vemircopan (ALXN2050) / AstraZeneca - LARVOL DELTA

Maternal and fetal pharmacokinetics (PK) of pegcetacoplan in paroxysmal nocturnal hemoglobinuria (PNH): A case report of use in pregnancy (ASH 2025) - "Aftertrials of vemircopan and iptacopan, she was transitioned to pegcetacoplan 1080 mg subcutaneous2x/week and achieved transfusion independence (hemoglobin ~110 g/L)...Thesefindings are consistent with preclinical non-human animal data and pegcetacoplan's physicochemicalproperties—a large, pegylated, and hydrophilic cyclic peptide, expected to have limited membranepermeability.In a patient with hemolytic PNH and inadequate hematologic response to eculizumab, conception onpegcetacoplan was not associated with adverse fetal/pregnancy outcomes, and third-trimesterreinitiation resulted in rapid hematologic improvement, transfusion independence, and anuncomplicated peripartum course.In conclusion, this report provides the first clinical and PK evidence suggesting that third-trimester use ofpegcetacoplan may be a viable treatment option in select pregnant patients with PNH with suboptimalresponse to C5 inhibitors. Following reinitiation of pegcetacoplan at 28 weeks GA,..."

Case report • Clinical • PK/PD data • Cardiovascular • Complement-mediated Rare Disorders • Diabetes • Genetic Disorders • Gestational Diabetes • Obesity • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Efficacy and Safety of ALXN2050 in IgAN: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial (KIDNEY WEEK 2025) - P2 | "Conclusion A non-statistically significant reduction in UP was observed with ALXN2050 180mg vs PBO. While ALXN2050 was generally well-tolerated in IgAN, a risk of liver enzyme elevation was identified from study-wide data review."

Clinical • P2 data • Glomerulonephritis • Hepatology • IgA Nephropathy • Immunology • Inflammatory Arthritis • Liver Failure • Lupus • Lupus Nephritis • Nephrology • Rare Diseases • Renal Disease

Efficacy and Safety of ALXN2050 (Vemircopan) in Lupus Nephritis: Results of a Phase 2 Trial (KIDNEY WEEK 2025) - P2 | "Conclusion There was no statistically significant difference in proteinuria reduction with ALXN2050 vs PBO. Liver enzyme elevation was determined to be an identified risk with ALXN2050 after study-wide data review."

Clinical • P2 data • Glomerulonephritis • Hepatology • IgA Nephropathy • Immunology • Inflammatory Arthritis • Liver Failure • Lupus • Lupus Nephritis • Nephrology • Rare Diseases • Renal Disease

Iptacopan Treatment Improves Clinical Parameters in a Real-World Cohort with Paroxysmal Nocturnal Hemoglobinuria: Evidence from a Managed Access Program (ASH 2024) - "Overall, 5 (14.3%) patients were complement treatment-naïve, and 30 (85.7%) patients were reported to receive ≥1 prior complement inhibitor therapies including eculizumab (23 [65.7%]), ravulizumab (15 [42.9%]), pegcetacoplan (7 [20.0%]), vemircopan (6 [17.1%]), and others. At the time of iptacopan retreatment request, a higher proportion of patients reported near normal Hb levels and reticulocyte count, had a reduced number of transfusion visits, and improved fatigue and treatment satisfaction. Additional long-term results may provide better understanding of iptacopan safety and efficacy in real-world patients with PNH."

Clinical • Real-world • Real-world evidence • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Efficacy and Safety of Vemircopan as Monotherapy in Patients With Paroxysmal Nocturnal Hemoglobinuria. (PubMed, Blood Adv) - P2 | "Adults (≥18 years) with PNH who were treatment-naive, switched from eculizumab with hemoglobin (Hgb) <10 g/dL, or rolled over from danicopan monotherapy (ACH471-103 trial; NCT03181633) were enrolled. This trial evaluating vemircopan monotherapy in patients with PNH met its primary efficacy endpoint; however, concerns regarding BT-IVH risk and suboptimal, inconsistent control of IVH emerged, leading to early trial termination. This trial was registered with ClinicalTrials.gov (NCT04170023) and EudraCT (2019-003830-17)."

Journal • Monotherapy • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases. (PubMed, Pharm Res) - "Preclinical evaluations of danicopan and vermicopan provided rationales to conduct clinical studies in complement-mediated diseases. Recently, danicopan was approved as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab for the treatment of extravascular hemolysis in patients with PNH."

