Wilson’s Disease Presents Unique Challenges and Demand for Novel Treatment Therapies

Wilson’s disease is a rare genetic disorder caused by mutations in the P-type ATPase gene. Wilson’s disease causes defective biliary excretion of copper, leading to its accumulation, particularly in the liver and brain. The ATP7B gene is responsible for the transportation of copper from the liver to the intestine to be defecated from the body, failure from which leads to accumulation of copper in the liver, brain, eyes, and other organs, causing life-threatening organ damage. As Wilson’s disease affects various systems in the body, affected individuals tend to develop various signs and symptoms. Some of the Wilson’s disease symptoms include chronic liver disease (jaundice, swelling, abnormal fluid retention, weight loss, nausea, and others), and neurologic symptoms (tremors, difficulty walking, speech problems, impaired thinking ability, depression, anxiety, and mood swings), among others. Wilson’s disease progression if left untreated, may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early symptoms of Wilson’s disease can lead to proper diagnosis and treatment may prevent serious long-term disability and life-threatening complications. Wilson’s disease treatment is life-long and aimed at lowering copper levels to nontoxic levels, and at preventing the progression of the disease. Also it’s goal is to reverse any symptoms of Wilson’s disease that have appeared because of copper accumulation in the body. Wilson’s disease treatment may be divided into three parts: first, treatment of symptomatic patients; second, maintenance therapy after the copper has been reduced in affected tissues; and third, in asymptomatic Wilson’s disease patients, maintenance therapy may be used from the beginning.

Wilson’s disease condition include a combination of liver disease and neurological and psychiatric problems. Wilson’s disease liver effecting is typically the initial feature in children and young adults. Individuals whose Wilson’s disease diagnosis is done at an older age usually do not have symptoms of liver problems, although they may have very mild liver disease. Liver disease signs and symptoms include yellowing of the skin or whites of the eyes (jaundice), fatigue, loss of appetite, and abdominal swelling. Nervous system or psychiatric problems are often the initial Wilson’s disease features in individuals diagnosed in adulthood and commonly occur in young adults. Symptoms of Wilson’s disease in young adults include clumsiness, tremors, difficulty walking, speech problems, impaired thinking ability, depression, anxiety, and mood swings.

Wilson’s Disease Epidemiology

Although damage due to Wilson’s disease begins as early as 6 years of age, symptoms are visible only in adolescence or early adulthood. The epidemiological studies related to Wilson’s disease are less in number and quote a similar prevalence throughout. Some genetic studies indicate a higher prevalence, and the reasons for inconsistency may be due to low rates of diagnosis and misdiagnosis. Wilson’s disease remains difficult to diagnose indication, and Wilson’s disease diagnosis has been historically based on clinical history, genetic testing, and biochemical evaluation; however, low sensitivity and specificity often lead to failure. Additionally, most symptoms are not specific, and varied clinical manifestations make diagnosis challenging.

This autosomal recessive disorder affects approximately 30,000-40,000 people worldwide, and around 1 in 90 individuals are carriers of its faulty gene. Assessments as per DelveInsight’s analysts showed that in Japan, the highest Wilson’s disease cases were found to be symptomatic which is around 2000 cases; whereas asymptomatic cases were around 300 in 2021. As per our analysis, Wilson’s disease symptoms-specific cases are expected to increase by 2032.

Assessments as per DelveInsight’s analysts showed that there were more than 500 cases with Hepatic manifestation, around 200 cases with Neurologic manifestation, more than 100 Neuro-hepatic cases and around 100 cases with other Wilson’s disease manifestations in France in 2021. DelveInsight estimates that the Wilson’s disease prevalence of these manifestations will increase by 2032.

DelveInsight’s analysts also indicated that in 2021, in Germany there was around 900 cases of WD, which was diagnosed and will increase by 2032.

Wilson’s disease epidemiology segmentation constitutes for the prevalent cases of Wilson’s disease, diagnosed cases of Wilson’s disease, prevalent cases of Wilson’s disease based on clinical manifestation, and prevalent cases of Wilson’s disease based on symptoms. 

The total prevalent Wilson’s disease patient population in the 7MM countries was estimated to be about 37,000 cases in 2021.

Wilson’s Disease Treatment Market

Wilson’s disease management requires a multidisciplinary approach. Life-long Wilson’s disease treatment aims to promote the removal of accumulated copper from the body to non-toxic levels and to reverse the signs and symptoms due to the accumulation of copper in the body. The conventional drug therapy for Wilson’s disease include treating symptomatic individuals, their maintenance after reducing copper, and advising maintenance therapy among asymptomatic individuals. The current Wilson market is valued at around USD 300 million, and there is just one late-stage product and two gene therapies in the pipeline. The several promising novel therapies, including chelators targeting specific cell types and cell- based and gene therapies, may revolutionize the care for Wilson’s disease patients. However, timely clinical diagnosis remains the main challenge, and many unmet needs exist because of possible clinical deterioration in treated patients.

Among the 7MM, the United States had the highest Wilson’s disease market share in 2021, which accounted for approximately 42% of the total 7MM market. The overall Wilson’s disease market size was around USD 120 million in 2021. DelveInsight’s analysts estimate that the market will show positive growth by the end of 2032.

In 2021, the Wilson’s disease market for the EU-5 was worth approximately USD 100 million. The Wilson’s disease market is expected to grow at a noticeable CAGR over the forecast period as per DelveInsight’s estimates. The Japanese Wilson’s disease market was a little under USD 70 million in 2021. DelveInsight’s forecasts a significant growth in the market size by 2032.

