dr. francisco javier hevia u. costa rica -...

Dr Francisco Javier Hevia U

Gastroenteroacutelogo-Hepatoacutelogo

Costa Rica

Nombre del gen ATP7B

Proteiacutena Proteiacutena Transportadora de Cobre ATPasa 2

Localizacioacuten 13q143

Exones 21 exones traducidos

Herencia Autosoacutemica Recesiva

- MUNDIAL

bull 1955 Walshe D-P

bull 1970 Hoogenraad - Zinc

bull 1981 Walshe Trietilen tetramina

Dra Mildred Jimeacutenez HBT Indira Chaves G

MSc Jessica Arroyo H

fheviaugmailcom

2015 Dec 18 7(29) 2859ndash2870

Wilsonrsquos disease A review of what we have learnedKryssia Isabel Rodriguez-Castro1 Francisco Javier Hevia-Urrutia2 and Giacomo Carlo Sturniolo3

Policlinico Abano Terme Padua Italy 1

Hospital San Juan de Dios Hospital CIMA San Joseacute Costa Rica2

Padua University Hospital Padua Italy3

National alliance for Wilsonrsquos disease health policy in Costa Rica(2017) 25

Francisco Hevia-Urrutia1 Ileana Alvarado-Echeverriacutea1 Alfredo Sanabria-Castro1 Marta Saacutenchez-Molina Luis Meza-Sierra1 Alexander Parajeles-Vindas1 Oscar Meacutendez-Blanca1 Aacutelvaro Saacutenchez-Siles2 Manuel Saboriacuteo-Rocafort3 Marcela Barguil-Gallardo1 Iliana Chavarriacutea-Quiroacutes1 and Cecilia Monge-Bonilla1

1Hospital San Juan de Dios Caja Costarricense del Seguro Social 4917-1000 San Jose Costa Rica 2Hospital Mexico Caja Costarricense del Seguro Social San Jose Costa Rica 3Hospital Nacional de Ninos Caja Costarricense del Seguro Social San Jose Costa Rica

EPIDEMIOLOGIacuteA EN CENTROAMEacuteRICA Y EL CARIBE

bull Guatemala El Salvador Honduras Panamaacute Rep Dominicana casos aislados

bull Nicaragua 2 casos neuroloacutegicos y 1 Wilson Fulminante (Costa Rica)

bull Cuba mutacioacuten N41S en 130 pts

SURAMEacuteRICAbull BRASIL mutaciones maacutes frecuentes

3402delC 308L708P 167

Enf Wilson en el sur de Brasil 40 antildeos de seguimientoClinics (Sao Paulo) 2011 Mar 66(3) 411ndash416

36 pts 1970-2010 75 origen Europeo

bull ARGENTINA El exjugador de Gimnasia La Plata sufre la enfermedad de Wilson y necesita ayuda del mundo del fuacutetbol para poder seguir luchando por su vida

bull PERUacute Enfermedad de Wilson forma nueropsiquiaacutetrica dominante presentacioacuten de un caso

bull CHILE La enfermedad de Wilson es infrecuente en Chile aunque existen comunicaciones de casos y series cliacutenicas en nuestro medio (Dr Marco Arrese)

Revista medica de ChileRev meacuted Chile v138 n10 Santiago oct 2010rtamento de Neurologiacutea Cliacutenica Las Condes Santiago de ChileMiranda M Brinck P Roessler JL Troncoso M Gonzaacutelez M Villagra R Enfermedad de Wilson Experiencia Cliacutenica en 16 pacientes Rev Med Chile 1995 123 1098-107

bull URUGUAY Comunicacioacuten de un caso cliacutenico y su evolucioacuten a los 8 antildeos Forma de presentacioacuten neurosiquiaacutetrica Drs Tarigo H Legnani E

Med Int Mex 200723(5)458-63

Enfermedad de Wilson reporte de un caso y

revision de la literatura

Marco Antonio Lopez Hernandez Marlene Serrano Rufino

MEacuteXICO

bull Costa Rica 49 100000 h (1989)

HEPAacuteTICONEUROLOacuteGICO Y OTROS

-COSTA RICA

bull mutante Asn 1270 Ser

bull Insuficiencia hepaacutetica fulminante con hemoacutelisis

COSTA RICA ndash DRA MARIacuteA A MATAMOROS

bull 92

(15)

( 21)

EW357

bull Tx con chaperones 4 fenil-butirato (4-PBA) y curcumina

bull Antioxidante

Quelante de Cu

Wilson Therapeutics ndash Improved treatment for Wilson DiseaseSeptember 2016

36

Wilson Therapeutics in brief

Founded in 2012 based in Stockholm

Develops novel therapies for rare diseases with high unmet medical needs

Current focus on Wilson Disease

Orphan indication

Approximately 25000 patients in EU and US combined

Lead program WTX101 ndash Decupratereg (bis-choline-tetrathiomolybdate)

