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

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

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

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

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

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

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

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

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.

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

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

TM THERAPY REDUCTION OF FREE COPPER Figure 1.

TM vs. Trientine Figure 2.

Trientine Free Copper and Neurologic Deterioration Figure 3.

Weeks on TM Two Dosing Arm Comparison Figure 4.

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

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

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