Short course of treatment with RNS60 extends survival in ALS
Trial data up to 6 years show benefits to patients with Revalesio therapy
A short course of treatment with Revalesio‘s RNS60 as an add-on to standard amyotrophic lateral sclerosis (ALS) therapies extended the median survival of people with the progressive disease by about six months compared with a placebo.
That’s according to up to six years of data from an investigator-sponsored Phase 2 clinical trial (NCT03456882) taking place at nearly two dozen sites in Italy. The participants received RNS60 for six months in addition to standard riluzole therapy (sold as Rilutek and others), and were then monitored for survival in the long term.
Survival was particularly greater in a group of patients with slower decline in lung function over the trial’s duration. Also, benefits from RNS60 were only significantly different from the placebo in patients with low levels of key ALS biomarkers — specifically neurofilament light chain (NfL) and monocyte chemoattractant protein-1 (MCP-1).
“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, MD, professor of neurology and director of the Tertiary ALS Center at the University of Piemonte Orientale in Italy and one of the trial’s clinical centers, said in a company press release.
The study detailing the results, titled “Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis,” was published in the journal Brain, Behavior, and Immunity.
Assessing the impact of RNS60 on clinical outcomes
RNS60 is an experimental therapy that uses fluid dynamics to address key mechanisms involved in ALS. These include inflammation, abnormalities in the function of mitochondria — the cell’s powerhouses — and nerve cell death.
In preclinical studies, the drug has shown the ability to protect the integrity of neurons and other supporting cells in the brain and spinal cord, preventing cell damage and death.
The Phase 2 trial, conducted across 22 centers in Italy, was designed to assess the impact of RNS60 on a number of ALS biomarkers and several clinical outcomes. A total of 147 ALS patients were randomly assigned to receive either RNS60 or the placebo. Administration was via an intravenous, or into-the-vein, infusion once a week, containing 375 mL of the therapy, and via a nebulizer that delivered 4 mL of treatment on non-infusion days.
This regimen was followed for 24 weeks, or six months, after which patients were followed without receiving additional RNS60 treatment. All participants also took riluzole, the only approved medication known to have an impact on ALS survival.
Data after six months showed that the decline in forced vital capacity (FVC), a measure of lung function that evaluates how much air a person can forcibly exhale after a deep breath, was significantly slower in the RNS60 compared with the placebo group. While a decrease in lung function decline has been associated with improved outcomes, no differences were detected in disease progression after six months. Moreover, the short duration of the trial also precluded meaningful survival analyses.
New trial data comes after an average 2.8 years of follow-up
Now, the researchers reported on the data collected after a mean follow-up of 2.8 years. This post-hoc analysis, meaning it was specified and conducted after the trial was complete, comprised data from all patients who had originally entered the trial.
The results showed that the median survival time was six months longer for patients treated with RNS60 for six months compared with those given the placebo. Patients lived a median of three years after treatment with RNS60, versus 2.4 years following the placebo; this difference, however, failed to reach statistical significance.
Patients in the overall population — both the placebo and RNS60 groups — were then divided based on how fast their FVC declined in the first four weeks of the trial, when treatment was not expected to have had a significant effect. The data showed that slow FVC progressors lived significantly longer than fast progressors (median 3.7 years vs. 1.6 years).
A Phase 3 clinical trial of RNS60 is warranted … [to] evaluate whether longer administration of this investigational product is associated with slower decline in respiratory function and improved survival in people living with ALS.
Importantly, most patient characteristics had no impact on RNS60’s survival benefits. The only exceptions were NfL and MCP-1 levels at the trial start. In the groups of patients where these biomarkers were low at the beginning of treatment, those treated with RNS60 survived significantly longer compared with those on the placebo.
These findings suggest that measuring the NfL and MCP-1 levels may help identify which ALS patients are more likely to respond to RNS60.
“These results warrant further investigation, and I look forward to the future development of RNS60 for the treatment of ALS,” said Mazzini.
According to the researchers overall, “a Phase 3 clinical trial of RNS60 is warranted,” the team wrote. Specifically, the scientists want to “evaluate whether longer administration of this investigational product is associated with slower decline in respiratory function and improved survival in people living with ALS,” they wrote.
RNS60 has been granted both orphan drug and fast track status for ALS by the U.S. Food and Drug Administration. These designations are expected to support and accelerate the development and review of RNS60 for this indication.
“We are committed to advancing RNS60 in additional clinical trials to further evaluate [its] potential to benefit people with ALS and other neurological disorders,” said Bert van den Bergh, Revalesio’s executive chairman on the board of directors.
“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,” van den Bergh added.
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