673603T3 - Método de tratamiento basado en polimorfismos del gen KCNQ1 - Google Patents
Método de tratamiento basado en polimorfismos del gen KCNQ1 Download PDFInfo
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- ES2673603T3 ES2673603T3 ES15199673.3T ES15199673T ES2673603T3 ES 2673603 T3 ES2673603 T3 ES 2673603T3 ES 15199673 T ES15199673 T ES 15199673T ES 2673603 T3 ES2673603 T3 ES 2673603T3
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- Prior art keywords
- snp
- kcnq1
- disorder
- individual
- genotype
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 3
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- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 1
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- 241000282414 Homo sapiens Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 230000002759 chromosomal effect Effects 0.000 description 1
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
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- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
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Classifications
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
Un compuesto que comprende iloperidona o 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-il)-1-piperidinil]propoxi]-3- metoxifenil]etanol para uso en el tratamiento de un trastorno en un individuo, cuyo genotipo KCNQ1 se determina que está asociado con un riesgo incrementado de la prolongación de QT, en donde la cantidad del compuesto a administrar al individuo es menor que 24 mg/día y menor que la que se administraría a un individuo que tiene un genotipo KCNQ1 no asociado con un riesgo incrementado de prolongación de QT, en donde el trastorno es esquizofrenia, trastorno esquizo-afectivo, depresión, manía bipolar/depresión, síndrome de Tourette, un trastorno psicótico, un trastorno delusional o trastorno esquizofreniforme, y en donde el genotipo KCNQ1 asociado con el riesgo incrementado de prolongación de QT es AA en la posición 286414 de la secuencia de referencia AJ006345.1; o TT en la posición 2483474 de la secuencia de referencia AJ006345.1.
Description
- SNP_A-1905948
- rs179428 2507085 noAA 0,548076 A G
- SNP_A-2063010
- rs10832134 2459062 AA 0,613499 C T
- SNP_A-2070173
- rs10832405 2605095 noAA 0,421724 G T
- SNP_A-2128672
- rs10798 2826741 noAA 0,149325 C T
- SNP_A-2138827
- rs548566 2739224 AA 0,533236 A G
- SNP_A-2155585
- rs231915 2705591 noAB 0,811901 A G
- SNP_A-2170993
- rs170786 2707279 BB 0,609952 C T
- SNP_A-2176134
- rs10766379 2782775 BB 0,149903 A G
- SNP_A-2203798
- rs8181588 2788117 noBB 0,486341 A G
- SNP_A-2217853
- rs179429 2507306 BB 0,323283 C T
- SNP_A-2244304
- rs7128926 2653320 AB 0,074244 C T
- SNP_A-2264175
- rs6578283 2630151 BB 0,385571 A G
- SNP_A-2299737
- rs163177 2794989 AA 0,03059 A G
- SNP_A-2301145
- rs163166 2781804 BB 0,147875 G T
- SNP_A-2305877
- rs231916 2704944 noAB 0,033582 A G
- SNP_A-4241656
- rs231907 2708706 noBB 0,802946 A T
- SNP_A-4242308
- rs2283208 2700435 AA 0,019908 A G
- SNP_A-4248246
- -- 2667398 noAA 0,381774 C T
- SNP_A-4254887
- rs231348 2630257 noBB 0,626472 A G
- SNP_A-4257005
- rs16928297 2442696 AA 0,483607 G T
- SNP_A-4281714
- rs3852527 2783179 noAA 0,197306 A G
- SNP_A-4288131
- rs231890 2732635 noAB 0,573 C T
- SNP_A-4288827
- rs10766218 2594657 AA 0,357049 A G
- SNP_A-4301076
- rs163171 2777641 noAB 0,259187 C T
- SNP_A-4301585
- rs9666537 2642440 noBB 0,262343 C T
- SNP_A-4302062
- rs1971929 2729947 AA 0,611517 C G
- SNP_A-4302119
- rs3852528 2783193 noBB 0,041388 A G
- SNP_A-1819033
- rs151291 2731415 noAA 0,260891 C T
- SNP_A-1824380
- rs179409 2483882 AA 0,310425 C G
- SNP_A-1829337
- rs231873 2742118 noAB 0,422393 C G
- SNP_A-1845199
- rs2412058 2597705 AA 0,29063 C T
- SNP_A-1866128
