NP-001

Paper Published in "Cells" Identifies Disease Pathogenesis and Highlights Role of Inflammation PALO ALTO, Calif., March 30, 2023 /PRNewswire/ -- Neuvivo today announced the publication of a peer-reviewed paper titled: "Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS". The biomarker study used vital capacity (VC), a quantitative test for respiratory function, to highlight the relationship between a compromised innate immune system and ALS disease activity. ALS is a heterogeneous, currently terminal neurodegenerative disease, involving progressive loss of voluntary muscle function. The disease typically leads to death in 2-5 years, generally due to respiratory failure. In this study, NP001 was shown to have a significant positive impact on respiratory activity by augmenting the natural function of the innate immune system. The study evaluated data and newly obtained biomarker results from patients who were enrolled in the NP001 Phase 2 placebo-controlled 6-month clinical trial (Jan 2011-Nov 2012 at 17 sites in the US). Patients under 65 years old receiving 2mg/kg NP001 treatment, plus placebo arms, who completed the 6-month trial and had accessible plasma from baseline and at end of trial (stored at -80) were included. The study, in accordance with FDA guidance published in 2019, defined a subgroup of patients that responded clinically to NP001. The objective was to test whether regulation of the innate immune system with NP001 would be associated with effects on respiratory vital capacity. Role of CRP and the Immune System Patients in this vital capacity study were stratified based on plasma levels of a well-known marker of inflammation, C-reactive protein (CRP). Levels defined patients as "high CRP" (>1.13mg/L) and "low CRP" (<1.13mg/L) (CRP levels of under 3mg/L are typically considered within normal range, thus a 1.13mg/L level would not generally cause concern). CRP plays an important role in the body clearing misfolded proteins, dying cells and infectious agents as part of a normal innate immune system response. Once stimuli that caused the inflammatory response have been cleared, CRP levels in a healthy person return to normal. An ongoing elevated plasma CRP level indicates that there is disturbance of the cycle, such that the inflammatory response does not resolve. In the study reported by McGrath and colleagues at UCSF and Neuvivo in "Cells", data showed that patients treated with NP001 and with high CRP were able to better maintain lung function – treated patients had a 64% slower rate of VC loss than patients on placebo. These observations showed that patients with high CRP had stable vital capacity, leading to the possibility that high CRP values may be a biomarker for an immune system that is engaged but has been compromised. Key points presented in the study: NP001-treated patients with high CRP lost 0.75% of vital capacity per month Placebo group patients with high CRP lost 2.1% of vital capacity per month These data represent a 64% slower rate of decline in high CRP patients receiving NP001 (p=0.05) Importantly, plasma TGFB1, a dominant regulator of inflammation, was 95% higher after 6 months in high CRP treated patients compared with controls. (p < 0.02). The 95% increase in plasma TGFB1 that occurred after treatment with NP001 vs placebo and the elevated level of this factor one month after the last dose of treatment, suggests that NP001 may have acted in part to reset the innate immune system. Vital Capacity and Inflammation Recent studies of ALS pathogenesis have confirmed that inflammation caused by misfolded proteins such as SOD1 and TDP-43, begins at the neuromuscular junction (NMJ) and involves innate immune system activated macrophages. When the immune system is dysfunctional, inflammation in this area compromises the phrenic nerve - the nerve responsible for supplying motor signals to the diaphragm, essential for breathing. Vital capacity tests objectively assess the operation of the NMJ between the phrenic nerve and the diaphragm - potentially linking innate immune function with a measurable, survival-associated clinical outcome. "In terms of immune system regulation, the presence of high CRP (plasma level > 1.13 mg/kg) is a strong signal that the innate immune system, including other acute phase reactants, is engaged and trying to regulate an inflammatory process, contributing to ALS pathogenesis" said Michael McGrath, MD, PhD, CSO Neuvivo and Professor Emeritus of Medicine, UCSF. "NP001 treatment acts to augment the naturally occurring immune response and supports resolution of the CRP-mediated process related to ongoing loss of respiratory function. Data regarding treatment initiation and effect on vital capacity confirm that respiratory function is measurably failing early in the disease course as NP001 slows VC loss early on. These observations are important even if vital capacity is near normal at date of diagnosis. Given its objectivity, the VC test used as a biomarker may allow for the direct evaluation of innate immune activity in relation to ALS disease progression." "Results of this study demonstrate the role of the innate immune system in ALS pathogenesis and importantly, in the maintenance of respiratory capacity," said Ari Azhir, PhD, CEO, Neuvivo. "Given elevated levels of necessary anti-inflammatory proteins induced well after dosing, we postulate it may be possible to regulate immune function to the point where no further damage would be forthcoming in patients adequately controlled with NP001 treatment. A notable area of interest would be in additional neurodegenerative diseases with evidence of CRP elevation." Link to Study in Cells: Cells | Free Full-Text | Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS (mdpi.com) – McGrath, et al. Editor's Note: The macrophage is the most primordial cell in the innate immune system. It is a type of white blood cell involved in the functioning of the inflammation-resolution cycle. Normally, in response to infection/activation, a subset of macrophages become inflammatory, and another subset become wound healing to maintain immune activation equilibrium. In ALS, the process is compromised, resulting in unchecked inflammation. Macrophage-targeted treatment with NP001 restores the innate immune activation balance. About Neuvivo: Neuvivo is a private, late-clinical stage biopharmaceutical company developing advanced treatments for ALS and other neurodegenerative diseases. The company was formed by industry leaders and scientists, focused on improving the prognosis for patients diagnosed with ALS and a range of diseases for which few current treatment options exist. Lead candidate NP001 has been shown to be effective in a large subset of people living with ALS and has an exceptional safety profile. Neuvivo is working to make this treatment broadly available to patients as soon as possible. For more information please visit: Contact: Jennifer Larson 415 409 2729 Jennifer@neuvivo.com

