Activity Transcript

Chapter 1

Michael L. Schilsky, MD, FAASLD: Hello, I'm Dr Michael Schilsky, professor of medicine and surgery at Yale University and director of Center of Excellence for Wilson Disease at Yale. Welcome to this program titled, "Do You Know Wilson Disease? Expert Insights to Advanced Diagnosis and Treatment."

Wilson disease is a rare autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. The prevalence of Wilson disease has been estimated as 1 in 30,000, but some recent analyses have suggested genetic prevalence is higher. Copper accumulation in various organs, primarily the liver and brain, may result in hepatic, neurologic, and psychiatric symptoms.

Wilson disease requires coordination of care and medication among several specialists due to its complex nature, but many patients do not have access to multiple specialties due to geographical or insurance barriers. In Wilson disease, we desire a complete reversal of symptoms; however, this is not always achieved. Some patients experience slow progression of disease during treatment, and unwanted effects may prevent the use of the most effective drug. Long-term adherence to therapy is a major problem and may be related to unwanted drug effects, dosing, medication storage, cost, and other factors. Early drug-induced neurological deterioration, known as paradoxical neurologic worsening, has been reported with all available treatments, most commonly with chelation therapy.

The modules in this program will discuss identification and diagnosis of Wilson disease, established therapies for Wilson disease, new therapies and future directions, and a real-world case example.

Thank you for joining this discussion. Please continue to the next module.

Chapter 2

Peter Hedera, MD, PhD: Hello. I'm Dr Peter Hedera, professor and director of the Movement Disorders Program in the Department of Neurology at the University of Louisville in Kentucky. Welcome to this module titled, ''Raising Disease Suspicion in Your Practice: Overcoming Key Challenges.'' One of the key challenges in Wilson disease is very pleomorphic, nonspecific presentation.

One of the major challenges in the diagnosis of Wilson disease is a very varied and nonspecific clinical presentation. Clinical symptoms of Wilson disease can be grouped into 2 major categories: liver and brain or hepatic and central nervous system (CNS) presentation. Liver presentation can vary from asymptomatic liver enzyme elevation to acute hepatitis to acute fulminant liver failure to consequences of chronic cirrhosis. Within the CNS presentation, involuntary movements, such as tremor or dystonia, followed by dysarthria, drooling, and gait balance and disturbances are very typical, yet nonspecific presentations of Wilson disease. Additional clusters of symptoms include neuropsychiatric symptoms, which can vary from personality disorder to mood disorder and acute psychosis.

This disease can be also diagnosed in the presymptomatic stage, and this can be achieved through screening of siblings of affected proband, because each of them has a 1-in-4 chance to be affected by Wilson disease. Additionally, Wilson disease can affect other organ systems, even though they are very difficult to diagnose if the hepatic or CNS symptoms are absent.

I would like to spend some time discussing ophthalmologic symptoms, which are asymptomatic but can be very specific and suggestive of Wilson disease.

Kayser Fleischer ring is the discoloration of cornea and is caused by the copper deposits, and this is very highly suggestive of Wilson disease and can be detected by slit lamp examination. Additionally, sunflower cataracts, which are also completely asymptomatic, are very suggestive of Wilson disease.

There are certain symptoms and clusters of symptoms which we would consider red flags and that should increase your index of suspicion for diagnosis of Wilson disease. Within the liver presentation, it is failure to respond to treatment for autoimmune hepatitis, presence of fatty liver in younger patients, liver disease overlapping with the neuropsychiatric symptoms, acute hepatitis with a rapid onset of jaundice, hemodynamic anemia with Coomb's negative antibodies, and, if liver biopsy was performed, early histologic features of Wilson disease.

Within the neurological symptoms, dysarthria is most common but very nonspecific. Dystonia, tremor, and parkinsonism should raise red flags for the diagnosis of Wilson disease, especially in younger patients. Additionally, psychiatric manifestations with or without movement disorders in younger patients should raise high initial suspicion for the presence of Wilson disease.

Differential diagnosis reflects the nonspecific overlap with other conditions and can include autoimmune hepatitis, fatty liver disease, chronic hepatitis, or other neurometabolic conditions, such as alpha-1 antitrypsin deficiency, or Niemann-Pick type C disease.

