Neuvivo Submits NDA to FDA for Investigational ALS Treatment NP001

Ari Azhir, PhD

(Credit: LinkedIn)

According to a new announcement, Neuvivo has submitted a new drug application (NDA) to the FDA for NP001, the company's investigational regulator of innate immune function, for treating patients with amyotrophic lateral sclerosis (ALS). If approved, NP001 could potentially be the first disease-modifying therapy that restores balance over uncontrolled inflammation in the body’s own innate immune system for ALS.¹

In March 2023, the company announced that data from a phase 2 study published in Cells assessing NP001 showed that C-reactive protein (CRP) levels in patients with ALS correlated with lung function. Notably, plasma TGFB1, a dominant regulator of inflammation, was 95% higher after 6 months in high CRP-treated patients relative to controls, suggesting the therapy may have acted in part to reset the innate immune system.^2,3

“ALS is a devastating disease and patients who are fighting ALS need much better treatment options,” Ari Azhir, PhD, founder and CEO at Neuvivo, said in a statement.¹ “Our organization was built on our passion and commitment to help those struggling with ALS by finding new treatments that can make a meaningful difference in their quality of life. We are thrilled to have submitted NP001 for FDA approval as the treatment platform may substantially preserve lung function and extend overall survival by up to a year, especially in patients identified through therapeutic biomarkers as having underlying, uncontrolled inflammation as a result of ALS.”

Prior studies have shown that 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. In accordance with FDA guidance published in 2019, the prior analysis stratified and defined patients as high CRP (>1.13 mg/L; n = 75) or low CRP (<1.13 mg/L; n = 50). Following this, findings showed a 64% slower rate of vital capacity (VC) decline in patients with high CRP compared with placebo (P = .05) and those with low CRP, who showed no response.

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All ALS baseline values were similar between treated and controls except for those older than 65 years who were excluded from the analysis. While those with low baseline CRP saw no change in VC over time regardless of treatment status, patients with high CRP on placebo lost an average of 2.1% VC per month. In comparison, those on NP001 with high CRP lost 0.75% VC per month. By age, there were no significant differences found between placebo and 2 mg/kg NP001 treated in both high and low CRP groups.

In patients with ALS less than 65 years, investigators reported a positive linear relationship between plasma levels of the acute phase reactant serum amyloid A (SAA), a factor related to innate immune system regulation, and high CRP at baseline (R2 = 0.25; P = .004). This confirmed that the immune activation in patients with high CRP is not isolated, but a component of a generalized acute phase reaction.

“Based on the evidence shown across the Phase 2a, Phase 2b, and Overall Survival studies as well as the biomarker analysis, we believe submitting the New Drug Application to the FDA for NP001 offers great promise to the ALS community,” Matthew W Davis, MD, RPh, chief medical officer at Neuvivo, said in a statement.¹

Because CRP elevation as an immune regulator alone was not controlling ALS disease progression, investigators examined plasma TGFB1 to see whether there would be evidence of alpha 2 macroglobulin (A2M) activation, another component of the humoral innate immune system. Following exposure to NP001, plasma TGFB1 levels increased by more than 95%, suggesting that the therapy caused an A2M dimerization with the release of TGFB1. Furthermore, elevated levels of TGFB1 observed 1 month after the final dose suggested that the other function of A2M dimers, the clearance of misfolded proteins, may have reset the innate immune activation cycle.

At the conclusion of the previous analysis, investigators noted that larger properly powered placebo-controlled trials would be needed to test the theory that clinical VC responses to NP001 would be related to the regulation of the innate immune system. Given that GCP is an acute phase reactant, inherently variable plasma CRP levels that differed between patients could have possibly confounded results tied to the selection of patients with slightly elevated CRP values.

“The submission of NP001 for FDA approval brings new hope to people living with ALS, their families and caregivers. We are truly honored to have collaborated with such a distinguished investigator team and thankful for Neuvivo’s resilience with continuing to develop NP001 to reach this critical milestone,” Namita Goyal, MD, a neuromuscular medicine specialist and clinical professor of neurology at University of California, Irvine, said in a statement.¹

REFERENCES
1. Neuvivo Seeks FDA Approval for Its Breakthrough ALS Treatment NP001. News Release. Neuvivo. Published October 7, 2024. Accessed October 8, 2024. https://www.neuvivo.com/news/neuvivo-seeks-fda-approval-for-its-breakthrough-als-treatment-np001/
2. New study of Neuvivo’s NP001 is first to link regulation of the innate immune system with respiratory function in ALS patients. News release. Neuvivo. March 30, 2023. Accessed October 8, 2024. https://www.neuvivo.com/news/new-study-of-neuvivos-np001-is-first-to-link-regulation-of-the-innate-immune-system-with-respiratory-function-in-als-patients/
3. McGrath MS, Zhang R, Bracci PM, Azhir A, Forrest BD. Regulation of the innate immune system as a therapeutic approach to supporting respiratory function in ALS. Cells. 2023;12(7). doi:10.3390/cells12071031