We intend to develop our lead drug candidate as a potent, efficacious, and disease-modifying treatment for theorphan disease, Neuromyelitis Optica Spectrum Disorder (NMOSD), with efficacy anticipated to be far superiorto the current monotherapy, Soliris (eculizumab). Soliris is approved for the treatment of NMOSD, atypicaluremic 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-spectrumcomplement blocker for NMOSD, despite its non-selectivity to the alternative pathway (AP), which has beenimplicated as the sole mechanism for cellular death of the brain cells in the disease. Soliris' mechanisticblockade of the classical pathway (CP) is concerning, given that treatment may render patients vulnerable tosecondary bacterial and viral infections. Use of Soliris continues to expand as a sole means of therapy for reliefof NMOSD-related pathology.Our clinical drug candidate, NM5072, is a selective inhibitor of the AP and therefore does not impair CPactivation. By selectively blocking the AP upstream, the production of the two most critical pro-inflammatorymolecules, C3a and C5a, is inhibited. Progress during development of this drug has established numerousbenefits, 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 accomplishedmilestones 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 healthyvolunteers, replicate our in vitro and ex vivo findings that at a 1mg/kg minimum dose, the drug blocks the AP ina dose-dependent manner, all while sustaining CP activity. Selective blockade of the AP at a 1 mg/kg dose inhumans further confirms this drug's superior therapeutic potency over Soliris. Another significant advantage ofour new drug is that it does not require a loading dose to reach therapeutic levels, demonstrating thatadministration 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 methodsdeveloped by Dr. Sean Pittock's laboratory to select those individuals who are positive AQP4-IgG. Theseserum samples will be further characterized using our AP/CP and convertase assays to determine NM5072'sselectivity of AP/CP activation and the extent of complement inhibition in vitro. Following this, we aim toconduct tissue cross-reactivity studies using the NMOSD serum to assess tissue binding. Finally, we will followup with a 3-month 12-weekly repeat-dose toxicology study in rhesus monkeys to enable future multi-dosestudies in human. Given the unique mechanism of action of our lead drug candidate and in-human potency forblocking the AP, we believe that our drug will provide exceptional therapeutic benefits for treatment of NMOSD.
Public Health Relevance Statement: PROJECT NARRATIVE
The estimated prevalence of NMOSD is 1-10 cases per 100,000 individuals in the United States, with
higher rates reported worldwide. These numbers are further augmented in countries with a higher proportion of
individuals of African ancestry. For acute attacks, high-dose intravenous corticosteroids or plasma exchange
therapy are employed as treatment. For long-term suppression of the disease, a variety of
immunosuppressive drugs have been traditionally prescribed by many clinicians as the first-line in therapy.
Corticosteroids, azathioprine, mycophenolate mofetil, and rituximab are the most widely prescribed treatments.
Rituximab, in particular, has shown to be helpful in retrospective studies, including in patients who fail with
other first-line immunosuppressive treatments. In 2019, Soliris (eculizumab) was approved by the US Food and
Drug Administration (FDA) for the treatment of NMOSD in adult patients who are seropositive for anti-
aquaporin-4 (AQP4) antibody. In 2020, Uplizna (inebilizumab-cdon, antibody) was also approved to treat
NMOSD in AQP4 seropositive adult patients.
