MIROCALS Trial — Low-Dose IL-2 in ALS (Lancet 2024)
MIROCALS — Modifying Immune Response and OutComes in ALS — was the first clinical trial to test whether boosting regulatory T cells (Tregs) with low-dose interleukin-2 could slow ALS progression. The trial enrolled around 220 patients across European centers, randomized them to aldesleukin (recombinant IL-2) or placebo, and published results in The Lancet in 2024. The primary endpoint was missed in the overall population. But a pre-specified subgroup analysis stratified by baseline neurofilament light chain — a biomarker of neurological injury — showed approximately 33% slower disease progression in patients with lower NfL levels. MIROCALS did not prove that IL-2 works in ALS, but it demonstrated that the neuroinflammation hypothesis is worth pursuing and that biomarker-based patient selection may be the key to unlocking it.
Mechanism of action: why target regulatory T cells?
ALS involves progressive inflammation around dying motor neurons. Regulatory T cells (Tregs) are immune cells that normally suppress excessive inflammatory responses. In ALS, Treg numbers and function are reduced compared to healthy controls, and lower Treg levels are associated with faster disease progression. This observation generated a therapeutic hypothesis: if restoring Treg function could dampen the neuroinflammatory component of ALS, it might slow the rate at which motor neurons are lost.
Low-dose interleukin-2 (IL-2LD) is an established method for selectively expanding the Treg population without triggering the broad immune activation that high-dose IL-2 produces. At low doses, IL-2 preferentially drives Treg expansion rather than general immune stimulation, making it a candidate for safely shifting the immune environment toward a neuroprotective rather than neurotoxic state. Aldesleukin (recombinant human IL-2) was the specific agent used in MIROCALS.
What they did
MIROCALS was a Phase 2b, double-blind, randomized, placebo-controlled trial conducted across multiple European centers. Approximately 220 newly diagnosed MND/ALS patients were recruited between 2017 and 2019. Participants were randomized to receive low-dose aldesleukin or placebo in addition to standard care (which included riluzole for eligible patients).
The primary endpoint was change in ALSFRS-R (ALS Functional Rating Scale — Revised) slope over the treatment period — the standard functional decline measure in ALS trials. Secondary and exploratory endpoints included survival, biomarker changes (including CSF phosphorylated neurofilament heavy chain, pNFH), and safety.
Critically, the trial pre-specified a biomarker subgroup analysis stratifying patients by baseline NfL levels. This was not a post-hoc fishing expedition: the researchers anticipated that a more biologically homogeneous patient population might show clearer signal, and they registered the subgroup analysis prospectively.
What they found
The primary analysis — ALSFRS-R slope in the full intention-to-treat population — did not show a statistically significant difference between the IL-2 and placebo groups. On this basis, MIROCALS missed its primary endpoint.
However, the pre-specified biomarker subgroup analysis told a more interesting story. In approximately 80% of participants who had lower baseline CSF pNFH levels — indicating less severe neurological injury at enrollment — low-dose IL-2 was associated with a statistically significant slowing of disease progression. In this subgroup, the risk of death was reduced by more than 40%, and ALSFRS-R decline was approximately 33% slower than placebo.
IL-2LD was safe compared to placebo in the overall trial population. No significant treatment-related safety signals emerged.
Why it matters
MIROCALS is important for at least three reasons, all of which extend well beyond whether this specific drug goes forward to Phase 3.
First, it is direct evidence that the neuroinflammation hypothesis in ALS has clinical traction. The Treg hypothesis was not just biologically plausible — it produced a measurable signal in a clinical trial. That signal was in a subgroup, and it needs to be replicated, but it is not nothing. Multiple research programs targeting neuroinflammation in ALS can now point to MIROCALS as clinical proof of concept for the general approach.
Second, the biomarker stratification finding may be the most important result from this trial. The fact that the treatment worked in the subgroup with lower baseline NfL — and apparently did not work in those with higher NfL, who had more aggressive disease — suggests that patient selection by NfL level might be a method for enriching trial populations and increasing the statistical power to detect treatment effects. This has implications for how future ALS trials are designed, not just for IL-2 specifically.
Third, MIROCALS supports further Phase 3 investigation with prospective NfL-based patient selection. If a larger trial enrolling only patients with lower baseline NfL replicates the 33% slowing of progression seen in the subgroup, it would be a clinically meaningful result.
PLS relevance
MIROCALS enrolled ALS patients, not PLS patients. The immune and inflammatory mechanisms in PLS are not well characterized, and there is no published evidence that Treg dysfunction is a feature of PLS pathophysiology in the same way it has been documented in ALS. The IL-2 approach is not currently being studied in PLS.
That said, PLS involves upper motor neuron degeneration in an inflammatory context. If future research establishes that Treg dysfunction contributes to PLS progression — which has not yet been studied — an immune modulation approach like IL-2 would become relevant. The MIROCALS findings are worth following for PLS researchers and patients, even though direct applicability is not established today.
How this connects
MIROCALS sits alongside other active ALS immunotherapy approaches and platform trial innovations. For context on the broader ALS trial landscape, the Drug Trial Research hub and the HEALEY Platform Trial page explain how modern multi-arm trial designs are changing the pace of ALS research. For the role of NfL in PLS and ALS research more broadly, see the Biomarker Research page.
Citation
MIROCALS investigators (led by Al-Chalabi A, Pradat PF). Modifying Immune Response and OutComes in ALS: results of the MIROCALS Phase 2b randomized controlled trial. The Lancet. 2024. UCL / Queen Mary University of London press release, May 2025.