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Treatment of Complement-Mediated Myelitis

补体介导的脊髓炎的治疗

基本信息

批准号：
10254752
负责人：
Rekha Bansal
金额：
$ 30万
依托单位：
NOVELMED THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254752
关键词：
Acute Adrenal Cortex Hormones Adult Adverse event Affect African Alternative Complement Pathway Animals Antibodies Antibody Response Azathioprine Bacterial Infections Binding Biological Assay Cell Death Cells Cessation of life Chronic Clinic Clinical Clinical Research Clinical Trials Complement Complement 3a Complement 5a Complement Membrane Attack Complex Control Groups Country Cytolysis Deposition Diagnosis Disease Dose Drug Kinetics Evaluation Exhibits Female Flow Cytometry Food and Drug Administration Drug Approval Future Guidelines Half-Life Headache Hemolysis Host Defense Human Immunoglobulin G Immunologics Immunosuppressive Agents In Vitro Incubated Individual Infection Inflammation Mediators Inflammatory Injury Intravenous Intravenous infusion procedures Label Laboratories Lactate Dehydrogenase Lead Length Macaca mulatta Measurement Mediating Methods Modeling Monitor Monkeys Monoclonal Antibodies Motor Myasthenia Gravis Myelitis Neuromyelitis Optica Optic Nerve Organ Pain Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology and Toxicology Pharmacotherapy Phase Phase I Clinical Trials Plasma Exchange Pleural Empyema Prevalence Primates Production Prognosis Properdin Rare Diseases Recovery Relapse Reporting Research Design Retrospective Studies Rhesus Safety Sampling Secondary to Sensory Serum Spinal Cord Symptoms Syndrome Testing Therapeutic Time Tissues Toxicology United States United States Food and Drug Administration Upper Respiratory Infections Virus Diseases Vision aquaporin 4 biobank brain cell cell type central nervous system demyelinating disorder cost cross reactivity drug candidate drug development follow-up healthy volunteer human tissue in vivo evaluation inhibitor/antagonist male multi-site trial mycophenolate mofetil novel therapeutics open label phase 1 study phase 2 study phase I trial phase II trial prevent rituximab secondary infection seropositive success water channel

项目摘要

ABSTRACT We intend to develop our lead drug candidate as a potent, efficacious, and disease-modifying treatment for the orphan disease, Neuromyelitis Optica Spectrum Disorder (NMOSD), with efficacy anticipated to be far superior to the current monotherapy, Soliris (eculizumab). Soliris is approved for the treatment of NMOSD, atypical uremic syndrome (aHUS), and Myasthenia Gravis (MG). Mechanistically, Soliris blocks both the classical (CP) and the alternative pathways (AP) of complement. In 2019, the FDA approved this broad-spectrum complement blocker for NMOSD, despite its non-selectivity to the alternative pathway (AP), which has been implicated as the sole mechanism for cellular death of the brain cells in the disease. Soliris' mechanistic blockade of the classical pathway (CP) is concerning, given that treatment may render patients vulnerable to secondary bacterial and viral infections. Use of Soliris continues to expand as a sole means of therapy for relief of NMOSD-related pathology. Our clinical drug candidate, NM5072, is a selective inhibitor of the AP and therefore does not impair CP activation. By selectively blocking the AP upstream, the production of the two most critical pro-inflammatory molecules, C3a and C5a, is inhibited. Progress during development of this drug has established numerous benefits, including; a) lack of CP inhibition, b) potency in AP inhibition, c) successful toxicology studies, and d) completion of a successful phase I clinical trial in healthy volunteers. Collectively, these accomplished milestones offer confidence in clinical success as a therapeutic drug for treatment of NMOSD. Collectively, preliminary non-clinical data of our drug in normal human serum and results from the phase I trial in healthy volunteers, replicate our in vitro and ex vivo findings that at a 1mg/kg minimum dose, the drug blocks the AP in a dose-dependent manner, all while sustaining CP activity. Selective blockade of the AP at a 1 mg/kg dose in humans further confirms this drug's superior therapeutic potency over Soliris. Another significant advantage of our new drug is that it does not require a loading dose to reach therapeutic levels, demonstrating that administration of this drug is also patient-friendly. Patients who exhibit positivity to Aquaporin-4 (AQP4)-IgG are officially diagnosed as NMOSD. In this proposal, we outline our strategy in evaluative screenings of NMOSD samples using the flow cytometry methods developed by Dr. Sean Pittock's laboratory to select those individuals who are positive AQP4-IgG. These serum samples will be further characterized using our AP/CP and convertase assays to determine NM5072's selectivity of AP/CP activation and the extent of complement inhibition in vitro. Following this, we aim to conduct tissue cross-reactivity studies using the NMOSD serum to assess tissue binding. Finally, we will follow up with a 3-month 12-weekly repeat-dose toxicology study in rhesus monkeys to enable future multi-dose studies in human. Given the unique mechanism of action of our lead drug candidate and in-human potency for blocking the AP, we believe that our drug will provide exceptional therapeutic benefits for treatment of NMOSD.

摘要