- rs12804445 2834275 BB 0,431295 A C
- SNP_A-2045452
- rs7942590 2590291 AA 0,7495 C G
- SNP_A-2078818
- rs4430486 2741967 BB 0,177528 C G
- SNP_A-2089816
- rs10741669 2600056 noAB 0,154721 C T
- SNP_A-2108877
- rs10766212 2589728 AA 0,181241 A G
- SNP_A-2111327
- rs11517737 2481124 noAB 0,612965 A G
- SNP_A-2115624
- rs4930013 2818735 AB 0,762452 G T
- SNP_A-2139714
- rs4930149 2692602 AA 0,42212 A C
- SNP_A-2147212
- rs11023096 2484579 BB 0,011594 A G
- SNP_A-2167641
- rs7927129 2672108 noAA 0,905521 A C
- SNP_A-2185200
- rs231901 2687761 AA 0,399107 C T
- SNP_A-2188014
- rs2237866 2486738 AA 0,016676 C T
- SNP_A-2199433
- rs12576156 2455394 noAA 0,055461 C T
- SNP_A-2207071
- rs163183 2801017 noBB 0,080842 A G
- SNP_A-2222217
- rs231841 2680180 AB 0,041003 A C
- SNP_A-2248126
- rs3819506 2484900 BB 0,043565 A G
- SNP_A-2279904
- rs16928561 2672031 BB 0,222103 A G
- SNP_A-2279707
- rs179407 2483474 noBB 0,011184 C T
- SNP_A-2281097
- rs1079714 2717317 noBB 0,583124 C T
- SNP_A-2286096
- rs11023094 2483937 noAB 0,158471 C T
- SNP_A-2306355
- rs17744869 2780438 noBB 0,236986 C G
1Nomenclatura Oficial del SNP de acuerdo con NCBI SNP db versión 126, mayo de 2006. 2Posición cromosómica basada en el NCBI Build 36.1, marzo de 2006. 3 Valor P del genotipo que tiene altos valores de QT frente a todos los otros genotipos.
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predictivos positivos, desde 0,68 para QTs mayores que 5 milisegundos a 0,17 para QTs mayores que 30 milisegundos) sugiere que factores adicionales afectan a una prolongación más severa del QT.
Como muestran los datos de la Tabla 17, secuencia de KCNQ1 de un individuo en los loci SNP anteriores puede utilizarse para predecir si un individuo está predispuesto a la prolongación de QT, debido a la administración de un compuesto capaz de prolongar el intervalo QT. Esto es, se puede predecir de manera fiable que los individuos que tienen uno o más genotipos SNP asociados con una predisposición a la prolongación de QT experimentarán un intervalo QT prolongado (es decir, un intervalo QT prolongado en al menos 5 milisegundos) después de la administración de un compuesto capaz de prolongar el intervalo QT. De manera similar, se puede predecir de manera fiable que los individuos que no tienen cualquiera de los genotipos de SNP anteriores asociados con una predisposición a la prolongación de QT no experimentan una prolongación severa de QT (es decir, un intervalo de QT prolongado de más de 15 milisegundos) después de la administración de un compuesto capaz de prolongar el intervalo de QT.
Métodos de acuerdo con la invención pueden implicar la secuenciación directa o el genotipado de genes KCNQ1 y/o CYP2D6 de un individuo o la caracterización de productos de expresión de los genes. Por ejemplo, tal como se señaló anteriormente, el polimorfismo CYP2D6G1846A resulta en la terminación prematura de la proteína CYP2D6 y el polimorfismo CYP2D6C100T resulta en la sustitución de una prolina en la posición 34 por serina. Cualquiera de estos polimorfismos se podría determinar a partir de las proteínas o ARN resultantes. Por consiguiente, la invención incluye genes de ensayo y/o sus productos de expresión.
Se describen aspectos adicionales:
Aspecto 1. Un método de tratar a un paciente con un compuesto capaz de prolongar el intervalo QT, comprendiendo el método: determinar al menos una parte de la secuencia del gen KCNQ1 del paciente; y administrar al paciente una cantidad del compuesto basado en la secuencia del gen KCNQ1 del paciente.
Aspecto 2. El método del aspecto 1, en el que la cantidad del compuesto administrado es menor si el genotipo de KCNQ1 del paciente en la posición 79764 de la secuencia de referencia AJ006345.1 es GG que si el genotipo del paciente no es GG.