Journal • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

The Role of Complement in the Pathogenesis and Treatment of Myasthenia Gravis. (PubMed, Cells) - "This has led to the development of the first C5 inhibitors approved for myasthenia gravis with AchR antibodies: eculizumab, ravulizumab, and zilucoplan. Other clinical trials are currently in progress, investigating the potential therapeutic role of other targets, including the Factor B inhibition or hepatic synthesis of the C5 protein. Other proposed potential targets that have not yet been clinically tested are also discussed in this review article."

Journal • Review • CNS Disorders • Immunology • Myasthenia Gravis

Study of ALXN2050 in Participants With Hepatic Impairment (clinicaltrials.gov) - P1 | N=26 | Terminated | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: May 2025 ➔ Aug 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2025 ➔ Aug 2024; Sponsor decision.

Trial completion date • Trial primary completion date • Trial termination • Hepatology

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

Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P2 | N=102 | Terminated | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Jun 2026 ➔ Dec 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jun 2026 ➔ Dec 2024; Sponsor Decision.

Trial completion date • Trial primary completion date • Trial termination • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

Study of ALXN2050 in Participants With Hepatic Impairment (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Oct 2024 ➔ May 2025 | Trial primary completion date: Oct 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Hepatology

Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P2 | N=126 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting | N=70 ➔ 126

Enrollment change • Enrollment closed • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

Study of ALXN2050 in Participants With Hepatic Impairment (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

Study of ALXN2050 in Participants With Hepatic Impairment (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial primary completion date: Apr 2024 ➔ Sep 2024

Trial primary completion date • Hepatology

Study of the Oral Factor D (FD) Inhibitor ALXN2050 in PNH Patients as Monotherapy (clinicaltrials.gov) - P2 | N=29 | Terminated | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Oct 2026 ➔ Mar 2024 | Active, not recruiting ➔ Terminated; Did not appropriately control IVH; significantly increased rates of BTH and LDH excursions (LDH excursions is defined by LDH values > X2ULN) compared to ravulizumab.

Monotherapy • Trial completion date • Trial termination • Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

A Study to Investigate the Pharmacokinetic Profile of ALXN2050 Modified Release Prototype Formulations and Immediate Release Reference Tablet in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=80 | Completed | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Completed | N=30 ➔ 80

Enrollment change • Trial completion

Potential Drug Interaction Study Between Vemircopan and Rosuvastatin, Metformin, Levonorgestrel/Ethinyl Estradiol-containing Oral Contraceptives, and Carbamazepine (clinicaltrials.gov) - P1 | N=60 | Completed | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion

ALXN2050-MG-201: Study of ALXN2050 in Adult Participants With Generalized Myasthenia Gravis (clinicaltrials.gov) - P2 | N=70 | Terminated | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Dec 2025 ➔ Apr 2024 | Active, not recruiting ➔ Terminated; Sponsor decision

Trial completion date • Trial termination • CNS Disorders • Myasthenia Gravis

Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P2 | N=70 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | N=126 ➔ 70

Enrollment change • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

Potential Drug Interaction Study Between Vemircopan and Rosuvastatin, Metformin, Levonorgestrel/Ethinyl Estradiol-containing Oral Contraceptives, and Carbamazepine (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Initiation date: Oct 2023 ➔ Jan 2024

Trial initiation date

Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN) (clinicaltrials.gov) - P2 | N=126 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial primary completion date: Jan 2024 ➔ Jun 2026

Trial primary completion date • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

Potential Drug Interaction Study Between Vemircopan and Rosuvastatin, Metformin, Levonorgestrel/Ethinyl Estradiol-containing Oral Contraceptives, and Carbamazepine (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open

Targeting complement in IgA nephropathy. (PubMed, Clin Kidney J) - "Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-L), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN."

Journal • Review • Glomerulonephritis • IgA Nephropathy • Lupus Nephritis • Nephrology • Renal Disease

221: RestoreD: A clinical trial with oral ALXN2050 – a Complement Factor D inhibitor - for Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (lgAN) (ACR Convergence 2023) - "Non-CME"

Clinical • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease

ALXN2050-MG-201: Study of ALXN2050 in Adult Participants With Generalized Myasthenia Gravis (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Myasthenia Gravis • CFB