Decuprate (bis-choline tetrathiomolybdate) / AstraZeneca - LARVOL DELTA

Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion. (PubMed, Nat Commun) - "Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects."

Journal • CNS Disorders • Oncology • ALDH1A1

AstraZeneca CEO defends 'fantastic' Alexion buyout in face of $753M hit from dropped drug (FierceBiotech) - "Buying Alexion remains a 'fantastic acquisition' for AstraZeneca, the Big Pharma’s CEO has said, even as the company takes a $753 million hit for abandoning one of the drugs from that acquisition...The drug in question, vemircopan, was once a hot prospect at AstraZeneca...the abandonment of other Alexion drugs in the form of ALXN1840 for Wilson disease and ALXN1820 for sickle cell disease...The drugmaker said....in its fourth-quarter clinical trials update that it stopped the studies because of a lack of efficacy. AstraZeneca used slightly different language when disclosing the broader termination of the program, attributing the decision to phase 2 safety and efficacy data."

Discontinued • Trial status • Genetic Disorders • IgA Nephropathy • Lupus Nephritis • Sickle Cell Disease

GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas (SNO 2024) - "The imipridones ONC201 and ONC206 have emerged as promising therapies for DMG patients, but efficacy as monotherapy is limited...Importantly, the clinically translatable GABAB receptor antagonist SGS742 and the SOD1 inhibitor ATN-224 exacerbate oxidative stress and synergistically induce apoptosis in combination with imipridones in DMG cells...Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for imaging drug-target engagement and for enhancing response to therapy. Clinical translation of our studies will enable precision therapy and imaging for DMG patients."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • ATF4 • SOD1

Efficacy and Safety of ALXN1840 Administered for 48 Weeks Versus Standard of Care in Participants With Wilson Disease (clinicaltrials.gov) - P3 | N=214 | Terminated | Sponsor: Alexion Pharmaceuticals, Inc. | Trial primary completion date: Feb 2021 ➔ Jun 2023

Trial primary completion date • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease. (PubMed, J Hepatol) - "While we did not show an increase in biliary excretion of Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal Cu uptake and retained Cu in the blood stream, limiting Cu exposure to organs like the liver and the brain."

Journal • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • Rare Diseases

Efficacy and Safety of ALXN1840 Administered for 48 Weeks Versus Standard of Care in Participants With Wilson Disease (clinicaltrials.gov) - P3 | N=214 | Terminated | Sponsor: Alexion | Trial completion date: Feb 2026 ➔ Jun 2023 | Active, not recruiting ➔ Terminated; Sponsor decision to terminate the program

Trial completion date • Trial termination • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Study of ALXN1840 Versus Standard of Care in Pediatric Participants With Wilson Disease (clinicaltrials.gov) - P3 | N=40 | Terminated | Sponsor: Alexion | Trial completion date: Dec 2024 ➔ Jun 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2024 ➔ Jun 2023; Sponsor decision to terminate the program

Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • Pediatrics

Efficacy and safety of tiomolibdate choline in Wilson disease: 96-week results from an ongoing phase 3 study (EAN 2023) - P3 | " At enrollment, 214 patients (aged >=12 years) were randomised to tiomolibdate (15mg every-other-day to 60mg daily) or SoC (penicillamine, trientine and/or zinc) for 48W. Treatment with tiomolibdate over 96W was generally safe and well-tolerated and was associated with sustained copper sequestration and improvement in neurologic symptoms."

Clinical • P3 data • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Copper Concentration & Histopathologic Changes in Liver Biopsy in Participants With Wilson Disease Treated With ALXN1840 (clinicaltrials.gov) - P2 | N=31 | Completed | Sponsor: Alexion | Active, not recruiting ➔ Completed

Biopsy • Trial completion • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Effects of tetrathiomolybdate on copper distribution and biliary excretion: a controlled 64CuCl2 PET/MRI (EASL-ILC 2023) - "Bis-choline tetrathiomolybdate (TTM) is a high affinity copper chelator with therapeutic potential in WD... PET/MRI is a useful tool for examining copper metabolism and mechanism of action of copper chelation therapy. TTM did not enhance biliary excretion of 64Cu after TTM administration to patients with WD, in contrast to earlier reports in rodents, suggesting an alternative mechanism of action for this drug. TTM initially acted to reduce exposure of the liver and other organs to Cu by retaining 64Cu in the plasma, but with time the copper may be redistributed."

Gastroenterology • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Effects of tetrathiomolybdate, trientine, and penicillamine on intestinal copper uptake: a randomized placebo-controlled 64Cu PET/CT study (EASL-ILC 2023) - "Treatments include D-penicillamine (PEN) and trientine tetrahydrochloride (TRI), which chelate Cu and cause cupriuresis, and the investigational copper binding agent bis-choline-tetrathiomolybdate (TTM). 64Cu PET/CT is useful for evaluating the effect of medical therapy on intestinal copper absorption and copper distribution in the body. The greater inhibition of intestinal copper absorption of TRI compared to PEN may explain recent observations of more urinary copper excretion with PEN but equal efficacy in treating WD patients. TTM markedly reduced hepatic 64Cu uptake, reducing both intestinal absorption and hepatic clearance by TTM-Cu-albumin complex formation."

