Inhibition of p38α MAPK increases short-term astrocyte reactivity: the exploratory VIP trial in early Alzheimer’s disease

Neuro-inflammation is an early mechanistic target in Alzheimer’s disease (AD). However, the effect of anti-inflammatory drugs on biomarkers of neuro-inflammation has yet to be described. Biomarkers of neuro-inflammation showed distinct evolution over the course of AD, suggesting that anti-inflammatory interventions could be beneficial or interfere with mechanisms of immune defense. We conducted a pilot and exploratory phase II trial to evaluate the short-term effects of neflamapimod, a drug known to inhibit the neuro-toxic pro-inflammatory properties of the p38α MAPK. Participants with early AD were randomized to receive neflamapimod 40 mg (n = 17) or placebo (n = 16) twice-daily for 12 weeks. The primary endpoint was the treatment-related change in PET imaging of the translocator protein (TSPO) using [18F]-DPA-714. The main secondary endpoints were cerebrospinal fluid (CSF) markers of microglial and astrocyte reactivity. We hypothesized that neuro-inflammation would be reduced at three months in PET and in CSF markers. Neuro-inflammation was not reduced between the neflamapimod and placebo groups, and no change was observed in [18F]-DPA-714 PET. However, neflamapimod induced a significant increase in CSF GFAP levels compared to placebo. Multivariate analyses based on CSF biomarkers highlighted the contribution of sTREM2 in the pattern of variation that discriminated the two groups (accuracy = 71%). Patients who received neflamapimod and had baseline sTREM2 level above the median had the highest increase in GFAP compared to placebo, suggesting that neflamapimod may exacerbate reactive astrogliosis as a function of the TREM2-related microglial state. Safety analysis showed that three cases of CSF pleocytosis occurred during follow-up in participants receiving neflamapimod. Neflamapimod at a dose of 40 mg twice-daily interfered with mechanisms of immune defense in early AD. Although this study is exploratory, our results may provide an explanation for the failure of previous anti-inflammatory interventions in early AD. Biomarkers of neuro-inflammation should be required in the next-generation trials targeting neuro-immune mechanisms in AD. ClinicalTrials.gov, Clinical Trial registration number: NCT03435861.