Differential diagnosis with a neurologic presentation also reflects the other cardinal symptoms of Wilson disease such as ataxia. So, we need to consider genetic ataxias or multiple sclerosis. The presence of tremor can be seen in Parkinson disease or other types of parkinsonism such as associated with iron accumulation disorders.

Additionally, if hyperkinetic movements are present, such as choreoathetoid movements, Huntington's disease and Fahr syndrome need to be considered.

As we discussed, clinical symptoms of Wilson disease are very nonspecific, and the diagnosis remains laboratory based. Leipzig scoring system for the diagnosis of Wilson disease has been proposed, which combines clinical symptoms and signs with diagnostic laboratory tests.

We already talked about clinical presentation. I would like to again point out the usefulness of, presence of, Kayser-Fleischer rings and Coombs-negative hemolytic anemia. Laboratory testing can be used as a screening test, and serum ceruloplasmin has been used for screening for the presence of Wilson disease. Values less than 0.1 g/L are highly suggestive of Wilson disease. I would like to also point out that ceruloplasmin is an acute phase reactant and rarely, it can be elevated in patients with Wilson disease and thus, normal ceruloplasmin doesn't fully exclude the presence of Wilson disease.

24-hour urine copper assay in the absence of acute hepatitis and cholestasis can be used as a diagnostic test, and the values higher than twice of normal values are highly suggestive of Wilson disease with values more than 100 micrograms per 24 hours.

Lastly, genetic analysis has also improved our ability to diagnose Wilson disease. And the detection of biologic mutations on both chromosomes can be essentially diagnostic for Wilson disease. Total score evaluation can lead to the diagnosis of definite Wilson disease with a score 4 and higher, possible Wilson disease with a score around 3, and scores less than 2 make the diagnosis of Wilson disease highly unlikely.

Thank you for joining our discussion. Please continue to the next module.

Chapter 3

Aurelia Poujois, MD, PhD: Hello, my name is Aurelia Poujois. I'm a neurologist. I'm head of the Rare Disease Reference Center dedicated to Wilson disease in Hôpital Fondation Rothschild in Paris, France. So, welcome to this module titled, "Evaluating Treatment Options in Wilson Disease: Established Therapies."

So, the goals of treatment in Wilson disease are really dependent on the phase of the disease. So, in an asymptomatic patient with no biological anomalies or only slight elevation of serum aminotransferases, the goal of the treatment will be to prevent hepatic inflammation and, of course, to prevent the diffusion of disease outside the liver.

In patients with symptoms, like nonspecific symptoms of liver disease or even cirrhosis, but they also can present neuropsychiatric symptoms or other symptoms like amenorrhea, the goal of the treatment will be to treat the disease and to decrease the symptoms of the liver disease or the brain involvement. Of course, the goal will be to prevent the complication of cirrhosis, especially the complication of portal hypertension. The treatment could be a rescue treatment, especially in end-stage liver failure, so liver transplantation could be another solution to treat these patients.

So, how could we approach the treatment of Wilson disease? After verifying the diagnosis, the important thing to do is to determine the state of the disease. In asymptomatic patients, the first step will be to assess tissue damage, and if there is no tissue damage, we will start with low dose of treatments, the dose we use usually in maintenance therapy with chelation, with dose of chelation around 10 mg/kg to 15 mg/kg, or zinc salt 50 mg, 3 times a day.

If, during this assessment, you have tissue damage, the patient is considered symptomatic, then we will start initial chelation therapy with higher dose until the patient will be stabilized clinically, but also biologically. It can take a few years. When the patient is stabilized, we can decrease the treatment and go to the maintenance therapy phase.

Acute liver failure is another situation, very specific. In this situation, the first step will be to determine the prognostic score with the new Wilson Index and to start rescue medical treatment and, at the same time, to push the patient to the transplant pathway. So, if the medical treatment fails, the patient will be ready to go to the liver transplantation.

