Wilson disease Flashcards
Prevalence of wilson
1 in 30,000
Percentage of pts with kayser fleischer rings
95%, all neuro patients,
-50% of liver patients
-presymptomatic 20-30%
Most common neuro symptoms
-dysarthria 46-97%
-dystonia 38-69%
-Tremor 55%
-Parkinsonism
-Dysphagia (50%)
-gait abnormality 28-75%
24 hr urine copper measurement
> 100 mcg in 75% of pts
Copper intake goal in wilson
< 1.0 mg/day
Name of ultragenyx trial
UX701
Cyprus
UX701 Stage 1 breakdown
OPEN LABEL (dose selection)
Cohort 1: gene therapy + prednisone (n=5)
Cohort 2: gene therapy dose 2 + prednisone (n=5)
Cohort 3: gene therapy dose 3 + prednisone (n=5)
Follow up to 52 weeks
UX701 Stage 2 Breakdown
DOUBLE BLIND, PLACEBO CONTROLLED
Cohort 1: Gene therapy (dose determined in stage1 ) + prednisone (n=42)
Cohort 2: Placebo (n=21)
UX701 Stage 3 breakdown
Cohort 1: pts that originally received placebo will receive gene therapy + prednisone at stage 2 dose
Cohort 2: pts originally that got gene therapy will get placebo
Age cutoff of UX701
18+
Inclusion criteria of UX701
-confirmed diagnosis of wilson
-ongoing copper chelator and or zinc therapy for at least 12 months (no dose or med change for at least 6 months)
-ongoing copper restricted diet for at least 12 months–stable lab values
Normal copper movement in cell
-CTR (copper transporter) brings copper into hepatocyte
-ATP7b transports copper to golgi apparatus
-ceruloplasmin binds to copper
-ceruloplasmin + copper vesicles released into bile and excreted, some released into blood
Percentage of patients with low ceruloplasmin
> 90%, usually less than 20
<5 is fairly diagnostic
Name of diagnostic scoring system
Leipzig score = >4
How does zinc work?
Increases metallothionine (protein in gut) that binds copper and decreases absorption in Gi tract
Estimated worldwide prevalance
12.7 in 100,000
Carrier frequency
1:90
Most common symptom in pts with neuro wilson disease
Dysarthria (97%)
Classic fixed dystonic smile
risus sardonicus
Percentage of patients that present with psych symptoms
10%
Wilson disease misdiagnosis: Alagille syndrome
-genetic condition, build builds up due to lack of bile ducts
Leipzig score that = a diagnosis of wilsons
4
American association for study of liver diseases (AASLD) diagnosis algorithm
-Pathways for liver and neuro symptoms
-Based on KF rings, ceruloplasmin, 24h urine copper measurements
-if still inconclusive, move on to liver biopsy and genetic testing
Diagnostic guidelines that use Leipzig score
-European association for the study of the liver (EASL)
-European association for pediatric gastroenterology , hepatology and nutrition (ESPGHAN)
normal dose of penicillamine
-titration to 1-1.5 g/day
-maintenance can be 750-1000 mg /day
-pediatrics: 20 mg/kg/day
Taken 2-4x per day on empty stomach
Trientine dosing
-Adults: 750-1500 mg/day
-Peds: 20 mg/kg/day
-Taken 2-3x per day on empty stomach
-Has to be refridgerated
Zinc dosing
Adults: 150 mg/d divided TID
Peds (6-16 y.o.): 75 mg/d divided TID
Peds (<6 y.o.): 50 mg/d divided BID
Must be taken 1 hour before or after meals
What is the King score
Scale used to judge how severe liver disease is, requiring a transplant
-score more than or equal to 11 = death without transplant
-calculated by looking at INR, bili, albumin, AST, wbc
Target urinary copper level in maintenance chelation therapy
-Chelators: 200-500 ug/day
-Zinc: < 75-100 ug/day
What tests would show evidence of non compliance with therapies?
-increase in serum free copper > 15 ug/dl
-increase in urine copper in pts on chronic chelation
-appearance/reappearance of KF rings with persistent abnormal liver tests
Average annual cost of trientine
~ $300,000
AAV used in UX701
AAV9
Difference in ATP7B and transgene used in UX701
contains last 3 of the 6 total metal binding domains
In UX701, when will chelation/zinc withdrawal challenge occur?
week 12 for gene therapy pts
UX701 Stage 1 endpoints
-safety (incidence of AE)
-biomarkers of copper metabolism
-percent reduction of standard of care
-response of chelation/zinc withdrawal
UX701 stage 2 primary endpoints
-change in 24h urine copper in treatment vs placebo at week 52
-percent reduction of SOC by week 52 compared to placebo
UX701 stage 2 secondary endpoints
CHANGE AT 52 WKS COMPARED TO PLACEBO
-change in ceruloplasmin activity
-change in WDFRS patient scores
-change in WDFRS clinician scores
-chelation/zinc withdrawal challenge (how many pts can discontinue this)
-liver biopsy copper concentration
-safety, AEs
-development of anti ATP7B antibodies
UX701 sites
-Vanderbilt
-UCLA
-Stanford
-U of Miami
-Northwestern
-Indiana University
-U of Michigan
-Duke
-MGH
-Seattle Childrens