Clinical • CNS Disorders • Gastroenterology • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • ATP7B

Monitoring of Copper in Wilson Disease. (PubMed, Diagnostics (Basel)) - "A new method to assess Cu metabolism during treatment with ALXN1840 (bis-choline tetrathiomolybdate [TTM]) has been developed...While many patients are diagnosed and adequately assessed with currently available methods, diagnosis and monitoring is a real challenge in a group of patients who are stuck with borderline results, ambiguous genetic findings, and unclear clinical phenotypes. Technological progress and the characterization of new diagnostic parameters, including those related to Cu metabolism, may provide confidence in the more accurate diagnosis of WND in the future."

Journal • Review • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Study of ALXN1840 Versus Standard of Care in Pediatric Participants With Wilson Disease (clinicaltrials.gov) - P3 | N=40 | Active, not recruiting | Sponsor: Alexion | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • Pediatrics

Efficacy and safety of tiomolibdate choline in patients with an incomplete or intolerant response toprior Wilson disease therapy: subgroup analysis of the phase 3 FoCus trial (EASL-ILC 2023) - No abstract available

Clinical • P3 data • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Efficacy and safety of tiomolibdate choline versus standard of care in patients with Wilson disease with and without compensated cirrhosis: sub-analysis of an ongoing phase 3, randomized, controlled study (EASL-ILC 2023) - No abstract available

Clinical • P3 data • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Movement Disorders

"2021 story on ALXN1840 and what else is/was going on in Wilson's disease, via @ByMadeleineA -> https://t.co/jDUpXY04vs $RARE $PFE $AZN" (@JacobPlieth)

Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

"$AZN says discontinuation of Wilson's disease project ALXN1840 came after review of ph2 mechanistic data & discussions with regulators" (@JacobPlieth)

Review • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Efficacy and Safety of ALXN1840 Versus Standard of Care in Wilson Disease: Primary Results from an Ongoing Phase 3, Randomized, Controlled, Rater-Blinded Trial (AAN 2023) - No abstract available

Clinical • P3 data • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Neurological Manifestations of Wilson Disease in Treatment-Naive Patients and in Patients Receiving Standard of Care (AAN 2023) - P3 | "Objective An ongoing phase 3 study (NCT03403205) will assess the efficacy and safety of ALXN1840, a novel copper-binding agent in patients with WD...The most common neurological manifestations, defined as an abnormal UWDRS III score >0, at baseline in Cohort 1 were impaired speech (43.1%), finger taps (41.9%), rapid alternating hand movements (39.4%) and postural arm tremor (38.9%) and in Cohort 2 were postural arm tremor (48.9%), salivation (38.3%), wing-beating tremor (36.1%) and impaired speech (34.0%). Conclusions Tremor and speech disturbances are among the most common neurological symptoms in patients with WD in these cohorts."

Clinical • CNS Disorders • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

A phase II study of copper-depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence: Updated results (SABCS 2017) - "TM is safe, well tolerated and appears to affect multiple components of the tumor microenvironment that have been identified in pre-clinical models as important for progression. Ongoing studies in banked specimens are underway to further delineate its effect on copper dependent processes necessary for metastases. Randomized trials are warranted, especially in patients who are at high risk for relapse such as those with TNBC."

P2 data • Triple Negative Breast Cancer

Study of ALXN1840 Versus Standard of Care in Pediatric Participants With Wilson Disease (clinicaltrials.gov) - P3 | N=48 | Recruiting | Sponsor: Alexion | Trial completion date: Jul 2024 ➔ Dec 2024 | Trial primary completion date: Jan 2024 ➔ May 2024

Trial completion date • Trial primary completion date • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • Pediatrics

Early Access Program for ALXN1840 in Patients With Wilson Disease (clinicaltrials.gov) - P=N/A | N=N/A | Available | Sponsor: Alexion Pharmaceuticals

New trial • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Pharmacokinetic Study of Oral ALXN1840 in Japanese and Non-Japanese Adult Healthy Participants (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Alexion Pharmaceuticals

New P1 trial • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

Copper and Molybdenum Balance in Participants With Wilson Disease Treated With ALXN1840 (clinicaltrials.gov) - P2 | N=8 | Completed | Sponsor: Alexion Pharmaceuticals | Recruiting ➔ Completed | Trial completion date: May 2022 ➔ Sep 2022

Trial completion • Trial completion date • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders

EFFICACY AND SAFETY OF ALXN1840 VERSUS STANDARD OF CARE IN WILSON DISEASE: PRIMARY RESULTS FROM AN ONGOING PHASE 3, RANDOMIZED, CONTROLLED, RATER-BLINDED TRIAL (AASLD 2022) - "ALXN1840 treatment for 48W provided superior Cu control to SoC and was generally well tolerated. Future data analysis of the 60-month open-label extension will evaluate long-term efficacy and safety of ALXN1840."

Clinical • P3 data • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders