Investigational Agent ALXN1840 Demonstrates Superior Efficacy to Standard of Care in Wilson Disease

Newly announced 48-week findings from a phase 3 randomized, controlled, rater-blinded trial (NCT03403205) showed that ALXN1840 (AstraZeneca), an investigational copper (Cu)-binding agent that forms a stable tripartite, was superior to standard of care (SoC) in the treatment of patients with Wilson disease (WD).

Led by Karl H. Weiss, MD, head of Liver Transplant Section, Universitats Klinikum Heidelberg, the study included 214 patients with WD, aged at least 12 years old with preserved liver function. The study assessed mean daily area under the effect-time curve of directly measured non-ceruloplasmin-bound Cu over a 48-week period (dNCC AUEC0-48W) as the primary end point, with change in neurological Unified WD Rating Scale (UWDRS) Part II and III scores, and Clinical Global Impression-Improvement (CGI-I) scores as secondary outcomes.

Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, patients were randomly assigned 2:1 to either ALXN1840 or SoC, which consisted of penicillamine, trientine, and/or zinc. ALXN1840 was administered orally at doses ranging from 15 mg every other day (QOD) up to a titrated dose of 60 mg daily. The study consisted of 2 cohorts. Cohort 1 included participants who received SoC therapy for more than 28 days while those in Cohort 2 were treatment-naïve or had received SoC therapy for less than 28 days.

In total, 207 patients were treated, 137 with ALXN1840 and 70 with SoC. After 48 weeks of treatment, mean daily dNCC AUEC was 3.2 times greater with ALXN1840 than with SoC overall (least square means [LSM] difference, 2.18 [SE, 0.244]; P <.0001), and 2.5 times greater with ALXN1840 for Cohort 1, despite a mean prior SoC duration of more than 12 years. Over this time period, investigators observed modest reductions in UWDRS scores in symptomatic patients on ALXN1840 (mean change in Part III score: –2.91 [95%, –4.74 to –1.09]; Soc: –1.17 [95% CI, –3.20 to 0.86; P = NS).

Patients treated with ALXN1840 showed superior scores on CGI-I after 48 weeks (LSM difference, –0.3 [SE, 0.15]; P = .0316). Throughout the treatment period, 100.1 and 86.5 patients on ALXN1840 and SoC, respectively, experienced adverse events (AEs)/100 patient-years; however, most of them were not serious (ALXN1840: 94.1%; SoC: 92.7%). For ALXN1840-treated individuals, the most frequent AE was alanine transaminase increase, occurring in 14.6% of patients. Two deaths, considered unrelated to ALXN1840, were reported.

WD, a rare inherited disorder diagnosed typically between the ages of 5 and 35, can result in several complications, which can lead to death if untreated. Of these include scarring of the liver, liver failure, persistent neurological issues, and other kidney, psychosocial, and blood problems. Tremors, involuntary muscle movements, gait and speech issues gait typically improve with treatment, but some patients continue to have persistent difficulties despite treatment.

ALXN1840, an oral, targeting decoppering therapy, has a unique mechanism of action. While other chelators promote the elimination of copper through the urine, ALXN1840 decreases plasma non-ceruloplasmin-bound copper by building tripartite complexes with albumin, targets hepatic intracellular copper, and accelerates biliary copper excretion.

Prior to the phase 3 trial, ALXN1840 was successful in an open-label phase 2 study (NCT02273596) that featured 28 individuals with WD. In the study, patients received ALXN1840 monotherapy with response-guided individualized dosing for a maximum of 42 months. At baseline, 57% (16 of 28) and 89% (25 of 28) of individuals had abnormal UWDRS parts II and II scores, respectively. After 124 weeks of treatment, significant improvements (P <.05) from baseline were seen in UWDRS parts II and III scores for the total population and both cohorts, which were divided based on prior WD treatment.