Background

VX-745 selectively inhibits the alpha isoform of the mitogen-activated serine/threonine protein kinase p38 MAPK, a "stress kinase" considered 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; Corrêa 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 2-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 postsynaptic 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 (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 compared two doses of VX-745, 40 mg or 125 mg, given orally for six weeks to 16 people with clinical diagnoses of MCI due to AD or mild AD, and brain hypometabolism as per FDG-PET scan. Primary outcomes were change on CSF biomarkers and FDG-PET; secondary outcomes were safety and exposure measures. Conducted at the Alzheimer Research Center, VU Medical Center, Amsterdam, the second study also enrolled 16 people with the same diagnosis who had evidence of brain amyloid deposition as per 11C PiB PET. This study administered either 40 mg or 125 mg VX-745 twice daily for 12 weeks, and measured the effect on safety and on brain amyloid burden, using a dynamic, DVR protocol developed to reduce measurement variability in amyloid PET.

Results of both were presented at the 2016 CTAD and the 2017 AAIC meetings (see Dec 2016 conference news, Aug 2017 conference news). Neflamapimod caused no serious adverse events, and was reported to have shown signals on both amyloid removal and cognition, though interpretating open-label results of small trials versus practice effects remains limited. The Amsterdam study was formally published (Scheltens et al., 2018).

In December 2017, a blinded and placebo-controlled Phase 2 study of 152 people with CSF biomarker-confirmed mild AD started. Called REVERSE-SD, this proof-of-concept study will compare a six-month course of a 40 mg neflamapimod capsule taken twice daily to placebo on change in total and delayed recall on the Hopkins Verbal Learning Test, Revised (HVLT-R). Secondary outcomes include the Wechsler Memory Scale (WMS) Immediate and delayed Recall, CDR-Sum of Boxes, MMSE, as well as CSF p-tau181 and Aβ1-40. The trial is recruiting at nine U.S. sites, and will run through summer 2019 (Alam et al., 2017).

In February 2018, a fourth Phase 2 efficacy study was listed. This study will enroll 40 people with prodromal AD as per Dubois et al., 2014, whose memory impairment on the Free and Cued Selective Reminding test (FCSRT, Grober, Hall et al. 2008) falls into a defined range, and who have cerebral amyloidopathy as per CSF analysis or amyloid PET. This trial uses the microglial activation tracer DPA-714, which binds the microglial translocator protein TSPO, in an attempt to monitor brain inflammation in response to a 12-week course of treatment with 40 mg neflamapimod twice daily. Three DPA-714 SUV measures represent the primary outcome; secondary outcomes span 35 measures ranging from neuropsychological assessments to blood and CSF markers of inflammation. This trial is sponsored by University Hospital, Toulouse; as of May 16, 2018, sites were not yet listed.

For trials on this compound, see clinicaltrials.gov.

Clinical Trial Timeline