Background

VX-745 selectively inhibits the alpha isoform of the mitogen-activated serine/threonine protein kinase p38 MAPK, a "stress kinase" considered to be a drug target in CNS diseases (Duffy et al., 2011). p38 MAPKα is expressed in microglia and neurons. In microglia, the enzyme stimulates release of pro-inflammatory cytokines such as TNFα and IL-1β  in response to a variety of stressors including Aβ42; in neurons, signaling via p38 MAPKα has been implicated in tau localization and neuronal plasticity (Yasuda et al., 2011; Bachstetter et al., 2011; Correa and Eales, 2012). Other p38 MAPKα inhibitors are reported to slow progression in AD mouse models (Roy et al., 2015 ). 

In animal models, VX-745 reportedly shifts microglial activation from a pro-inflammatory to a phagocytic state, improving mitochondrial function, synaptic transmission, and memory. In two-year-old Tg2576 mice treated with 3 mg/kg for two weeks, amyloid plaque load was halved. In aged rats, which develop more neuroinflammation than Tg2576 mice, VX-745 lowered IL-1β, increased the post-synaptic marker PSD95, and improved performance in the Morris water maze, though these effects were apparent at different doses (Dec 2014 conference news; Alam 2015). 

This is a drug-repurposing program. VX-745 was discovered at Vertex Pharmaceuticals. It was being tested for rheumatoid arthritis, but was later discontinued, in part due to adverse effects in the central nervous system in preclinical studies (see Haddad, 2001; news release). This drug has been reported to reach higher concentrations in the CNS than peripheral blood.

Findings

In April 2015, two small, open-label, Phase 2 trials began. Run by Parexel in Glendale, California, a pharmacology study is enrolling 16 people with a clinical diagnosis of MCI due to AD or mild AD plus brain hypometabolism as per FDG-PET scan,  and will compare a six-week course of two doses of VX-745. Primary outcomes are change on CSF biomarkers and FDG-PET; secondary outcomes are safety and exposure measures.

Conducted at the Alzheimer Research Center, VU Medical Center, Amsterdam, the second study is enrolling 16 people with the same diagnosis, who also have evidence of brain amyloid deposition as per 11C PiB PET. This study will administer either 40 mg or 125 mg VX-745 twice daily for 12 weeks, and measure the effect of this course of treatment of brain amyloid burden, and on safety. This trial uses a dynamic, DVR protocol developed to reduce measurement variability in amyloid PET. 

For trials on this compound, see clinicaltrials.gov.

Clinical Trial Timeline