Aspecto 3. El método del aspecto 1, en el que la cantidad del compuesto administrado es menor si el genotipo de KCNQ1 del paciente en la posición 286414 de la secuencia de referencia AJ006345.1 es AA que si el genotipo del paciente no es AA.
Aspecto 4. El método del aspecto 1, en el que la cantidad del compuesto administrado es menor si el genotipo de KCNQ1 del paciente en la posición 78927 de la secuencia de referencia AJ006345.1 es CC que si el genotipo del paciente no es CC.
Aspecto 5. El método del aspecto 1, en el que el compuesto se selecciona de un grupo que consiste en:
amiodarona, trióxido arsénico, bepridil, cloroquina, clorpromazina, cisaprida, claritromicina, disopiramida, dofetilide, domperidona, droperidol, eritromicina, halofantrina, haloperidol, ibutilida, iloperidona, levometadilo, mesoridazina, metadona, pentamidina, pimozida, procainamida, quinidina, sotalol, sparfloxacina, tioridazina; alfuzosina, amantadins, azitromicina, cloral hidrato, clozapina, dolasetrona, felbamato, flecainida, foscarnet, fosfenitoína, gatifloxacina, gemifloxacina, granisetron, indapamida, isradipina, levofloxacina, litio, moexipril, moxifloxacina, nicardipina, octreotida, ofloxacina, ondansetron, quetiapina, ranolazina, risperidona, roxitromicina, tacrolimus, tamoxifeno, telitromicina, tizanidina, vardenafil, venlafaxina, voriconazol, ziprasidona; albuterol, amitriptilina, amoxapina, anfetamina, dextroanftamina, atomoxetina, cloroquina, ciprofloxacina, citalopram, clomipramina, cocaína, desipramina, dexmetilfenidato, dobutamina, dopamina, doxepina, efedrina, epinefrina, fenfluramina, fluconazol, fluoxetina, galantamina, imipramina, isoproterenol, itraconazol, ketoconazol, levalbuterol, metaproterenol, metilfenidato, mexiletina, midodrina, norepinefrina, nortriptilina, paroxetina, fentermina, fenilefrina, fenilpropanolamina, protriptilina, pseudoefedrina, ritodrina, salmeterol, sertralina, sibutramina, solifenacin, terbutalina, tolterodina, trimetoprim-sulfa, trimipramina y metabolitos, sales farmacéuticamente aceptables y combinaciones de los mismos.
Aspecto 6. El método del aspecto 5, en el que el compuesto tiene la fórmula
10
en donde:
R es, independientemente, hidrógeno, alquilo inferior, alcoxi inferior, hidroxilo, carboxilo, hidroxicetona
inferior, alcanol inferior, ácido hidroxil acético, ácido pirúvico, etanodiol, cloro, flúor, bromo, yodo, amino, mono o di
alquil inferior-amino, nitro, alquil inferior tio, trifluorometoxi, ciano, acilamino, trifluorometilo, trifluoroacetilo, aminocar
bonilo, monoalquilaminocarbonilo, dialquilaminocarbonilo, formilo,
alquilo es alquilo inferior, ramificado o lineal y saturado o insaturado; 10 acilo es alquilo inferior o alquiloxi inferior unido a través de un carbonilo;
arilo es fenilo o fenilo sustituido con al menos un grupo, R5, en donde cada uno de los R5 es, independientemente, hidrógeno, alquilo inferior, alcoxi inferior, hidroxi, cloro, flúor, bromo, yodo, monoalquil inferioramino, dialquil inferior-amino, nitro, ciano, trifluorometilo o trifluorometoxi;
heteroarilo es un anillo de arilo de cinco o seis miembros que tiene al menos un heteroátomo, Q3, en donde
15 cada uno de los Q3 es, independientemente, -O-, -S-, -N(H)-o -C(H)=N-, W es CH2 o CHR8 o N-R9; R1 es -H, alquilo inferior, -OH, halo, alcoxi inferior, trifluorometilo, nitro o amino; R2 es alquileno C2-C5, alquenileno (cis o trans), o alquinileno, opcionalmente sustituido con al menos un
grupo alquilo C1-C6 lineal, grupo fenilo o
en que Z1 es alquilo inferior, -OH, alcoxi inferior, -CF3, -NO2, -NH2 o halógeno;
R3 es alquilo inferior o hidrógeno;
R7 es hidrógeno, alquilo inferior o acilo;
R8 es alquilo inferior;
R9 es hidroxi, alcoxi inferior o -NHR10;
R10 es hidrógeno, alquilo inferior, acilo C1-C3, arilo,
X1, X2 y X3 son, independientemente, -O-, -S-, =N-o -N(R3)-, o X1 y X2 no están unidos covalentemente entre sí y son, independientemente, -OH, =O, -R3 o =NR3; inferior es 1-4 átomos de carbono;
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Aspecto 13. El método del aspecto 1, en el que paciente padece al menos una afección seleccionada de un grupo que consiste en esquizofrenia, trastorno esquizo-afectivo, depresión, manía bipolar/depresión, arritmia cardiaca, síndrome de Tourette, un trastorno psicótico, un trastorno delusional y trastorno esquizofreniforme.
