Arthritis Treatment Eases Signs of Inflammation in ALS Patients in Trial

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by Forest Ray PhD |

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Actemra (tocilizumab), an approved treatment for rheumatoid arthritis, was found to be safe and well-tolerated, and to reduce a key marker of inflammation in amyotrophic lateral sclerosis (ALS) patients with evidence of systemic inflammation in a Phase 2 study.

Trial results did not demonstrate that Actemra could slow ALS disability progression. But this study in 22 people “was not originally powered to detect clinical effect,” its researchers wrote, and a larger “efficacy trial” is warranted.

Findings for this study, “Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients,” were published in the journal Muscle & Nerve.

Actemra, an injectable medication, works to reduce inflammation by blocking a protein called IL-6.

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Although it remains unclear whether inflammation plays a role in ALS onset, it has a clear role in disease progression, which makes anti-inflammatory therapies attractive approaches for treating the disorder.

To test Actemra’s potential as an ALS therapy, researchers at the Barrow Neurological Institute in Arizona recruited 22 adults with ALS, whose symptoms started up to three years earlier, into their placebo-controlled Phase 2 study (NCT02469896).

To be eligible, participants had to have high amounts of inflammatory markers in their blood cells, a criteria used to ensure that they had an underlying disease mechanism dependent on active inflammation.

Patients were randomized to either three once-monthly intravenous infusions of Actemra or a placebo. Investigators followed participants every four weeks for 16 weeks, monitoring for safety, tolerability, inflammatory markers, and various clinical measures, such as disability progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R; declining scores indicate progression).

Overall, Actemra appeared to be safe for these patients, with few reports of adverse side effects. A severe incident of aspiration pneumonia occurred in one placebo group individual, and infections were reported in one patient each in the treatment and placebo groups.

Side effects led two Actemra group patients to stop taking their infusions, although both completed their trial visits. One acquired a bacterial infection, and certain white blood cells dropped to abnormally low levels in the other participant, raising the risk of infection. Both of these cases resolved without complications.

Levels of C-reactive protein (CRP) — released from the liver in response to inflammation — dropped by 88% in the blood of Actemra group patients, compared with a 4% increase in the placebo group. Levels of IL-6 and its receptor, meanwhile, “dramatically” increased in the Actemra group.

Similar changes occurred in patients’ cerebrospinal fluid (CSF), the transparent liquid that surrounds the brain and spinal cord.

High amounts of circulating IL-6 typically associate with declines in ALSFRS-R scores. But the higher levels seen in this study, the researchers noted, are likely due to having impeded its normal breakdown, rather than to an actual increase in IL-6 production.

Individual changes in the levels of these biomarkers appeared to vary based on specific variations found within individuals’ IL6R genes, which code for the IL-6 receptor.

Although the drug was safe and well-tolerated, and eased biochemical signs of inflammation, investigators observed no clinical benefit with Actemra treatment, namely changes in ALSFRS-R scores.

“These results,” they concluded, “warrant further study in ALS patients where IL6R genotype and CRP levels may be useful enrichment biomarkers.”