Project Terms: Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Animals ; inhibitor/antagonist ; inhibitor ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Azathioprine ; Azothioprine ; Immuran ; Imuran ; Imurel ; Bacterial Infections ; bacteria infection ; bacterial disease ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Clinical Research ; Clinical Study ; Clinical Trials ; Complement ; Complement Proteins ; Complement 3a ; C3 a ; C3a ; Complement C3a ; Complement 5a ; C5 a ; C5a ; Complement C5a ; Recombinant C5a ; Complement Membrane Attack Complex ; C 5b-9 ; C5b-9 ; Complement Complex C5b-9 ; Cytolytic Terminal Complement Complex ; Membrane Attack Complex ; Terminal Complement Complex ; Alternative Complement Pathway ; Properdin Pathway ; Control Groups ; Cessation of life ; Death ; central nervous system demyelinating disorder ; central nervous system demyelinating disease ; Diagnosis ; Disease ; Disorder ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Pleural Empyema ; Pulmonary Empyema ; Pyothorax ; Thoracic Empyema ; Exhibits ; Female ; Flow Cytometry ; Flow Cytofluorometries ; Flow Cytofluorometry ; Flow Microfluorimetry ; Flow Microfluorometry ; flow cytophotometry ; Future ; Half-Life ; Headache ; Cephalalgia ; Cephalgia ; Cephalodynia ; Cranial Pain ; Head Pain ; head ache ; Hemolysis ; erythrolysis ; Human ; Modern Man ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immunosuppressive Agents ; Immunosuppressants ; Immunosuppressive drug ; Immunosuppressive treatment ; immune suppressive agent ; immune suppressor ; immunosuppressive substance ; immunosuppressor ; In Vitro ; Infection ; Intravenous infusion procedures ; IV Infusion ; intravenous infusion ; Laboratories ; Lactate Dehydrogenase ; EC 1.1.1.27 ; L-Lactate Dehydrogenase ; L-Lactic Acid Dehydrogenase ; NAD-Lactate Dehydrogenase ; lactic acid dehydrogenase ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Macaca mulatta ; M mulatta ; M. mulatta ; Rhesus Macaque ; Rhesus Monkey ; male ; Methods ; Monkeys ; Myasthenia Gravis ; Myelitis ; Inflammatory Myelopathy ; Spinal Cord Inflammation ; Neuromyelitis Optica ; Devic Disease ; Devic's Syndrome ; Optic Nerve ; Cranial Nerve II ; Second Cranial Nerve ; Pain ; Painful ; Pathology ; Patients ; Drug Kinetics ; Pharmacokinetics ; Plasma Exchange ; Primates ; Primates Mammals ; Production ; Properdin ; Complement Factor P ; factor P ; Relapse ; Research Design ; Study Type ; study design ; Retrospective Studies ; Safety ; Spinal Cord ; Medulla Spinalis ; Syndrome ; Testing ; Time ; Tissues ; Body Tissues ; Toxicology ; United States ; United States Food and Drug Administration ; Food and Drug Administration ; USFDA ; Upper Respiratory Infections ; Upper Respiratory Tract Infection ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Vision ; Sight ; visual function ; Mediating ; Guidelines ; Secondary to ; Injury ; injuries ; Organ ; Label ; Acute ; Chronic ; Clinical ; Phase ; mycophenolate mofetil ; mycophenolic acid morpholinoethyl ester ; Evaluation ; Serum ; Blood Serum ; Individual ; Recovery ; African ; Measurement ; Inflammation Mediators ; inflammatory mediator ; AQP4 protein ; aquaporin 4 ; Therapeutic ; Inflammatory ; Deposit ; Deposition ; Intravenous ; C2B8 Monoclonal Antibody ; MabThera ; Rituxan ; rituximab ; human tissue ; Clinic ; secondary infection ; Sensory ; cell type ; Country ; Host Defense ; brain cell ; success ; Aquaporins ; Water Channel Proteins ; water transporter ; water channel ; Orphan Disease ; Rare Disorder ; orphan disorder ; Rare Diseases ; Pharmacology and Toxicology ; Reporting ; Pharmacodynamics ; Modeling ; Sampling ; cross reactivity ; drug development ; Adverse Experience ; Adverse event ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Molecular Interaction ; Binding ; Lysis ; Cytolysis ; preventing ; prevent ; Incubated ; Length ; Dose ; Symptoms ; Motor ; Immunologics ; Immunochemical Immunologic ; Immunologic ; Immunological ; Immunologically ; Monitor ; follow-up ; Active Follow-up ; active followup ; follow up ; followed up ; followup ; Pathway interactions ; pathway ; open label ; open label study ; cost ; Prevalence ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; healthy volunteer ; multi-site trial ; multisite trial ; drug candidate ; biobank ; biorepository ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; phase II trial ; phase 2 trial ; phase I trial ; phase 1 trial ; seropositive ; Antibody Response ; Food and Drug Administration Drug Approval ; FDA Drug Approval ; in vivo evaluation ; in vivo testing ; Rhesus ; Prognosis ;