Aspecto 14. El método del aspecto 13, en el que paciente padece al menos una afección seleccionada de un grupo que consiste en: esquizofrenia paranoide, esquizofrenia catatónica, esquizofrenia desorganizada, esquizofrenia no diferenciada y esquizofrenia residual.
Aspecto 15. El método del aspecto 13, en el que paciente padece al menos una afección seleccionada de un grupo que consiste en: trastorno psicótico breve, un trastorno psicótico no especificado de otro modo, un trastorno psicótico debido a una afección médica general y un trastorno psicótico inducido por sustancias.
Aspecto 16. Un método de determinar si un individuo está predispuesto a la prolongación del intervalo QTc, comprendiendo el método: determinar al menos una parte de una secuencia del gen KCNQ1 de un individuo.
Aspecto 17. El método del aspecto 16, en el que la determinación incluye determinar el genotipo del individuo en al menos un locus de polimorfismos (SNP) de un solo nucleótido, seleccionado de un grupo que consiste en: 79764 de la secuencia de referencia AJ006345.1, posición 286414 de la secuencia de referencia AJ006345.1 y posición 78927 de la secuencia de referencia AJ006345.1.
Aspecto 18. El método del aspecto 18, que comprende, además: concluir que el individuo está predispuesto a la prolongación del intervalo QTc, si el genotipo de KCNQ1 del individuo incluye cualquiera de lo siguiente:
GG en la posición 79764 de la secuencia de referencia AJ006345.1; AA en la posición 286414 de la secuencia de referencia AJ006345.1; o CC en la posición 78927 de la secuencia de referencia AJ006345.1.
Aspecto 19. El método del aspecto 16, que comprende, además: determinar al menos una parte de la secuencia del gen CYP2D6 del individuo.
Aspecto 20. El método del aspecto 19, en el que la determinación incluye determinar si la secuencia del gen CYP2D6 del individuo incluye el polimorfismo CYP2D6G1846A.
Aspecto 21. El método del aspecto 19, en el que la determinación incluye determinar si la secuencia del gen CYP2D6 del individuo incluye el polimorfismo CYP2D6C100T.
Aspecto 22. Un método de tratar un paciente con un compuesto capaz de prolongar el intervalo QT, comprendiendo
el método: caracterizar un producto de expresión del gen KCNQ1 del paciente; y administrar al paciente una cantidad del compuesto basado en el producto de expresión caracterizado.
Aspecto 23. El método del aspecto 22, en el que la cantidad del compuesto se reduce si el producto de expresión
caracterizado corresponde a cualquiera de lo siguiente: un genotipo KCNQ1 GG en la posición 79764 de la secuencia de referencia AJ006345.1; un genotipo KCNQ1 AA en la posición 286414 de la secuencia de referencia AJ006345.1; o un genotipo KCNQ1 CC en la posición 78927 de la secuencia de referencia AJ006345.1.
Aspecto 24. El método del aspecto 22, que comprende, además: caracterizar un producto de expresión del gen CYP2D6 del paciente.