What are the current medical therapies for treatment of Wilson disease? We have chelators and zinc salt. Among the chelators, we have d-penicillamine and trientine salts. Both are copper chelators and induce urinary copper excretions. So, during the monitoring of these treatments, the urinary copper excretion will be high. Concerning the zinc salt, the mechanism is different. Zinc salts induce enterocyte metallothionein and inhibit absorption of copper. So, we will have copper excretion in the feces. So, when we look at the urinary copper excretion in patients on zinc salt, they will have low urinary copper excretion.

So, what are side effects? D-penicillamine is the main treatment that induces side effects in 20% to 30% of patients. We can have early side effects with acute sensitivity reactions, subacute and late side effects with leukopenia, thrombocytopenia, even nephrotoxicity, including nephrotic syndrome. Lately, immunological disease and even skin disease can appear on d-penicillamine. Trientine salts have rarer side effects, mainly gastrointestinal disturbances. And zinc salts have common side effects, which are gastric irritation, nausea, and vomiting.

So, we have current guidelines, recommendations for treating Wilson disease. We have American and European guidelines, and all those guidelines have common features. For symptomatic patients, initial therapy guidelines recommend to use chelators, and American guidelines may propose to adjunct zinc salt to chelators. In an asymptomatic patient and in the maintenance phase of the treatments, both guidelines propose chelators or zincs, and usually, we propose to reduce the dose of chelating agents during this maintenance phase.

When you treat patients, you really have to monitor them – clinically, of course, but also biologically -- with classical biological assessment but also with copper balance assessment, urinary copper excretion, and non-ceruloplasmin-bound copper. When in the maintenance phase, twice a year is a good routine monitoring, but of course, at the beginning of the disease, we monitor this patient more frequently.

The objective of the treatment monitoring will be to have the urinary copper excretion adapted to the treatment. It should be between 3 and 8 μmol/d for chelators and below 1.6 μmol/d for zinc salts. Of course, you can look at the NCC, which should normalize under treatment.

Unfortunately, we have limitations with currently available treatments. First, the current treatments have established efficacy in 80% of patients, especially in those with liver manifestations. But for the brain, the efficacy is less, as we know that neurologic symptoms may persist in up to 50% of patients. The second limitation is that side effects are quite prominent, especially in d-penicillamine, so that can lead to treatment discontinuation. Pay attention also to zinc salt -- that could also lead to discontinuation of treatment due to gastrointestinal side effect. The third limitation is that adherence to treatment is not so high, with 40% of patients having this problem with adherence to treatment, and this is due to treatment regimens that require multiple daily dosing apart from meals.

So, thank you for joining our discussion, and please continue to the next module.

Chapter 4

Michael L. Schilsky, MD, FAASLD: Hello, I'm Dr Michael Schilsky, professor of medicine and surgery at Yale University and director of Center for Excellence for Wilson Disease at Yale. Welcome to this module titled "Evaluating Treatment Options in Wilson Disease, New Therapies and Future Directions."

Chelating agents, including penicillamine and trientine, are recommended as first-line therapies for symptomatic patients with Wilson disease. D-penicillamine has the labeling for first-line treatment. Severe adverse effects requiring discontinuation of d-penicillamine occur in approximately 30% of patients with long-term usage. Additionally, paradoxical neurologic worsening, rapid deterioration of neurologic function that usually occurs during the first 1 to 3 months of treatment initiation was reported in approximately 10% to 20% of patients during the initial phase of treatment with d-penicillamine.

Trientine is indicated for patients with Wilson disease who are intolerant to penicillamine, with less negative effects. Trientine exists as 2 salts, the dihydrochloride and tetrahydrochloride forms. The dihydrochloride form is not stable at room temperature and has cold storage requirements. The tetrahydrochloric form can be stored at room temperature and is more stable.

The TRIUMPH study compared the tetrahydrochloride form and the dihydrochloride form in healthy volunteers. There was a faster rate and greater absorption of the tetrahydrochloride form vs the dihydrochloride form, and this was observed about 56% greater area under the curve and 68% higher maximum concentration, with similar half-life and elimination rates.

