RNS60 Extends Survival and Improves Respiratory Function in ALS, Post-Hoc Analysis Shows

Letizia Mazzini

Newly published data from a post-hoc analysis of a phase 2 investigator-initiated trial (NCT03456882) showed that treatment with Revalesio’s RNS60, an anti-inflammatory and cytoprotective agent, resulted in beneficial impacts on survival and slowing the decline of respiratory function in patients with amyotrophic lateral sclerosis (ALS). Overall, the therapy was most successful in those with lower neurofilament light (NfL) and Monocyte Chemoattractant Protein-1 (MCP-1) levels at study entry, suggesting this could be a subgroup to target in future studies assessing RNS60’s effect on survival.^1,2

Published in Brain, Behavior, and Immunity, the double-blind, placebo-controlled study randomly assigned 147 patients with ALS to either RNS60 (n = 74) or placebo (n = 73) for 24 weeks. Over a mean duration follow-up of 2.8 years, long-term median survival was 6 months longer in the RNS60 group (P = .0519) over placebo. During that time, the number of deaths was 40 (54.1%) in the group randomized to RNS60 and 46 (63.0%) in the group randomized to placebo.

Although the baseline forced vital capacity (FVC) and rates of FVC decline were similar between RNS60 and placebo through the first 4 weeks, the active treatment group started to separate at the end of the 6-month treatment period. There, investigators recorded significantly slower declines in FVS in the RNS60 group relative to placebo (difference per week, 0.41 [SE, 0.16]; P = .0101), further demonstrating the agent’s impact on respiratory and bulbar function.

"These promising findings suggest that RNS60 may have a beneficial effect on survival and slowing the decline of respiratory function in patients with ALS," Letizia Mazzini, a professor of neurology and director of the Tertiary ALS Center at the University of Piemonte Orientale, said in a statement.¹ "These results warrant further investigation, and I look forward to the future development of RNS60 for the treatment of ALS.”

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This was not the first reported instance of RNS60’s impact on bulbar and respiratory function in ALS. Previously reported data at the 2022 Annual NEALS Meeting from the same study showed that RNS60 had no disease-modifying effects on candidate biomarkers or functional decline; however, did demonstrate positive impacts on those such outcomes. In that analysis, RNS60-treated patients showed a –0.46 per week decrease in FVC over the 24-week period, vs decreases from 102.6% to 81.6% for those on placebo.³

In the newly published analysis, rates of FVC progression during RNS60 treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). Furthermore, the effects of the anti-inflammatory therapy in prolonging long-term survival was higher in those with low NfL (median survival: >4 years in low NfL RNS60 groups; 3.3 years in low NfL placebo group; 1.9 years in high NfL RNS60 group; 1.8 years in high NfL placebo group) and MCP-1 (median survival: 3.7 years in low MCP-1 RNS60 group; 2.3 years in low MCP-1 placebo group; 2.8 years in high MCP-1 RNS60 group; 2.6 years in high MCP-1 placebo group) levels at baseline.

"With these encouraging results, RNS60 has shown benefit across two randomized clinical trials in ALS and ischemic stroke, underscoring its potential to impact patients with both acute and chronic neurological disorders. We are committed to advancing RNS60 in additional clinical trials to further evaluate RNS60's potential to benefit people with ALS and other neurological disorders," Bert van den Bergh, executive chairman, Revalesio, said in a statement.¹ "On behalf of Revalesio, I would like to thank the investigators for conducting this important additional analysis, as well as the patients and their families for their participation. I would also like to thank the ALS Association for contributing to the original study through the ALS Ice Bucket Challenge."

RNS60 is designed to provide potentially restorative treatment for neurological diseases, including ALS and acute ischemic stroke (AIS). Earlier this year, at the 2024 International Stroke Conference, data from a phase 2 study dubbed RESCUE (NCT04693715) showed that RNS60 has potential impacts on reducing poststroke disability. In addition to meeting its primary end point, treatment with high-dose RNS60 resulted in significantly lowered infarct growth by 50% (nominal P <.05) when compared with placebo based on imaging done at 48 hours.⁴

Additional data showed that the high-dose active treatment group outperformed placebo in number of secondary end points, including modified Rankin Scale score at day 90, Barthel Index at day 90, and NIHSS at each specified time point for both absolute value and change from baseline. Overall, the therapy was safe, with similar rates of serious adverse events and numerically lower rates of mortality (with no statistical comparison).

REFERENCES
1. Revalesio's Investigational RNS60 Extended Survival in Patients with Amyotrophic Lateral Sclerosis (ALS) in Post-Hoc Analysis of Phase 2 Investigator-Sponsored Trial. Revalesio. September 17, 2024. Accessed September 25, 2024. https://www.prnewswire.com/news-releases/revalesios-investigational-rns60-extended-survival-in-patients-with-amyotrophic-lateral-sclerosis-als-in-post-hoc-analysis-of-phase-2-investigator-sponsored-trial-302250190.html
2. Pupillo E, Bianchi E, Bonetto V, et al. Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis. Brain, Behav, and Immunity. 2024;122(456-462). doi:10.1016/j.bbi.2024.08.044
3. Pupillo E, Bianchi E, Bendotti C, et al. Randomized, double-blind placebo controlled trial on the use of RNS60 in ALS subjects: final results and perspectives. Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 8.
4. Revalesio announces positive topline data from phase 2 RESCUE study of RNS60 in patients with acute ischemic stroke in late-breaking oral presentation at ISC 2024. News release. February 7, 2024. Accessed September 25, 2024. https://revalesio.com/press-releases/revalesio-announces-positive-topline-data-from-phase-2-rescue-study-of-rns60-in-patients-with-acute-ischemic-stroke-in-late-breaking-oral-presentation-at-isc-2024/