Trial supported Orphalan’s successful application to the United States Food and Drug Administration (FDA) for approval of Cuvrior™ (trientine tetrahydrochloride) for Wilson’s disease
Paris, France 30 September, 2022 – Orphalan SA (“Orphalan” or “the Company”), an international orphan drug development and commercialization company, today announces the publication of the Company’s phase III CHELATE trial in The Lancet Gastroenterology & Hepatology1, presenting the efficacy and tolerability of trientine tetrahydrochloride for the treatment of Wilson’s disease over a period of one year.
The CHELATE trial was the first prospective randomized trial comparing penicillamine with trientine tetrahydrochloride (TETA-4HCl), and supported Orphalan’s successful application to the United States Food and Drug Administration (FDA) for approval of Cuvrior™, an oral TETA-4HCl formulation for the treatment of adult patients with stable Wilson’s disease who are de-coppered and tolerant to penicillamine. It was the first treatment for Wilson’s disease to be approved by the FDA in over five decades.
During the trial, an innovative assay was developed to measure non-caeruloplasmin bound copper (NCC), the free and potentially toxic pool of copper in the blood. This assay measures NCC by separation and quantification of caeruloplasmin and its bound copper in serum with greater accuracy and precision than methods used in clinical practice today.
Using this NCC measurement, TETA-4HCl was determined to be non-inferior to penicillamine at the primary endpoint of the study (24 weeks), with the same observation at the end of the extension phase of the study (one year from randomization) in patients previously receiving maintenance penicillamine therapy.
Trial design and results
53 adult patients receiving maintenance penicillamine therapy for at least a year, were randomized to switch to TETA-4HCl (n=26) or continue with penicillamine (n=27) once stability was confirmed by three independent Wilson’s disease experts. These experts, blinded to treatment allocation, re-assessed patient data to determine clinical stability, at the primary endpoint (24 weeks) and at the end of an extension period (48 weeks).
After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was –9·1 micrograms per liter (mcg/L; 95% CI –24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin of minus (-50 mcg/L). The mean difference in serum NCC remained non-inferior at 48 weeks.
All evaluations of patient well-being during the study (measured using the Unified Wilson’s Disease Rating Score, a standardized neurological evaluation, cognition testing, and clinician global impression of change) remained unchanged from baseline to both 24- and 48-week endpoints. In addition, the three independent Wilson’s disease experts confirmed all participants as stable at both the primary endpoint and at 48 weeks.
TETA-4HCl was well tolerated with no serious adverse events (SAE) reported, compared with five SAEs for penicillamine in the 48-week study period. Dr Omar Kamlin, Senior Medical Director, Orphalan, commented:
“Wilson’s disease is a rare inherited disorder of copper transport, primarily affecting the liver and brain, which can be fatal if left untreated. The results of the CHELATE trial mark an important milestone for the Wilson’s disease community, providing further evidence on the efficacy of trientine tetrahydrochloride for prescribing physicians and evidence-based options for patients. Our thanks go to everyone who supported the trial, especially the patients who participated for the benefit of this and future generations of individuals with Wilson’s disease.”
Professor Michael Schilsky, Director, Center for Excellence for Wilson Disease at Yale, stated:
“This is an important study and underlines the need for more options for patients with this rare and challenging disease. The non-inferiority of TETA-4HCl to penicillamine over 48 weeks is extremely reassuring and raises the question of whether penicillamine should remain first line therapy for patients with Wilson’s disease who are on maintenance therapy after their initial de-coppering phase. We look forward to doing more research, especially with Cuvrior™ in real-world settings, and evaluating the potential of the NCC assay as a tool to monitor and guide therapeutic decision making and building on the findings published in The Lancet Gastroenterology & Hepatology.”
1 Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial, https://www.thelancet.com/journals/langas/article/PIIS2468-1253(22)00270-9/fulltext
Orphalan is a pioneering, international orphan drug development and commercialization company. Founded in 2011, the company develops and delivers innovative therapies for people living with orphan diseases, and is initially focused on Wilson’s Disease, a rare genetic disorder that can be life-threatening if untreated. Orphalan commercializes Cuprior®, its trientine tetrahydrochloride product for the treatment of Wilson’s disease in Europe, and will be launching Cuvrior™, recently approved by the FDA, in the US. For more information visit www.orphalan.com and follow us on LinkedIn.
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