NeuroNascent Presents Results of Phase 1a Human Safety Clinical Trial of NNI-362 at the CTAD conference in Boston, November 9-12.

Table 5. Adverse Events AE Category (All of Mild Grade) Placebo (n=2) NNI-362 (n=6) Placebo (n=2) NNI-362 (n=6) Placebo (n=2) NNI-362 (n=6) Placebo (n=2) NNI-362 (n=6) Placebo (n=2) NNI-362 (n=6) Placebo (n=2) NNI-362 (n=6) Placebo (n=2) NNI-362 (n=6) Placebo (n=14) NNI-362 (n=42) Eye Disorders1 1 (17%) UL 1 (50%) 1 1 Gastrointestinal Disorders2 1 (17%) U 2 (50%) 1 (17%) 3 (50%) U UL 1 (17%) 2 (50%) 1 (17%) 7 4 Nervous System Disorders3 1 (17%) 1 (50%) 1 (50%) 1 (17%) 2 (100%) 2 (50%) 1 (17%) 6 3 Respiratory, thoracic and mediastinal4 1 (17%) UL 1 Psychiatric5 2 (50%) 1 (17%) 2 1 Cardiac Disorders6 1 (17%) UL 1 Injury poisoning/procedural complications7 2 (33%) U U 2 Genl Disorders and Administrative sites8 1 (50%) 2 (33%) U 1 (17%) 1 3 Musculoskeletal and connective tissue9 1 (17%) U 1 17 17 Pre-lock Definition U=Unrelated 1 1 1 3 UL=Unlikely 1 1 1 1 Possibly Treatment Related 15 9 # Oral Lipid Formulation 1Eye redness, conjunctivitis; 2Diarrhea, constipation, nausea, emesis, borborygmi, discolored feces; 3Headache, dizziness, light headed, somnolence; 4Sinus discomfort; 5Abnormal dreams, insomnia; 6Bigeminy-asymptomatic; 7Laceration, thermal burn; 8Feeling calm, somber, catheter site pain, foggy; 9Back pain SAD+MAD 240 mg# SAD 120 mg SAD 10 mg SAD 20 mg SAD 60 mg MAD 20 mg SAD+MAD 120 mg# A Phase 1a, Randomized, Placebo-controlled, Single & Multiple Dose-Escalation Study to Evaluate the Safety & Tolerability of Novel Regenerative Therapeutic NNI-362 Judith Kelleher-Andersson1, Esther Yoon2, Carol Green3, Claire Mcfarlane3 and R. Scott Turner4 1Neuronascent, Inc., Clarksville, USA. 2CA Clinical Trials Med Grp, Glendale, USA. 3SRI, Menlo Park, USA. 4Georgetown Univ., Washington DC USA. INTRODUCTION NNI-362, a NCE, was discovered through a phenotypic screen to identify neuron generation and neuroprotection capacity from human neural progenitors (Sumien et al., Stem Cell Res. & Ther. 12:59, 2021). NNI- 362’s unique MOA allosterically targets S6 kinase downstream of mTOR, that selectively stimulates translation in neural progenitor cells and promotes maturation of new neurons in aging and progressive disorders. Preclinical efficacy and safety was demonstrated prior to start of Phase1a clinical testing in an aged population (supported by NIA 1RO1 AG056561, PI: JK-A). Safety and tolerability of oral NNI-362 were the primary readouts. Secondary pharmacokinetic readouts involved two liquid formulations - the first being aqueous liquid in Cohorts A-E and the second being a lipid based liquid in Cohorts F and G. Planned studies will include plasma levels of phosphoTau181 pre and post treatment in MAD Cohort 240 mg to determine potential differences with NNI-362 treatment in aged subjects (Mayo Laboratories). Further preclinical analysis of NNI-362 in an rat AAV-alpha synuclein model of Parkinson’s disease showed behavioral benefit including reversal of anosmia (J Kelleher-Andersson manuscript in preparation) with immunohistochemical analysis of neuron regeneration still in progress (MOTAC, France). Long-term GLP safety in rats and dogs for 6 and 9 months, respectively, will need to be completed prior to POC trials. Proposed POC trial designs with lipid-based formulated NNI-362 for mild to moderate Alzheimer’s disease and for early Parkinson’s disease are provided. BACKGROUND: NNI-362 is a new chemical entity discovered through a phenotypic assay to identify small molecules that promote new neurons from human neural progenitor cells. Preclinical efficacy and safety studies supported a first-in-human testing in a healthy aged population. A placebo-controlled study allowed the determination of safety and tolerability, as well as secondary pharmacokinetics of two distinct NNI-362 formulations. OBJECTIVES: The aim of this study was to determine the safety and tolerability of NNI-362 in a first-in-human study. METHODS: NNI-362 was formulated by Parexel (Glendale, CA) as an aqueous suspension or lipid suspension. Individuals were