In late April 2022, the tetrahydrochloride form was approved by the Food and Drug Administration (FDA) for the treatment of adult patients with stable Wilson disease who are de-coppered and tolerant to d-penicillamine. The most common adverse reactions included abdominal pain, change of bowel habit, rash, alopecia, and mood swings.

The CHELATE study, which was the pivotal study of the tetrahydrochloride form, was a randomized, open-label, noninferiority phase 3 trial in which the tetrahydrochloride form was compared with d-penicillamine. There was continuance of d-penicillamine treatment in patients or a switch to the tetrahydrochloride form of trientine for 24 weeks with a 24-week extension. The study cohort consisted of stable patients with Wilson disease who were on d-penicillamine, and 53 patients ultimately were randomized. This was the first clinical study to use liquid chromatography and inductively coupled plasma mass spec on speciated copper bound proteins in order to quantify the non-ceruloplasmin copper (NCC), the bioavailable copper, and this became the primary endpoint for this study.

Shown here are the results from the pivotal study. The urinary copper excretion differed between the d-penicillamine group, which is shown on the upper line in purple, and the trientine tetrahydrochloride group, who had less urinary copper excretion for each individual, on average, but well within the still acceptable range for treatment with trientine. Now, despite this difference, the bioavailable copper, as measured by the NCC using this special speciation assay, was statistically not different between these 2 groups. This suggests that there is possibly another mechanism by which the trientine is functioning, not just to excrete copper in the urine, but possibly to block copper by the non-absorbed portion of the drug that remains within the intestine.

Now, there is consideration for gene therapy for Wilson disease, and the background for that is that there is a lifetime need for medical therapy, and non-adherence in Wilson disease is not insignificant. So, the question is, could gene replacement therapy improve or augment current medical therapy? Now, from a practical aspect, there is the opportunity to introduce the gene into the liver, as well as continuing standard of care therapy, and then once it's determined that the gene therapy is functional, there can be withdrawal of the standard of care therapy, and then one can evaluate how effectively the gene therapy is working.

This is an example of how gene therapy, using the adeno-associated virus, can function and deliver DNA for the target into the liver cells. This particular virus has the capability of packaging the DNA, and it is a hepatotropic, that is if you inject it into the circulation, it goes to the liver mainly and it's bound by receptors where it is taken up into the cell and there it delivers its payload into the nucleus, where you end up with episomal DNA that has been delivered, and this is not integrated into the genome. Integration of the DNA that's delivered by this method is extraordinarily rare, and that's important for the safety of this particular, vehicle.

There are currently 2 gene therapy trials in Wilson disease in adult patients, the GATEWAY trial, the phase 1/2 trial using VTX801, an investigational gene therapy, and the clinical study of UX701 adeno-associated virus mediated gene transfer.

Both of these use the adeno-associated mediated virus with a form of the ATP7B gene that fits within the viral vector, and they are at study sites worldwide. Shown to the left here are 2 of the preclinical studies showing that these mini genes that were placed into the vectors were effective in restoring copper balance in the rodent models of Wilson disease, and therefore, they have progressed to clinical studies in patients.

Thank you for joining our discussion. Please continue on to the next module.

Chapter 5

Michael L. Schilsky, MD, FAASLD: Hello, I'm Dr Michael Schilsky, professor of Medicine and Surgery at Yale University and director of Center of Excellence for Wilson Disease at Yale. Welcome to this module entitled, "Integrating New Treatments into Practice: Real-World Case in Wilson Disease."

I present to you a 37-year-old male who had newly diagnosed Wilson disease. His evaluation showed liver disease with advanced fibrosis and elevation of liver tests, and he had concurrent neurologic symptoms, including tremor and dysarthria. Now, it's important to stage the liver disease in patients, and the options for this include liver biopsy, imaging of the liver, that in particular, if coupled to elastography, can sometimes give similar information that you can gain from the biopsy. In patients with advanced fibrosis and cirrhosis, use of the Model for End-Stage Liver Disease (MELD) score, and in particular, for those with very advanced disease where there's consideration for liver failure, the use of the new Wilson Index, which is one of the only prognostication indexes for Wilson disease, can be helpful to define that medical therapy is still useful for patients.