Global Phase II study ongoing

gt500 patients exposed to tetrathiomolybdate for up to 8 years adds to the knowledge around safety

Public company listed on Nasdaq Stockholm

37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)

Trientine(Syprinetrade)

~1000 mg

250 mg caps

2-4 times day

Penicillamine(Cupriminetrade)

~1000 mg

250 mg caps

2-4 times day

Zinc (Galzintrade) 150 mg50 mg

caps3-5 times

day

Decupratereg ~30 mg30 mg tablet

1 time day

Capsules (L=19mm) and tablet (D=64mm) drawn to scale

Convenient dosing expected to improve treatment compliance

Decupratereg ndash once daily ndash one tablet ndash small size

Iron

B6

38

Decupratereg is being developed as a monotherapy for Wilson Disease

Phase 2 is ongoing

Trial sites

28 Wilson Disease patients in US and EUPatient population

Open label non-comparator evaluating free Cu and clinical outcomes for 24 weeks

Trial design

Fully recruited

Status 14 out of 14 patients have enrolled in extension phase

Top line data expected late 2016early 2017

Note Status as of August 3 2016

Terapia Geacutenica corrige a largo plazo metabolismo del Cu en modelo murino de EW

bull Patologiacutea primaria

bull Transportador de cobre ATP7B

bull Tx actuales

bull Problema

bull Trasplante

bull tx geacutenicos fallaron

bullNuevo vector de tx geacutenica

bullVectores AAV8

bullRatoacuten modelo EW Atp7b --

bullRevierte

bullPreviene

bullRestaura

bull Tx geacutenica realidad en la cliacutenica

Conclusiones

TUacute ERES EL MEacuteDICO QUE ME

DIAGNOSTICARAacute

ENFERMEDAD DE WILSON EN

AMEacuteRICA LATINAfheviaugmailcom

45

Bis-choline tetrathiomolybdate (WTX101) ndash New mode of action

Removes Cu from intracellular metallothionein (MT) copper stores by forming TTM-Cu complexes

TTM-Cu complexes are excreted into bile

TTM expands endogenous copper buffering capacity by forming stable TTM-Cu-Albumin complexes in blood

Specifically binds to copper (not iron or zinc) with high affinity

Active ingredient Tetrathiomolybdate

(TTM)

Bis-choline

tetrathiomolybdate

Ammonium TTM has been explored in Wilson Disease in the past The comparability of the two salt forms has been

established

Modelo de funcionamiento de la ATPasa Wilson (ATP7B) en el hepatocito

Nombre del gen ATP7B

Proteiacutena Proteiacutena Transportadora de Cobre ATPasa 2

Localizacioacuten 13q143

Exones 21 exones traducidos

Herencia Autosoacutemica Recesiva

- MUNDIAL






fheviaugmailcom

2015 Dec 18 7(29) 2859ndash2870













3402delC 308L708P 167








Med Int Mex 200723(5)458-63




MEacuteXICO



-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


- MUNDIAL






fheviaugmailcom

2015 Dec 18 7(29) 2859ndash2870













3402delC 308L708P 167








Med Int Mex 200723(5)458-63




MEacuteXICO



-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established




fheviaugmailcom

2015 Dec 18 7(29) 2859ndash2870













3402delC 308L708P 167








Med Int Mex 200723(5)458-63




MEacuteXICO



-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


2015 Dec 18 7(29) 2859ndash2870













3402delC 308L708P 167








Med Int Mex 200723(5)458-63




MEacuteXICO



-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established







3402delC 308L708P 167








Med Int Mex 200723(5)458-63




MEacuteXICO



-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


Med Int Mex 200723(5)458-63




MEacuteXICO



-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established




-COSTA RICA




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established




bull 92

(15)

( 21)

EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


EW357


bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established



bull Antioxidante

Quelante de Cu


36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established



36





Orphan indication






37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


37

DrugRecommended

daily doseFrequenc

yIllustration

(daily dosage)


~1000 mg

250 mg caps

2-4 times day


~1000 mg

250 mg caps

2-4 times day


caps3-5 times

day


1 time day




Iron

B6

38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


38


Phase 2 is ongoing

Trial sites



Trial design

Fully recruited







bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established





bull Tx actuales

bull Problema

bull Trasplante



bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established




bullVectores AAV8


bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established



bullRevierte

bullPreviene

bullRestaura


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


Conclusiones


DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established



DIAGNOSTICARAacute



45







(TTM)

Bis-choline

tetrathiomolybdate


established


45







(TTM)

Bis-choline

tetrathiomolybdate


established


dr. francisco javier hevia u. costa rica -...

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