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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. Solirisandapos; 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 drugandapos;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 Pittockandapos;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 NM5072andapos;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.PROJECT NARRATIVEThe 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.