For evaluation of the neurologic disease and examination by a qualified neurologist, especially movement disorder specialists, the use of the Unified Wilson Disease Rating Scale can be very helpful. This is a scale that was designed for use in patients with Wilson disease and contains many of the different elements that are important in their evaluations. In addition, brain imaging can be helpful. In particular, magnetic resonance imaging (MRI) is preferred over computed tomography (CT) scan; however, the utility of this sometimes is to exclude other diseases as well, and you cannot entirely prognosticate the disease just from a single imaging.

With respect to choices of initial therapy, the American Association Study for Liver Disease guidance that was released in 2022 recommends chelation therapy for symptomatic patients. D-penicillamine has the labelling as first line for initial treatment, and trientine is labeled for penicillamine-intolerant patients with respect to treatment initiation.

This particular patient was started on d-penicillamine therapy that was slowly ramped up over a 2-month period to reach approximately 15 mg/kg, and in this individual, it was very well tolerated. He remained on this treatment for several years, the liver tests normalized, and he had minimal residual neurologic symptoms.

In time, he took a new job, which required a great deal of travel, and he had problems maintaining refrigeration of his medication. He was looking for another way to eliminate the need to keep the product refrigerated during his travels. Therefore, he changed from d-penicillamine to the trientine tetrahydrochloride compound, and to note that this compound is approved for d-penicillamine tolerant patients. In this particular instance, he underwent a milligram-for-milligram change of dosing. He then did testing to determine how well the change in therapy was working. He did a 24-hour urine copper, and he noted that the urine copper was only 210 µg in the 24-hour period, whereas previously he was excreting 370 µg. Importantly, there were no changes in his liver tests, and his serum copper remained the same.

Now, as discussed previously, in the CHELATE study, which was the head-to-head d-penicillamine study for maintenance therapy for Wilson disease, the milligram-for-milligram conversion from d-penicillamine to the tetrahydrochloride compound for trientine did result in a reduced copper excretion. However, importantly, it didn't cause an increase in the bioavailable copper as measured by the non-ceruloplasmin copper speciation assay.

Now, monitoring for maintenance therapy typically is done at 6-month intervals for patients, and this testing should include basic metabolic to look at renal function as well as electrolytes, a liver panel, as well as blood counts and an international normalized ratio (INR) in particular, for patients who have advanced fibrosis. Urine studies should include urine analysis, looking for any changes in protein excretion as well as any cellular elements that are present to exclude nephritis and a 24-hour urine for copper, and volume should be performed to look at the copper excretion.

This is an example of the copper speciation assay that was used in the CHELATE study, and this is shown for a nonaffected individual. But you can see in this assay that each of the peaks of the proteins -- one is labeled copper albumin, the other is labeled copper ceruloplasmin -- are separated, and you can measure from the individual peaks the quantity of copper within that individual protein. To determine the non-ceruloplasmic copper, you can measure that in the ceruloplasmic peak and subtract that from the total copper. And this is highly reproducible and highly accurate, and therefore, we think this will be an advance in the future.

Now, there is a real-world evidence study in patients with Wilson disease, which aims to describe the non-ceruloplasmic copper values using this speciation assay by taking additional blood samples from patients with Wilson disease at the time of their routine blood work. This study began in June 2023, and it's expected to be completed in December 2025. And unlike the CHELATE study, which looked at only the patients on d-penicillamine or on tetrahydrochloride, this includes all patients with Wilson disease on all different therapies.

In conclusion, it's extremely important before embarking upon treatment to know that your diagnosis is firmly established, because medical therapy is lifelong. The treatment choice should take into account whether the patient is symptomatic or not, and the staging of disease can help establish baselines and potentially prognosticate treatment for patients with advanced disease. Trientine is approved as maintenance therapy for patients with stable disease, and the tetrahydrochloride form of this compound is a nonrefrigerated option. The non-ceruloplasmic copper is a useful endpoint for treatment, but it does require further validation outside of patients with stable disease before it can be generally used for monitoring and for response-guided dosing of medication for treating Wilson disease. Unmet needs still exist for patients with Wilson disease, and clinical trials will help evaluate new therapies and help us with testing for monitoring as well.

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