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

The Company presented new data and analyses from the Phase 2 ALXN1840-WD-204 copper balance study at the American Association for the Study of Liver Diseases (AASLD) - The Liver Meeting 2025. (The Manila Times) - "...treatment with ALXN1840 led to a rapid and sustained improvement in daily copper balance in patients with Wilson disease, primarily through increased fecal copper excretion....Monopar is preparing to submit a New Drug Application ('NDA') to the FDA in early 2026."

FDA filing • P2 data • Genetic Disorders

Research and Development (“R&D”) Expenses (The Manila Times) - "R&D expenses for the third quarter of 2025 were $2,589,749, compared to $984,278 for the third quarter of 2024. This represents an increase of $1,605,471 attributed to (1) a $937,582 increase in manufacturing activities related to ALXN1840, (2) a $617,667 increase in R&D personnel expenses including stock-based compensation and (3) a net increase of $50,223 in other R&D expenses."

Commercial • Genetic Disorders

Oral Bis-choline Tetrathiomolybdate Rapidly Improves Copper Balance in Patients with Wilson Disease. (PubMed, J Hepatol) - No abstract available

Journal • Genetic Disorders • Metabolic Disorders • Movement Disorders

Living on the Edge: ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target. (PubMed, Antioxidants (Basel)) - "Inhibiting the glutathione system induces ferroptosis, a non-apoptotic form of cell death driven by lipid peroxidation, with compounds like withaferin A and altretamine showing strong preclinical activity...Trx reductase inhibition by auranofin or mitomycin C further destabilizes redox balance, promoting mitochondrial dysfunction and apoptosis. SOD1 inhibitors, including ATN-224 and disulfiram, selectively enhance oxidative stress in tumor cells and are currently being tested in clinical trials. Mounting preclinical and clinical evidence supports redox modulation as a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of cellular tolerance offers a rational and potentially powerful approach to eliminate malignant cells while sparing healthy tissue, highlighting novel strategies for targeted cancer therapy at the interface of redox biology and oncology."

Journal • Review • Metabolic Disorders • Oncology • HIF1A • STAT3

hucMSC-derived exosomes targeting macrophage polarization attenuate systemic inflammation in T1DM via INS/SOD1 delivery. (PubMed, Stem Cell Res Ther) - "This study demonstrates that hucMSC-EXOs ameliorate T1DM- associated hyperglycemia and multiorgan inflammation by targeting macrophage polarization through delivery of INS and SOD1. Our study reveals that hucMSC-EXOs exert their anti-inflammatory effects through coordinated delivery of insulin and SOD1, establishing a protein-centric mechanism for exosome-mediated immunomodulation in T1DM."

Journal • Diabetes • Immunology • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus • CCL2 • IL6 • SOD1 • TNFA

Monopar Therapeutics Reports First Quarter 2025 Financial Results and Recent Developments (GlobeNewswire) - "The data support ALXN1840 as a potential treatment for Wilson disease, a rare genetic disorder that causes toxic copper buildup in organs like the liver and brain. Pooled results from three clinical trials (n=255) showed sustained clinical benefits over a median treatment duration of 2.63 years. Safety data, which included an additional Phase 2 study (n=266), confirmed a favorable safety profile with fewer than 5% of patients experiencing a drug-related serious adverse event ('SAE') and no renal or urinary system SAEs....The Company is preparing to submit a New Drug Application ('NDA') to the U.S. Food and Drug Administration ('FDA') in early 2026."

FDA filing • Retrospective data • Genetic Disorders

Sustained long-term clinical improvement in Wilson disease patients on tiomolybdate choline (EASL 2025) - "Pooled analysis of clinical trial data from 255 WD patients on ALXN1840 treatment shows sustained clinical improvement over 6 years of treatment. Combined with long-term safety, this analysis supports the potential use of ALXN1840 as a therapy for Wilson disease."

Clinical • Late-breaking abstract • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • Rare Diseases

Monopar Announces ALXN1840 Data Selected for Late-Breaker Presentation at EASL Congress 2025 (GlobeNewswire) - "Monopar Therapeutics Inc...today announced that data on the long term efficacy and safety of its ALXN1840 (tiomolybdate choline) drug candidate for Wilson disease has been accepted for a late-breaker poster presentation at the European Association for the Study of the Liver ('EASL') International Liver Congress 2025. EASL is recognized as one of the premier events in the hepatology space and will be held in Amsterdam, Netherlands from May 7 – 10, 2025."

Clinical data • Late-breaking abstract • Genetic Disorders • Rare Diseases

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