Wilson disease

Question 1

Prevalence of wilson

Answer 1

1 in 30,000

Question 2

Percentage of pts with kayser fleischer rings

Answer 2

95%, all neuro patients,
-50% of liver patients
-presymptomatic 20-30%

Question 3

Most common neuro symptoms

Answer 3

-dysarthria 46-97%
-dystonia 38-69%
-Tremor 55%
-Parkinsonism
-Dysphagia (50%)
-gait abnormality 28-75%

Question 4

24 hr urine copper measurement

Answer 4

> 100 mcg in 75% of pts

Question 5

Copper intake goal in wilson

Answer 5

< 1.0 mg/day

Question 6

Name of ultragenyx trial

Answer 6

UX701
Cyprus

Question 7

UX701 Stage 1 breakdown

Answer 7

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

Question 8

UX701 Stage 2 Breakdown

Answer 8

DOUBLE BLIND, PLACEBO CONTROLLED
Cohort 1: Gene therapy (dose determined in stage1 ) + prednisone (n=42)
Cohort 2: Placebo (n=21)

Question 9

UX701 Stage 3 breakdown

Answer 9

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

Question 10

Age cutoff of UX701

Answer 10

18+

Question 11

Inclusion criteria of UX701

Answer 11

-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

Question 12

Normal copper movement in cell

Answer 12

-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

Question 13

Percentage of patients with low ceruloplasmin

Answer 13

> 90%, usually less than 20
<5 is fairly diagnostic

Question 14

Name of diagnostic scoring system

Answer 14

Leipzig score = >4

Question 15

How does zinc work?

Answer 15

Increases metallothionine (protein in gut) that binds copper and decreases absorption in Gi tract

Question 16

Estimated worldwide prevalance

Answer 16

12.7 in 100,000

Question 17

Carrier frequency

Answer 17

1:90

Question 18

Most common symptom in pts with neuro wilson disease

Answer 18

Dysarthria (97%)

Question 19

Classic fixed dystonic smile

Answer 19

risus sardonicus

Question 20

Percentage of patients that present with psych symptoms

Answer 20

10%

Question 21

Wilson disease misdiagnosis: Alagille syndrome

Answer 21

-genetic condition, build builds up due to lack of bile ducts

Question 22

Leipzig score that = a diagnosis of wilsons

Answer 22

4

Question 23

American association for study of liver diseases (AASLD) diagnosis algorithm

Answer 23

-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

Question 24

Diagnostic guidelines that use Leipzig score

Answer 24

-European association for the study of the liver (EASL)
-European association for pediatric gastroenterology , hepatology and nutrition (ESPGHAN)

Question 25

normal dose of penicillamine

Answer 25

-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

Question 26

Trientine dosing

Answer 26

-Adults: 750-1500 mg/day -Peds: 20 mg/kg/day -Taken 2-3x per day on empty stomach -Has to be refridgerated

Question 27

Zinc dosing

Answer 27

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

Question 28

What is the King score

Answer 28

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

Question 29

Target urinary copper level in maintenance chelation therapy

Answer 29

-Chelators: 200-500 ug/day -Zinc: < 75-100 ug/day

Question 30

What tests would show evidence of non compliance with therapies?

Answer 30

-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

Question 31

Average annual cost of trientine

Answer 31

~ $300,000

Question 32

AAV used in UX701

Answer 32

AAV9

Question 33

Difference in ATP7B and transgene used in UX701

Answer 33

contains last 3 of the 6 total metal binding domains

Question 34

In UX701, when will chelation/zinc withdrawal challenge occur?

Answer 34

week 12 for gene therapy pts

Question 35

UX701 Stage 1 endpoints

Answer 35

-safety (incidence of AE) -biomarkers of copper metabolism -percent reduction of standard of care -response of chelation/zinc withdrawal

Question 36

UX701 stage 2 primary endpoints

Answer 36

-change in 24h urine copper in treatment vs placebo at week 52 -percent reduction of SOC by week 52 compared to placebo

Question 37

UX701 stage 2 secondary endpoints

Answer 37

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

Question 38

UX701 sites

Answer 38

-Vanderbilt -UCLA -Stanford -U of Miami -Northwestern -Indiana University -U of Michigan -Duke -MGH -Seattle Childrens