Barriers and Challenges in Wilson's Disease Management

To begin with, researchers are aware of the diagnostic shortfalls. Biomarkers like ceruloplasmin and copper in the liver or 24 h urinary copper analysis are available but are of lesser significance. The absence of biomarkers or Wilson’s disease screening tests in the pediatric population can be another issue leading to no early diagnosis. Next comes challenges in the Wilson’s disease treatment landscape. Currently with no Wilson’s disease cure available, lifelong treatment is necessary to prevent the lethal symptoms. Although current Wilson’s disease treatment with chelating agents and zinc has improved the patients’ disease burden and quality of life. However, multiple dosages and severe side effects lead to poor adherence among the cohort. Outdated guidelines comprising of unbalanced recommendations exacerbate the problem. Furthermore, the lack of research studies for both epidemiology (patient registries) and treatment (including trials) related data adds to the challenges of gathering evidence related to the quality of life among Wilson’s disease patients.

The Future Treatment Landscape Looks Promising

A number of Wilson’s drugs are available for treatment, including D-penicillamine, trientine, zinc, tetrathiomolybdate, and dimercaprol. Once the Wilson’s disease diagnosis has been made, treatment needs to be lifelong. Wilson’s disease treatment ncludes three types of medications. First, those that remove (chelate) copper from the body by urinary excretion, such as penicillamine (Cuprimine) and trientine dihydrochloride (Syprine); second, zinc salts to prevent the gut from absorbing copper from the diet; and third, tetrathiomolybdate which both prevents absorbing copper and binds up toxic copper in the blood making it nontoxic.

Wilson’s disease patients who present symptomatically with mild to moderate liver failure can be effectively treated with a combination of trientine and zinc for 4–6 months and then go on maintenance therapy with zinc or trientine alone. A second choice would be penicillamine and zinc, but penicillamine has more side effects than zinc. Patients with severe liver failure may require liver transplantation. Patients who present neurologically can best be treated with tetrathiomolybdate, but it is not commercially available as yet. The second choice is zinc alone. Zinc is rather slow-acting but does not cause the drug catalyzed worsening, so common with trientine and penicillamine. Trientine and penicillamine are poor choices to treat neurologically presenting patients because of the high frequency of neurological worsening, from which many Wilson’s disease patients never recover.

Newborn Wilson’s disease screening tests are being prioritized in some geographies. For this, research and development are underway. As patients are becoming intolerant to chelating agents like penicillamine, the development of newer treatment choices has been emphasized. The recent FDA approval of Cuvrior marks achieving a better and tolerable safety profile. In addition, many other therapies are being assessed in this area – key Wilson’s disease market players include AstraZeneca, Vivet Therapeutics, Pfizer, Ultragenyx Pharmaceutical Inc., and others. AstraZeneca is developing a potential new once-daily oral medicine designed to be the first targeted de-coppering therapy. Vivet Therapeutics and Ultragenyx Pharmaceutical investigate a replication-deficient recombinant adeno-associated viral vector (rAAV-based gene therapy vector) and adeno-associated virus serotype 9 (AAV type 9) based gene therapies, respectively for Wilson’s disease treatment. The advent of these innovative Wilson’s disease therapies will reinvigorate the treatment landscape and better patient compliance.  Payer reimbursement for the costly Wilson’s disease gene therapies would be a challenge, and being in a nascent stage, gene therapies have to prove their cost-effectiveness.

Wilson’s Disease Emerging Drugs

To meet the current demands of the patient pool and to counter the unmet needs of the therapeutic Wilson’s disease market, drug developers are gradually shifting their attention toward the disease as a possible indication for new targeted therapies. Several companies are working robustly on many new Wilson’s disease therapies, includes ALXN1840 (AstraZeneca), VTX-801 (Vivet Therapeutics/ Pfizer), and UX701 (Ultragenyx Pharmaceutical). The mid-stage Wilson’s disease pipeline is crowded, with several potential therapies with the imminent attention of big pharmaceutical companies for this market space.

ALXN1840 (AstraZeneca) is a potential new once-daily oral medicine in development for Wilson’s disease. It is designed to be the first targeted de-coppering therapy that selectively and tightly binds to, and removes, copper from the body’s tissues and blood. The Wilson’s disease drug is currently in Phase III trial (FOCUS), with positive high-level results from the trial. ALXN1840 met the primary endpoint with a statistically significant improvement in daily mean copper mobilization from tissues, demonstrating superiority compared with standard-of-care (SoC) treatments. The drug has been granted Orphan Drug Designation in the US and EU for Wilson’s disease treatment. The trial enrolled 214 patients, including treatment-naïve participants and those who have been on SoC therapy for an average of 10 or more years. ALXN1840, a potential new oral medicine, demonstrated approximately three times greater copper mobilization than SoC.

UX701 (Ultragenyx Pharmaceutical) is an investigational AAV type 9 gene therapy designed to deliver a stable expression of a truncated version of the ATP7B copper transporter following a single intravenous infusion. The Wilson’s disease therapy has been shown in preclinical studies to improve copper distribution and excretion from the body and reverse pathological findings of Wilson liver disease. UX701 is currently in Phase I/II/III. The company has also received FDA IND clearance, which allows for advancing this new gene therapy in the clinic and hopes for a new treatment for patients with WD. UX701 has the potential to directly address the underlying basis of disease by restoring the normal transport and excretion of copper. The therapy was granted Orphan Drug Designation in the United States.

The Path Forward

Timely commencement of Wilson’s disease treatment achieved through early diagnosis is the key to managing the disease effectively. Clarity among recommendations gathered through thorough clinical evidence can help smoothen the management process. As more key pharma companies develop potential Wilson’s disease drug candidates and new players begin to focus on this indication, patients will eventually have plenty to choose from. With the launch of these promising agents, Wilson’s disease market is expected to grow with a significant CAGR. However, the high price of these therapies can be troublesome and must be kept in check.