June 23, 2022, 12:35 PM UTC
ALXN1840 Shows Rapid and Sustained Improvement in Copper Mobilization From
Tissues, Potentially Closing Treatment Gaps for Wilson Disease Community
FoCus Phase III trial evaluates new approach to copper mobilization for
patients with Wilson disease who have not seen meaningful innovation in
In Wilson disease, excess copper build-up in organs and tissues can lead to
liver disease as well as neurological and psychiatric symptoms
WILMINGTON, Del. – June 23, 2022
Detailed results from the positive FoCus Phase III trial in Wilson disease
showed that ALXN1840, an investigational once-daily, oral medicine, met its
primary endpoint demonstrating three-times greater copper mobilization from
tissues compared to the standard of care (SoC) arm (Least Square Mean
Difference [LSM Diff] 2.18 µmol/L; p< 0.0001), including in patients who had
been treated previously for an average of 10 years.^1
In the trial, people taking ALXN1840 experienced rapid copper mobilization,
with a response at four weeks and sustained through 48 weeks.^1
Results from the trial will be presented on June 23 at the 2022 International
Liver Congress (ILC) in London.
Wilson disease is a rare and progressive genetic condition in which the body’s
pathway for removing excess copper is compromised. This may result in the
accumulation of copper in a person’s liver, brain or other vital organs.
Damage from excess copper build-up in tissues and organs may lead to symptoms
of liver, neurological and psychiatric diseases, which may be
irreversible.^2,3,4 Even after SoC treatment is initiated, some patients
experience worsening of disease, especially of neurologic symptoms.^3,4
Change in neurological scale scores and clinician-reported functional
assessments with ALXN1840 treatment were also evaluated in a post-hoc analysis
as secondary endpoints in the Phase III trial.^1
In patients who were symptomatic at baseline, there were greater improvements
in neurological scores for those treated with ALXN1840 compared to SoC
(Unified Wilson Disease Rating Scale [UWDRS] part II symptomatic ALXN1840
-1.7, SoC -0.8; UWDRS Part III symptomatic ALXN1840 -2.91, SoC -1.31).
However, there were no significant differences between treatment groups
observed at 48 weeks.^1
Most patients in the trial had low symptom scores at baseline, so there was
minimal room for total score improvement (UWDRS Part II ALXN1840 -0.6, SoC
-0.3; UWDRS Part III ALXN1840 -2.20, SoC -1.02).^1 As people with Wilson
disease experience a highly varied degree of symptoms^4, this total score may
not reflect the extent of disease severity.
ALXN1840 was well tolerated and the long-term safety and efficacy of ALXN1840
is being assessed in an up to 60-month extension period.^1
Professor Karl Heinz Weiss, MD, Director of the Department of Internal
Medicine at Salem Medical Center Heidelberg and investigator in the FoCus
Phase III trial, said: “These data from the largest global trial in Wilson
disease to date show significant copper mobilization from the tissues with
ALXN1840, even in patients who were on standard of care for over a decade on
average. These results have the potential to reframe the way doctors can think
about the disease given that current therapies focus on removing copper from
the blood. We are also encouraged by initial neurological improvement with
ALXN1840 in those who were symptomatic and believe that assessing individual
patient experiences may provide a better understanding of the impact on daily
Marc Dunoyer, Chief Executive Officer, Alexion, said: “Many people with Wilson
disease continue to experience symptoms even after years of intervention with
current therapies, illuminating an urgent need to re-evaluate the standard of
care. Applying our 30 years of experience in rare disease clinical
development, Alexion has conducted rigorous scientific research to bring fresh
thinking to Wilson disease around the importance of copper mobilization from
the tissues. These data further our efforts to potentially introduce a novel
treatment for patients who have gone decades without meaningful innovation.”
Summary of efficacy and safety results^i
The primary endpoint gauged the daily mean Area Under the Effect Curve (AUEC)
for directly measured non-ceruloplasmin-bound copper (dNCC)^ii over 48 weeks.
^ The dNCC parameter includes copper bound in an inert complex with
Cohort 1^iii Cohort 2^iii
Treatment-experienced Naïve/minimally Total
ALXN 1840 SoC ALXN 1840 SoC ALXN SoC
N = 104 N= 56 N = 33 N = 14 1840 N = 70
N = 137
n^iv 91 51 27 12 118 63
Mean (Standard 2.68 0.72 (0.643) 4.58 1.09 3.12 0.79
Deviation) (2.118) (2.526) (0.484) (2.347) (0.629)
LSM^v 2.50 0.87 (0.204) 4.76 0.96 3.18 1.00
(Standard Error) (0.150) (0.319) (0.487) (0.167) (0.219)
LSM Difference ^ 1.64 (0.254) 3.79 (0.584) 2.18 (0.244)
p-value <0.0001 <0.0001 <0.0001
1. Results analyzed using ANCOVA model, model included treatment, cohort, and
baseline value. For cohort analysis, analysis was performed on each cohort
using ANCOVA model, cohort term was removed from model. Analysis results
were combined using Rubin’s rules.