Paper Published in 'Biomedicines' Highlights MOA, Links Biomarker Changes to Positive Clinical Outcomes PALO ALTO Calif., Dec. 1, 2022 /PRNewswire/ -- Neuvivo today announced the publication of a peer-reviewed paper titled: "Macrophage Targeted Sodium Chlorite (NP001) Slows Progression of ALS through Regulation of Microbial Translocation". The goal of the biomarker-focused study was to test the relationship between NP001 macrophage-targeted immune regulation and the theory that microbial translocation contributed to ALS progression. "The current study links the regulation of the innate immune system by NP001 with ALS disease modification." – McGrath, MD, PhD Published in the journal 'Biomedicines', the peer-reviewed study shows a clear relationship between microbial translocation, inflammation, and disease pathogenesis. Microbial translocation is a process that occurs when bacteria from the gut break through the epithelial barrier and leak into the bloodstream. This initiates a self-perpetuating cycle of inflammation now shown to be directly related to the pathogenesis of ALS and potentially other diseases. NP001 treatment has been shown to restore the normal process of resolution in the inflammatory cycle and in so doing, restore the integrity of the epithelial barrier in the gut – halting damaging microbial translocation. In this study, the immunoregulatory activity of NP001 treatment has been confirmed via the normalization of key blood biomarkers. Mechanism of Action "We have long-postulated that NP001, as a regulator of the innate immune system, restores the balance between macrophages that initiate inflammation and those that promote wound healing," said Michael McGrath, MD, PhD, CSO Neuvivo and Professor Emeritus of Medicine, UCSF. "The current study links the regulation of the innate immune system by NP001 with ALS disease modification, an approach potentially applicable to other inflammatory diseases. ALS was traditionally considered to affect primarily the central nervous system, but recent research supports what we have postulated – that ALS originates as a systemic immunologic reaction to abnormally processed proteins within neurons, ultimately leading to their dysfunction and death." Study Details Earlier in 2022, NP001's activity in two placebo-controlled, 6-month Phase 2 ALS trials was reported. The post hoc analysis defined a large subset of patients between 40-65 years old and with slightly elevated baseline levels of inflammation who were clinically responsive to NP001 treatment. Data showed that NP001 administration was associated with a significantly greater retention of physical function in patients as measured by the ALSFRS-R scale and a significantly greater maintenance of respiratory function. The current study reported in Biomedicines started by defining groups of ALS patients from the Phase 2A NP001 clinical trial that had clear slowing of disease progression compared to controls. Blood biomarkers from the two groups were then measured to determine whether any changes over the 6-month study would be linked to a positive clinical outcome in drug treated patients as compared to controls. Biomarker Data Biomarker data showed that factors associated with harmful microbial translocation (LPS, LBP and HGF), monocyte trafficking (sCD163) and inflammasome activation (IL-18) were significantly decreased in NP001 recipients as compared to placebo over 6 months. Biomarker values that significantly increased were those associated with suppression of inflammation (IL-10, neopterin) and wound healing (EGF). Plasma levels for IL-6, IL-8 and TNF-α were within the normal ranges and relatively stable over the 6-month study. A total of 9 biomarkers showed notable changes in the blood of patients treated with NP001 as compared to controls, linking a slowing of ALS disease progression with the regulation of microbial translocation. Patient Subsets "ALS is now recognized as such a heterogeneous disease that in 2019 the FDA published guidelines encouraging treatment developers to identify subsets of patients most responsive to their therapeutic approach," said Ari Azhir, PhD, CEO, Neuvivo. "This biomarker-based investigation utilized a patient population clinically responsive to NP001 - potentially a large subset - and we saw that macrophage regulation led to slowing, and in some cases halting of disease progression over the 6-month study. NP001 is currently the only treatment in development with a known mechanism of action linking biomarker changes to positive clinical outcomes in a subset of ALS patients. We are working to make treatment available as quickly as possible to people currently living with ALS who may benefit." Biomedicines Publication – Open Access: Biomedicines | Free Full-Text | Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation (mdpi.com) Editor's Note: The macrophage is the most primordial cell in the innate immune system. It is a type of white blood cell involved in the functioning of the inflammation-resolution cycle. Normally, in response to infection, a subset of macrophages become inflammatory and another subset become wound healing to maintain equilibrium. In ALS, the process is compromised, resulting in unchecked inflammation. Macrophage-targeted treatment restores the normal functioning in the epithelial barrier and throughout the body. About Neuvivo: Neuvivo is a private, late-clinical stage biopharmaceutical company developing advanced treatments for ALS and other neurodegenerative diseases. The company was formed by industry leaders and scientists, focused on improving the prognosis for patients diagnosed with ALS and a range of diseases for which few current treatment options exist. Lead candidate NP001 has been shown to be effective in a large subset of people living with ALS and has an exceptional safety profile. Neuvivo is working to make this treatment broadly available to patients as soon as possible. For more information please visit: Contact: Jennifer Larson 415 409 2729 Jennifer@neuvivo.com