Aspecto 25. El método del aspecto 24, que comprende, además:
determinar si el producto de expresión caracterizado corresponde a un polimorfismo CYP2D6 seleccionado de un grupo que consiste en: CYP2D6G1846A y CYP2D6C100T. Aspecto 26. El método del aspecto 22, en el que el compuesto se selecciona de un grupo que consiste en:
amiodarona, trióxido arsénico, bepridil, cloroquina, clorpromazina, cisaprida, claritromicina, disopiramida, dofetilide, domperidona, droperidol, eritromicina, halofantrina, haloperidol, ibutilida, iloperidona, levometadilo, mesoridazina, metadona, pentamidina, pimozida, procainamida, quinidina, sotalol, sparfloxacina, tioridazina;
13 5
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30
35
alfuzosina, amantadins, azitromicina, cloral hidrato, clozapina, dolasetrona, felbamato, flecainida, foscarnet, fosfenitoína, gatifloxacina, gemifloxacina, granisetron, indapamida, isradipina, levofloxacina, litio, moexipril, moxifloxacina, nicardipina, octreotida, ofloxacina, ondansetron, quetiapina, ranolazina, risperidona, roxitromicina, tacrolimus, tamoxifeno, telitromicina, tizanidina, vardenafil, venlafaxina, voriconazol, ziprasidona; albuterol, amitriptilina, amoxapina, anfetamina, dextroanftamina, atomoxetina, cloroquina, ciprofloxacina, citalopram, clomipramina, cocaína, desipramina, dexmetilfenidato, dobutamina, dopamina, doxepina, efedrina, epinefrina, fenfluramina, fluconazol, fluoxetina, galantamina, imipramina, isoproterenol, itraconazol, ketoconazol, levalbuterol, metaproterenol, metilfenidato, mexiletina, midodrina, norepinefrina, nortriptilina, paroxetina, fentermina, fenilefrina, fenilpropanolamina, protriptilina, pseudoefedrina, ritodrina, salmeterol, sertralina, sibutramina, solifenacin, terbutalina, tolterodina, trimetoprim-sulfa, trimipramina y metabolitos, sales farmacéuticamente aceptables y combinaciones de los mismos.
Aspecto 27. Un método de determinar si un individuo está predispuesto a la prolongación del intervalo QTc, comprendiendo el método:
caracterizar un producto de expresión de un gen KCNQ1 del individuo.
Aspecto 28. El método del aspecto 27, que comprende, además:
determinar si el producto de expresión caracterizado corresponde a cualquiera de los siguiente:
un genotipo KCNQ1 GG en la posición 79764 de la secuencia de referencia AJ006345.1;
un genotipo KCNQ1 AA en la posición 286414 de la secuencia de referencia AJ006345.1; o
un genotipo KCNQ1 CC en la posición 78927 de la secuencia de referencia AJ006345.1.
Aspecto 29. El método del aspecto 27, que comprende, además: caracterizar un producto de expresión del gen CYP2D6 del individuo.
Aspecto 30. El método del aspecto 29, que comprende, además:
determinar si el producto de expresión caracterizado corresponde a un polimorfismo CYP2D6 seleccionado de un grupo que consiste en: CYP2D6G1846A y CYP2D6C100T.
La anterior descripción de diversos aspectos de la invención se ha presentado con fines de ilustración y descripción.
<110> Wolfgang, Curt Polymeropoulos, Mihael
<120> Método de Tratamiento Basado en Polimorfismos del Gen KCNQ1
<130> VAND-0039-PCT
<140> PCT/US2010/029921
<141>
<150> US 61/167,136
<151>
<160> 59
<210> 1
<211> 404123
<212> ADN
<213> Homo sapiens
<220>
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WO2010117931A1 (en) | 2010-10-14 |
CA2757713A1 (en) | 2010-10-14 |
SI2417267T1 (sl) | 2017-02-28 |
US10563259B2 (en) | 2020-02-18 |
US8999638B2 (en) | 2015-04-07 |
SI3023506T1 (en) | 2018-08-31 |
JP2015180639A (ja) | 2015-10-15 |
JP5800798B2 (ja) | 2015-10-28 |
US20180002756A1 (en) | 2018-01-04 |
EP3023506B1 (en) | 2018-03-14 |
HUE037724T2 (hu) | 2018-09-28 |
JP2012522838A (ja) | 2012-09-27 |
EP3354753B1 (en) | 2020-02-12 |
US20150167091A1 (en) | 2015-06-18 |
US20120027871A1 (en) | 2012-02-02 |
US9157121B2 (en) | 2015-10-13 |
CA2757713C (en) | 2019-01-29 |
EP3354753A1 (en) | 2018-08-01 |
HUE030667T2 (en) | 2017-05-29 |
EP3023506A1 (en) | 2016-05-25 |
EP2417267B1 (en) | 2016-08-17 |
ES2604102T3 (es) | 2017-03-03 |
JP6108633B2 (ja) | 2017-04-05 |
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