Rapamycin fails to raise regulatory T-cell levels in RAP-ALS trial

Findings may have been affected by COVID-19 pandemic, researchers said

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Rapamycin, an approved medication used to prevent organ rejection after a kidney transplant, didn’t increase the number of regulatory T-cells in adults with amyotrophic lateral sclerosis (ALS) who are taking part in a Phase 2 clinical trial.

Along with not meeting its primary goal, RAP-ALS (NCT03359538) also failed to meet a number of secondary measures. The findings may have been impacted by the COVID-19 pandemic, which prevented many blood samples from being collected, and more trials may be needed to support the effectiveness of rapamycin, which was deemed generally safe and well tolerated.

“Rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS,” the researchers wrote in “Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis,” which was published in Nature Communications. The study was funded in part by Pfizer, which markets an approved version of rapamycin called Rapamune (sirolimus).

While the exact causes behind ALS are not clear, several disease processes are common to most patients. For example, most have an abnormal accumulation of proteins such as TDP-43 or SOD1 that form clumps outside the nucleus of nerve cells, triggering inflammation and damage.

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What does rapamycin do in ALS?

Rapamycin is believed to help nerve cells eliminate these toxic clumps by activating something called autophagy, a process cells use to recycle abnormal components or molecules that are no longer needed.

It also may increase the production of regulatory T-cells (Tregs), immune cells that regulate the excess activity of the immune system. These are often reduced and poorly active in ALS, and disease progression actually tends to occur faster in ALS patients with fewer Tregs, so increasing their amount has been an important consideration for new treatments.

To see if rapamycin could indeed impact the number of Tregs and other disease processes in ALS patients, researchers launched the RAP-ALS trial, which enrolled 63 participants across seven centers in Italy. They were randomly assigned to receive one of two doses of rapamycin — 1 or 2 mg per square meter of body surface area (mg/m2) — or a placebo, given daily for 18 weeks (about four months).

All continued to receive a stable dose of riluzole (sold as Rilutek, Tiglutik, and Exservan) during the trial, the main goal of which was to determine if more patients on rapamycin than a placebo saw a positive response — defined as an increase of at least 30% in the number of Tregs from the trial’s start (baseline) to week 18.

The proportion of patients showing a positive response was higher among those who received rapamycin at 1 or 2 mg/m2 versus a placebo (28 and 20% vs. 12%), but the difference wasn’t significantly different. Similar observations were made after correcting the results for sex, disease duration, rate of decline, and previous treatment with Radicava (edaravone).

Patients in all three groups saw a decline in the ALS Functional Rating Scale Revised (ALSFRS-R), a measure of disease severity where lower scores indicate more severe disease, for up to 54 weeks (about one year). The placebo group tended to progress at a faster rate than patients given the active treatment, but the differences between the groups weren’t significant.

Changes in inflammatory molecules, immune cells

Other secondary efficacy outcomes included changes in inflammatory molecules and in the activation and traveling ability of various immune cells.

The inflammatory cytokine interleukin (IL)-18 was significantly reduced with rapamycin compared with a placebo at week 18, indicating less inflammation, but the effect was lost after treatment stopped.

Rapamycin also significantly increased the numbers of certain immune cells such as monocytes and switch memory B-cells, a type of immune that may produce antibodies upon reactivation, suggesting “a compensatory mechanism of controlling inflammation by B cells,” wrote the researchers, who noted the findings “should be interpreted cautiously and require confirmation in larger studies, considering” corrections for multiple tests weren’t applied.

While the lower dose of rapamycin reached stable levels in the blood throughout the 18 weeks, the higher dose peaked at higher than desired levels, which required the next doses to be adjusted.

At week 18, rapamycin wasn’t detected in samples of the liquid that flows in and around the brain and spinal cord, called the cerebrospinal fluid, indicating it can’t enter the brain and reach the affected nerve cells.

The proportion of patients who had one or more side effects was similar in the rapamycin and placebo groups (55% vs. 52%), as was the proportion of those with serious side effects (19% for both).

Side effects related to the skin, such as redness, itching, and rash, were about five times as common with rapamycin than with the placebo. A case of acute hepatitis (liver inflammation) was reported in one patient and was likely related to the higher dose, but no lasting consequences were reported.

“In conclusion, this trial demonstrated that treatment with a low dose of rapamycin is safe in patients with ALS, but it failed to demonstrate an effect of the drug on Treg cells,” the researchers wrote.