Background

Baricitinib is an inhibitor of Janus kinase (JAK). It is approved in the U.S. and many other countries for the treatment of rheumatoid arthritis and severe COVID, approved in Japan and Europe but not yet the U.S. for atopic dermatitis, and used for alopecia areata. Baricitinib suppresses the immune system and reduces inflammation by interfering with cytokine signaling induced via the JAK/STAT, i.e., signal transducer and activator of transcription pathway.

The repurposing of baricitinib for neurodegeneration rests on studies from Massachusetts General Hospital that uncovered a role for JAK-mediated innate immunity in neuronal cell death in amyotrophic lateral sclerosis. In cells bearing the causative c9ORF72 gene hexanucleotide expansions, double-stranded RNA products of the expanded repeats triggered the Type I interferon inflammatory response, which caused neuron death. Baricitinib or other FDA-approved JAK inhibitors blocked this interferon response and rescued cell death (July 2021 news). In a separate study, the same investigators identified baricitinib as a candidate for repurposing for Alzheimer disease, based on a computational biology analysis of gene expression changes in AD brain, and reversal of these changes in drug-treated cells (Rodriguez et al., 2021).

Baricitinib carries box warnings for increased risk of serious infections, cancer, major cardiovascular events, blood clots, and death. In clinical trials, the most common side effects were upper respiratory tract infections, nausea, and shingles or herpes flare-ups. The drug is taken in tablet form, in doses of 2 mg per day for arthritis, and 4 mg per day for COVID.

Findings

In December 2022, a trial began to test baricitinib in people at risk for, or with, Alzheimer’s disease or ALS. The open-label study aims to enroll 20 participants with subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease, or ALS, or asymptomatic carriers of a C9ORF72 gene expansion. Participants must have elevated levels of the inflammatory cytokine CCL2 in CSF. Dosing will be 2 mg daily for eight weeks, then 4 mg for 16 weeks. Primary outcomes are CSF concentration of baricitinib and CCL2. Secondary outcomes include CSF biomarkers of inflammation and neurodegeneration, plasma levels of the RNA-binding protein TDP-43, and adverse effects. The study, at Massachusetts General Hospital and Holy Cross Hospital in Florida, will finish in mid-2024. For details on this study, see clinicaltrials.gov.

In Phase 3 trials, baricitinib reversed autoimmune hair loss (King et al., 2022). Trials are ongoing for a range of autoimmune conditions; see clinicaltrials.gov.