1. Wilson Disease Treatment Failures?
Fred Askari MD, PhD
Director, Wilson Disease Program
Associate Professor, University of Michigan Medical Center
Ann Arbor, Michigan

2. Wilson Disease Familial Copper Toxicity Variable Time Course
Pleiotropic Effects
Psychiatric
Neurologic
Hepatic
Vascular, Cardiac, Renal
Treatment toxicity

3. COPPER BACKGROUND – WILSON’S DISEASE
Copper Accumulates and Causes Brain and Liver Toxicity
• Due to a Failure of Biliary Excretion
• Fatal if Untreated
• Earlier Anticopper Drug Penicillamine is Quite Toxic,
Trientine Moderately Toxic
• Occurs 1 in 40,000 in Most Populations’
• Gene Codes for a Copper Binding ATPase
Mayo Clinic Treatment Study Showed 30% Mortatlity over 10 years

4. Presentation / Recognition a Problem
Types of Presentations
Neurological
Psychiatric
Hepatic
“Presymptomatic”
Other

5. Treatments BAL--no longer used Chelation: Penacillamine, Trientine
Zinc
TM—not approved
Plasmapheresis
Liver Transplant

6. Definition of Success? Definition of Failure?
Death—Natural History of Life and Disease
Symptom Progression
Symptom Persistence
Symptom Resolution
Toxicity
Time Course—Early Failure, Late Failure, Treatment Not Fast Enough, Success not Long Enough

7. Physician’s Definitions and Patient’s Definitions
My child did not get into Harvard
Bad Marriage
Bad Job
Fractured Personal Relationships
Cannot Sleep
People Keep Wanting to Put Me in Assisted Living
I don’t like taking medicines

8. Response to Therapy Not the same for everyone
Variable Ability to Compensate
Variable Treatment Adherence
Variable Disease Manifestations and Time of Progression
Variable Enzironment

9. Treatment Failures—>Chelation Toxicity
Drug
Problems
Penicillamine
Makes 50% of New Neurologic Patients Worse and 25% Permanently Worse.
Acute Hypersensitivity Syndrome in 25% of Patients.
Early Side Effects of Bone Marrow Depression And Proteinuria.
Late Side Effects of Autoimmunity, Connective Tissue Problems, and Immune Suppression.
Trientine
Early and Late Side Effects of Type Seen with Penicillamine Occur, But Less Frequently.
Effects on New Neurologic Patients Can Accelerate Worsening.

10. Neurolgoic Worsening on Therapy
In people with Neurologic Symptoms, Penicillamine and trientine both cause a high incidence (25-50%) of neurologic worsening,
Mechanism probably by mobilizing copper stores and further elevating brain copper.
Patients who experience neurological worsening very often never recover fully

11. Neurologic Worsening
TM Open Label Study: 2 of 55 patients in showed Neurologic Worsening (3.6%)
TM vs. Trientine Study: 1 of 25 (4%)people treated with TM showed Neurologic Worsening, While 6 of 23 (26%) people treated with Trientine showed Neurologic Worsening

12. TM THERAPY REDUCTION OF FREE COPPER
Figure 1.

13. TM vs. Trientine
Figure 2.

14. Trientine Free Copper and Neurologic Deterioration
Figure 3.

15. Weeks on TM Two Dosing Arm Comparison
Figure 4.

16. Zinc Therapy Least Toxic Main Concern is GI upset
Over Treatment, Under Treatment
Urine Testing
Monitor Levels

17. Treatment Failures Transplant
20% Renal Failure Long Term Toxicity from Immunosuppresants
10 year Mortality 46%--all causes
Increased Incidence of Cardiac Disease, Cancer, Infections
1/3 of late deaths due to graft failure, remainder split between cardiovascular deaths, malignancies and infections

18. Treatment Failures—Fortunately the Minority of Cases
20% Incidence of Significant Non-adherence
Disease Universally Fatal if Left Untreated
Take your copper reduction therapy and do follow up testing
The vast majority of treated patients do exceptionally well
Chronic Disease which can be managed