Adding low-dose IL-2 to riluzole may improve survival in ALS
MIROCALS clinical trial enrolled 220 people who'd had ALS for up to two years
Adding a low dose of the anti-inflammatory molecule interleukin-2 (IL-2) to treatment with riluzole is safe and may help extend survival in certain people with amyotrophic lateral sclerosis (ALS), according to findings from a clinical trial called MIROCALS.
The Phase 2b trial didn’t show a significant survival benefit in the overall population and failed to meet its main goal. But patients with less neuronal damage, as determined by low levels of phosphorylated neurofilament heavy chain (pNFH) in the spinal fluid, had a 48% reduction in their risk of death when IL-2 was added to their treatment regimen. The results were published in The Lancet, in a paper titled, “Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial.”
“The publication of the results of the MIROCALS study is a milestone in the progress toward the development of novel treatments and in the understanding of the role of disease biomarkers in ALS clinical trials,” Andrea Malaspina, PhD, co-author of the study at Queen Mary University of London, said in a university press release.
ALS is a neurodegenerative disease wherein motor neurons, the nerve cells that control movement, become damaged and die. Its causes aren’t fully understood, but data suggest that abnormal inflammation in the nervous system plays a key role in the disease’s progression.
IL-2 is a signaling molecule made in the body to help coordinate the activity of the immune system. At low doses, it promotes the activity of regulatory T-cells (Tregs), which are specialized immune cells that act to put the brakes on excessive immune activity, dampening inflammation.
Riluzole is a widely approved ALS treatment that’s been proven to slow ALS progression. The oral therapy, formerly sold as Rilutek and now available only as generics, is available as a tablet, and an oral suspension formulation is sold as Tiglutik.
Low dose of IL-2
The MIROCALS study (NCT03039673), sponsored by Centre Hospitalier Universitaire de Nīmes in France, was designed to see if adding a low dose of IL-2 to riluzole treatment could improve survival with ALS. It enrolled 220 people who’d been living with the disease for no more than two years and who hadn’t been treated previously. The median time from their diagnosis of ALS to being included in the study was 1.4 months.
For the first three to four months of the study, all the participants were treated with riluzole only to determine their tolerance to it. Then, the patients were randomly assigned to low-dose IL-2, or a placebo, along with riluzole for the remainder of the study. IL-2 was provided as aldesleukin, sold under the brand name Proleukin, which is a lab-made version of the human IL-2 protein.
After nearly two years, 37% of patients in the IL-2 group and 45% of those in the placebo group had died. Mathematically, that reflects a 19% lower risk of death with IL-2, but it’s not a statistically significant difference. The risk of needing a tracheostomy (breathing tube), gastrostomy (feeding tube), or noninvasive ventilation also tended to be lower in the IL-2 group, but again the difference wasn’t statistically significant.
Low pNFH levels and treatment
While the main outcome wasn’t statistically significant, the effect of treatment was significantly modulated by levels of a nerve damage marker called pNFH in the fluid that surrounds the brain and spinal cord, statistical analyses indicated.
Most (79%) trial participants had low pNFH levels. In these patients, IL-2 was associated with a statistically significant, 48% reduced risk of death, along with a lower risk of needing a tracheostomy, gastrostomy, or noninvasive ventilation.
For the 21% of participants with high pNFH, however, there was no significant difference. In fact, the rate of death was a bit higher for those given IL-2 in the high pNFH group.
“Although the unadjusted analysis of the primary endpoint, survival, showing a 19% decrease in the risk of death did not reach statistical significance, the planned adjusted analysis showed a significant treatment effect on decreasing the risk of death and a significant treatment by pNFH interaction,” the researchers wrote.
Safety data indicated IL-2 was generally well tolerated; in both the IL-2 and placebo groups, most serious safety issues were related to the underlying ALS, not the study drug. The most common safety issues in the IL-2 group included injection site reactions, flu-like symptoms, digestive issues, and fatigue. Five serious safety complications judged to be related to IL-2 were reported, including allergic reactions, pneumonia, altered state of consciousness, and autoimmune disease.
Biomarker data showed that IL-2 treatment was associated with an increase in Treg levels and decreased levels of pro-inflammatory signaling molecules, consistent with the idea that it reduces inflammation.
The data collectively support the idea that adding low-dose IL-2 to riluzole “could safely be administered over a prolonged period to improve survival and reduce the rate of functional decline in people with ALS,” said the scientists, who emphasized that more research is needed to validate their findings.
About the Author