2. Daily Mean AUEC for dNCC measured in µmol/L.
3. Cohort 1= Prior WD Treatment >28 days; Cohort 2= Treatment Naïve or Prior
WD Treatment ≤ 28 days.
4. Patient numbers for calculation of mean; all patients were included in the
calculation of LSM, LSM difference and p values.
5. LSM is a statistical method that determines the line of best fit for a
Most adverse events (AEs) were not considered serious (ALXN1840, 85.4%; SoC,
75.7%) and/or were not considered related to trial treatment (ALXN1840, 77.4%;
SoC, 75.7%). The most common AE associated with ALXN1840 was a reversible
increase in alanine aminotransferase levels (ALXN1840, 14.6%; SoC, 2.9%). Two
deaths were also reported but were unrelated to ALXN1840.^1
In addition to the Phase III trial, two ongoing mechanistic trials in Wilson
disease are also underway. Alexion is working closely with health authorities
worldwide and intends to submit these data for review.
Wilson disease is an inherited condition in which the body’s pathway for
removing excess copper is compromised. Over time, that results in the build-up
of excess copper levels in the liver, brain and other organs leading to damage
that greatly impacts patients.^2
Although the disease is present at birth, the age of diagnosis occurs between
five to 35 years.^3,4 People can develop a wide range of symptoms, including
liver disease and/or psychiatric or neurological symptoms.^2,3,4
FoCus (301) is a pivotal Phase III, randomized, controlled, rater-blinded
trial designed to evaluate the efficacy and safety of ALXN1840 versus SoC in
patients with Wilson disease aged 12 years and older. The primary endpoint
assessed copper mobilization over 48 weeks, defined as daily mean AUEC for
dNCC. In the trial, 214 patients were enrolled in one of two cohorts on a 3:1
basis (treatment-experienced:treatment-naïve). Each cohort was then randomized
2:1 (ALXN1840:SoC). The first cohort enrolled 161 patients who received SoC
(chelation therapy with penicillamine or trientine, zinc therapy or a
combination of both chelation and zinc therapy) for more than 28 days and the
second cohort enrolled 53 patients who were treatment-naïve or had received
SoC for 28 days or less.^1,5 Key secondary endpoints assessed over the 48-week
period included change in neurological function as measured by the UWDRS Part
II and III.^1
ALXN1840 is a potential new once-daily, oral medicine in development for the
treatment of Wilson disease. This investigational, novel molecule is designed
to selectively and tightly bind to and remove copper from the body’s tissues
and blood. ALXN1840 has been granted Orphan Drug Designation in the United
States and orphan designation in the European Union for Wilson disease.
Alexion, AstraZeneca Rare Disease, is the group within AstraZeneca focused on
rare diseases, created following the 2021 acquisition of Alexion
Pharmaceuticals, Inc. As a leader in rare diseases for 30 years, Alexion is
focused on serving patients and families affected by rare diseases and
devastating conditions through the discovery, development and
commercialization of life-changing medicines. Alexion focuses its research
efforts on novel molecules and targets in the complement cascade and its
development efforts on hematology, nephrology, neurology, metabolic disorders,
cardiology and ophthalmology. Headquartered in Boston, Massachusetts, Alexion
has offices around the globe and serves patients in more than 50 countries.
For more information, please visit www.alexion.com.
AstraZeneca is a global, science-led biopharmaceutical company that focuses on
the discovery, development and commercialization of prescription medicines in
Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular,
Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK,
AstraZeneca operates in over 100 countries, and its innovative medicines are
used by millions of patients worldwide. For more information, please visit
www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
1. Weiss, KH., Schilsky, M., et al. Efficacy and safety of ALXN1840 versus
standard of care in Wilson disease: primary results from an ongoing phase
3, randomized, controlled, rater-blinded trial. Oral presentation at:
International Liver Congress (ICL or EASL); June 23, 2022; Abstract No.
2. Patil, M., et al. (2013) J Clin Exp Hepatol, 3, 321-336.
3. Roberts, E.A., Schilsky, M.L. American Association for the Study of Liver
D. (2008). Diagnosis and treatment of Wilson disease: An update.
Hepatology, 47(6), 2089-2111.
4. European Association for the Study of the Liver. (2012). EASL clinical
practice guidelines: Wilson’s disease. J Hepatol, 56(3), 671-685
5. ClinicalTrials.gov. Efficacy and Safety of ALXN1840 (Formerly Named
WTX101) Administered for 48 Weeks Versus Standard of Care in Participants
With Wilson Disease With an Extension Period of up to 60 Months. NCT
Identifier: NCT03403205. Available online. Accessed May 2022.