Wilson's Disease

This is a multicenter, open-label, single-arm, single-dose Phase I/II clinical study. It aims to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of LY-M003 Injection in patients with Wilson's Disease (WD).

The goal of this clinical trial is to learn if a new trientine tetrahydrochloride (TETA 4HCl) formulation administered once a day compared to d-Penicillamine (DPA) as a first line treatment for people living with Wilson's disease (WD) is effective and safe. The study is enrolling children aged 8 years and older weighing at least 55 lb (25 kg) and adults with a recent diagnosis of WD. People recently diagnosed with WD, may be eligible for the study if they have either not started copper chelating treatment (such as DPA or trientine) or have been taking zinc salts for less than 28 days. Participants will be randomly allocated (like tossing a coin) to receive either DPA or TETA 4HCL for 48 weeks. During this time period participants will have up to 12 visits for health checks and assessments including blood and urine testing. In addition, at some visits participants may be asked to complete questionnaires on treatment satisfaction, and overall well-being.

This study adopted an open, single-arm, non-randomized, dose-escalation research design, aiming to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetic and immunogenicity characteristics of single and multiple intravenous infusions of DSL101 in patients with Wilson's disease.

Heart damage by copper accumulation has been reported in Wilson's Disease. However, the disease epidemiology is still poorly understood. A number of studies on pediatric populations have not shown any significant cardiac involvement apart from early dysautonomia. This could suggest that the clinical manifestations related to the copper accumulation in the heart appears with the duration of the disease. Case-control studies on adult populations have highlighted various electrocardiographic (ECG) abnormalities more frequent in patients with Wilson's Disease than in healthy volunteers, but all these studies involved small number of patients (maximum 60). The hypothesis is that there is cardiac involvement in Wilson's Disease, requiring screening, follow-up and appropriate support.

Wilson's disease is a rare genetic disease, affecting less than 1,500 people in France. The transmission is autosomal recessive linked to an anomaly of the ATP7B gene on chromosome.This gene codes for an ATPase-type transmembrane protein involved in the transport of copper through the cell plasma member.This gene codes for an ATPase-type transmembrane protein involved in the transport of copper through the cell plasma member. If there is no mutation, this ATPase incorporates copper into apo-ceruloplasmin to be released into the blood serum. The mutation of the ATP7B gene results in a defective biliary excretion of copper, leading to its accumulation in the liver, but also in other organs such as the eye or the brain. Advances in treatment have dramatically changed the prognosis for Wilson's disease, making the desire for pregnancy more confident. The consensus is to maintain treatment during pregnancy, reducing the dosage to limit teratogenicity as well as the risk of fetal copper deficiency.The mammary gland is the primary site of copper metabolism in lactation, and ATPase 7B is the primary effector. It has been shown in a mouse model of Wilson's disease (ATP7B - / - mouse) with treatment, that mothers accumulate copper in the liver but also in the mammary gland. However, a recent study showed that the copper level in breast milk was normal in 18 Wilsonian patients treated with D-penicillamine, trientine salts or zinc salts, suggesting that breastfeeding is possible in these patients without risk to the development of the infants.The problem of breastfeeding newborns for patients with Wilson's disease is therefore associated with a risk of copper deficiency in the newborn due to insufficiently rich breast milk in copper due to drugs. In addition, the passage into breast milk of treatments is not sufficiently known. These factors make breastfeeding not currently recommended for Wilsonian mothers,However, many patients wish to breastfeed and some of them breastfeed their newborns despite the risk of breastfeeding

Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism, caused by mutations in the \*ATP7B\* gene, leading to impaired copper metabolism and toxic accumulation in many organs including the liver, brain, and cornea with subsequent hepatic and neuropsychiatric manifestations (Członkowska et al., 2018). Early diagnosis and adherence to lifelong dietary restrictions and chelation therapy are critical to prevent irreversible damage (Wang et al., 2017). WD is one of the few inborn metabolic diseases that can be successfully treated, and its complications can be prevented especially if diagnosed early and managed properly (Członkowska et al., 2018). However, in low-resource settings, patients often face barriers such as delayed diagnosis, poor awareness, limited access to care, and financial constraints (Miloh et al., 2018). The long-term nature of the disease, possibility of debilitating symptoms, requirement of life-long and daily oral intake of medicines, life-long avoidance of copper-rich foods, frequent visits to the doctor/hospitals and the need for regular investigations impact the day-to-day physical and emotional functioning of these patients, their social lives and interpersonal relationships (Unavane et al., 2022). WD affects the quality of life of not only the patients but also their families, and the impact on patients with neuro-WD is worse than that of patients with hepatic disease (Unavane et al., 2022). Despite treatment being occasionally available, patient adherence remains suboptimal due to a range of psychosocial, geographic, behavioral, and economic barriers (Członkowska et al., 2018). Numerous studies suggest that concordance with drug therapy including compliance (taking the prescribed dose), persistence (continuing treatment over time), and adherence (following timing and dietary instructions for medication intake (Cramer et al., 2008; Masełbas et al., 2010) is particularly poor among individuals with chronic illnesses. These challenges, which also affect patients' families, significantly hinder treatment outcomes (Masełbas et al., 2010). There is a paucity of research exploring these dimensions in low- or medium-income countries, particularly in the Middle East and North Africa (MENA) region. Despite the clinical importance of WD, there is a significant research gap in understanding the lived experiences of Upper Egyptian patients and their families. Specifically, there is limited data on knowledge, attitudes, behaviors and perceived barriers (KAB-pB) related to WD, which are essential for effective disease management and public health interventions. Health literacy and cultural beliefs often shape how patients perceive their illness, adhere to treatment, and engage with healthcare providers. In Upper Egypt, where educational and socioeconomic disparities persist, assessing KAB-B can illuminate barriers to care and inform targeted educational strategies. Moreover, caregiver burden, which is often overlooked in chronic disease research, plays a pivotal role in patient outcomes and deserves focused attention (Adelman et al., 2014; Albani et al., 2024; Macharia et al., 2023). Geographic access to care is another pressing concern. Patients from remote areas must travel long distances to reach the WD specialized centers facing high transportation costs, unreliable transit options, and logistical challenges that can delay diagnosis and treatment (Mseke et al., 2024). Mapping the geographic distribution of patients and their travel patterns will provide critical insights into healthcare inequities and support the development of decentralized or mobile care models. Additionally, for genetic disease like WD, geographic distribution gives insights into disease clustering of foci of mutations or social behaviors like increased consanguinity (Ferenci, 2006; Gomes \& Dedoussis, 2016). These findings can guide policymakers in designing more equitable healthcare systems that accommodate the needs of rare disease populations. Dietary management is central to WD treatment, as patients must avoid copper-rich foods such as legumes (like peas, lentils, barley, millet, wheat, bran, and fava beans), nuts, fresh sweet potatoes, in addition to chocolate shellfish, liver, and commercially dried fruits (Li et al., 2022). It is well-known that traditional Egyptian diets - especially in rural communities - often include the above legumes due to cultural preferences and economic constraints. Therefore, understanding how patients navigate these dietary restrictions within their cultural and financial realities is essential for crafting practical, culturally sensitive nutritional guidelines (Nemec, 2020). Additionally, the psychosocial burden of WD including stigma, emotional distress, and coping mechanisms remains underexplored in Upper Egypt. Studies from other contexts suggest that chronic neurological and psychiatric manifestations include depression, personality changes, and cognitive

This cross-sectional study investigates endocrine changes in children diagnosed with Wilson's disease, aiming to characterize hormonal dysfunctions affecting pituitary, thyroid, adrenal, and gonadal axes.

Longitudinal, observational, non-interventional, standard of care Registry. Data will be collected from the routinely scheduled WD clinic visits at approximately 6-12 month intervals. At enrolment, in addition to data from the clinic visit, retrospective data will be collected from the diagnostic evaluation and any relevant past medical history and a summary of WD medication history.

Wilson disease (WD) is a rare autosomal recessive disorder caused by a genetic defect in ATP7B resulting in limited excretion of excess copper into the bile Pathological copper accumulation occurs in the entire body, with the liver and the brain being primarily affected

The aim of this study is to determine the clinical spectrum and natural progression of Wilson's Disease in a prospective multicenter natural history study, to assess the clinical, genetic, epigenetic features and biomarkers of patients with Wilson's Disease to optimize clinical management.