Low-dose Aldesleukin Slows ALS Progression, Extends Survival: Trial
Therapy's benefits were most effective in patients with less aggressive disease
A low dose of aldesleukin, an immunotherapy approved for certain cancers, slowed disease progression and significantly improved survival in people with amyotrophic lateral sclerosis (ALS), particularly in those with less aggressive disease.
These are the most recent results from the MIROCALS Phase 2 trial (NCT03039673), which tested aldesleukin versus a placebo in 220 patients whose symptoms of ALS began less than two years before enrolling.
This “is positive news for patients with ALS, for which there is currently no effective treatment, and we look forward to understanding what further research is planned,” said David Bryant, CEO of Clinigen, in a company press release. Clinigen is the company that markets aldesleukin.
The findings were presented at the recent 33rd International Symposium on ALS/MND by Gilbert Bensimon, MD, PhD, who coordinated the MIROCALS study. His presentation was titled, “Modifying immune response and outcomes in ALS (MIROCALS): design and results of a phase 2b, double-blind randomized placebo-controlled trial of low dose interleukin-2 (ld IL2) in ALS,” (abstract C03).
ALS occurs when motor neurons, the nerve cells in the brain and spinal cord that control voluntary movement, stop working over time. The exact causes of motor neuron damage are not fully clear, but an overly active immune system may play a role.
Aldesleukin, sold under the brand name Proleukin, is a lab-made version of a human protein called interleukin 2 (IL-2), which is essential for regulatory T-cells’ survival and function. Also known as Tregs, these cells work to dampen excessive inflammatory responses and maintain a healthy immune balance.
In ALS, a higher number of Tregs in circulation is associated with extended survival, suggesting boosting their levels could be a promising approach to slowing disease progression and increasing life expectancy.
A pivotal Phase 2 clinical trial called IMODALS (NCT02059759) investigated the effects of low-dose aldesleukin injections in 36 people with ALS. Results showed that three months of treatment significantly increased the number and activity of Tregs compared with a placebo.
Effects of low-dose aldesleukin in MIROCALS
The data supported the launch of the larger MIROCALS study, which took place in 17 clinics across the U.K. and France. Participants were randomly assigned to receive low-dose aldesleukin or a placebo, given via under-the-skin injections over a monthly five-day course, for 18 months. All continued on oral riluzole treatment during the study.
The trial’s main goal was to determine if the combination of aldesleukin plus riluzole extended patients’ survival compared with riluzole plus a placebo. Secondary measures included the rate of disease progression, respiratory function decline, and changes in biomarkers of inflammation and nerve damage.
In an initial analysis, aldesleukin tended to improve survival rates by 19% compared with a placebo, but the findings failed to reach statistical significance. However, when researchers took into account the amount of phosphorylated neurofilament heavy chain (pNFH) patients had in their cerebrospinal fluid at the trial’s start, the treatment had a significant effect on survival, reducing the risk of death by 73%.
The cerebrospinal fluid (CSF) is the liquid that surrounds the brain and spinal cord and pNFH levels are normally a good biomarker of disease severity. Higher levels of this protein in the CSF are indicative of more aggressive, fast progressing disease, while lower levels correspond to less aggressive disease progression.
Researchers found that aldesleukin didn’t induce any survival benefit versus a placebo in people with higher CSF-pNFH levels, but did result in a significant reduction – by 43% – in the risk of death in people with lower levels of this biomarker.
Patients with low CSF-pNFH levels also had a slower disease progression — as assessed with the decline in ALS Functional Rating Scale–Revised (ALSFRS-R) scores — suggesting the treatment is more effective in people with slower disease progression.
The treatment was well tolerated. Side effects, which were mostly mild to moderate, occurred across both low-dose aldesleukin and placebo groups.
The U.S. Food and Drug Administration granted orphan drug designation to aldesleukin in 2020 for treating ALS. The status is meant to advance the clinical development and review of therapies for rare and life-threatening conditions by providing benefits such as seven years of market exclusivity and exemption from FDA application fees.
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