enrolled in a placebo-controlled study with a 1:3 ratio of placebo:drug. The dosing in SAD cohorts was 10, 20, 60, and 120 mg and MAD cohort at 20 mg and a SAD/MAD at 120 and 240 mg, all under fasted conditions. Direct SAD and MAD pharmacokinetics were assessed at the two highest doses. A total of 56 subjects ages 50 to 72 were randomized to intervention or placebo, with the sponsor, PI, and subjects all blinded. Conclusions: Oral NNI-362 appears to be safe and well tolerated at doses up to 240 mg. A maximum tolerated dose (MTD) was not reached in this healthy aged population. The liquid-lipid formulation of NNI-362 at 120 and 240 mg revealed an increased Cmax and AUClast but no increase in AEs. These data support a proof-of-concept trial of oral NNI-362 in individuals with Alzheimer’s disease and other neurodegenerative disorders of aging associated with neuronal loss. Study Type Interventional, Phase 1b/2a Study Design Randomized, Intervention Model: Parallel Assignment Masking Triple (Participant, Care Provider, Investigator) Study Design Randomized, Intervention Model: Parallel Assignment Masking: Double (Participant, Investigator) Conditions Parkinson's Disease (Age 40-72) Interventions: Drug: NNI-362 oral liquid-gel cap Other: Placebo Enrollment 75 (no controls), Male and Female Endpoints 1o - Safety and Tolerability, compare to baseline vMRI hippocampus 2o - OLFACT™ Test Battery or UPSIT, MDS-UPDRS, MADRS-2, PDQ-39 A Proposed Study of NNI-362 in Early Parkinson’s Patients Arm Intervention/Treatment Experimental : NNI-362 oral liquid NNI-362 will be administered orally in the double-blind treatment over 6 months Drug: NNI-362 oral liquid 120 mg Drug: NNI-362 oral liquid 240 mg Placebo Comparator: Placebo will be administered orally in the double-blind treatment over 6 months Drug: Placebo Participants will receive Placebo oral liquid daily for 6 months A Proposed Study of NNI-362 in Mild to Moderate Alzheimer’s Patients Study Type Interventional, Phase 1b/2a Study Design Randomized, Intervention Model: Parallel Assignment Masking Triple (Participant, Care Provider, Investigator) Conditions Alzheimer's disease (Age 60-86) Interventions: Drug: NNI-362 oral liquid-gel cap Other: Placebo Enrollment 105 (no controls), Male and Female (>50% F) Endpoints 1o - Safety and Tolerability, compare to baseline vMRI hippocampus 2o - OLFACT™ Test Battery or UPSIT, ADAS-cog., Mini Mental State Examination (MMSE), ADCS-ADL, Plasma-PhosphoTau, Arm Intervention/Treatment Experimental : NNI-362 oral liquid NNI-362 will be administered orally in the double-blind treatment over 6 months Drug: NNI-362 oral liquid 120 mg oral liquid daily for six months Drug: NNI-362 oral liquid 240 mg oral liquid daily for six months Placebo Comparator: Placebo will be administered orally in the double-blind treatment over 6 months Drug: Placebo Participants will receive Placebo oral liquid daily for 6 months - Safety/Efficacy Model Male/Female Sprague-Dawley Rats - 10 mg/kg, po (lipid formulation) showed behavioral efficacy in a rat AAV-alpha synuclein model (both motor and anosmia) (J. Kelleher-Andersson, manuscript in preparation) - AUC at 10 mg/kg in rat is approximately equal to the AUC at 240 mg in humans, when considering a 20-fold protein binding ratio from rat to human - Cmax at 10 mg/kg in rats approximately 2-fold Cmax at 240 mg in humans, when considering a 20-fold protein binding ratio from rat to human - T1/2 in humans at 120 & 240 mg = 12 hrs (~6 hrs in rat) - No safety concerns in either rat or human (no dose dependent AEs, see Table 5) Efficacious Dose Level Potentially Met at Highest Human Oral Dose (240 mg) Table 2 Asian Black or African- American White Other Total Female 10 5 18 0 33 Male 2 3 16 2 23 Total 12 8 34 2 56 Table 3 Hispanic or Latino Not Hispanic or Latino Unknown Total Female 6 26 1 33 Male 3 20 0 23 Total 9 46 1 56 Table 4 Avg Age Total Female 60.1 + 5.3 33 Male 59.0 + 5.8 23 Total 59.6 + 5.5 56 Table 1 Placebo (n=14) NNI-362 (n=42) Male 5 (36%) 18 (43%) Age (yrs) 59.6 + 5.4 59.6 + 5.5

The release as fetched from its publisher. neuronascent.com ↗