Background

Neflamapimod 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). In addition, p38 MAPKα regulates Ras-related protein Rab5, a key regulator of early endosomes whose role in endolysosomal and synaptic vesicle function have made it a target in neurodegenerative disease drug development (Germann and Alam, 2020). 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). 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 (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 interpreting open-label results of small trials versus practice effects remains questionable. The Amsterdam study was formally published (Scheltens et al., 2018).

December 2017 saw the start of REVERSE-SD, a Phase 2 study of 161 people with CSF biomarker-confirmed mild AD. This proof-of-concept trial compared 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 (Alam et al., 2017). The trial took place at 38 study locations in the U.S., Europe and the U.K.

On November 7, 2019, EIP Pharma announced that REVERSE-SD had failed to meet its primary endpoint of improving episodic memory. Neflamapimod was safe but performed like placebo on the HVLT-R, WMS, or any of the other secondary endpoints. A prespecified subgroup analysis found trends toward improvement in the HVLT-R and WMS in patients with the highest plasma drug concentrations. Compared with placebo, the treatment group had statistically significant reductions in the biomarkers CSF phospho-tau, total tau, and a trend toward reduced neurogranin (see press release). This data was subsequently presented at CTAD 2019 (see conference news, slides posted on company website).

In October 2018, a fourth Phase 2 efficacy study began at University Hospital Toulouse. It is enrolling 40 people with prodromal AD as per Dubois et al., 2014, whose memory impairment on the Free and Cued Selective Reminding test (FCSRT; Grober 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, or placebo. 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. The trial is expected to run until January 2021.

In 2019, EIP Pharma began additional Phase 2 trials in people with dementia with Lewy bodies and early Huntington's disease (HD). Called AscenD-LD, the first planned to recruit 80 people with DLB, who will take 40 mg neflamapimod two or three times daily, based on weight, or placebo, for 16 weeks. The primary endpoint is change on a study-specific composite of six components of the Cogstate Neurological Test Battery, focused on attention, executive and visuospatial function. Secondary outcomes include the CDR-sb, MMSE, NPI, and International Shopping List Test, as well as a mobility test and electroencephalogram measures to evaluate potential biomarkers for DLB. The study will take place at 18 sites in U.S. and two in the Netherlands. The second study enrolls 16 people with genetically confirmed HD and cognitive deficits in Cambridge, England, U.K. Participants take 40 mg drug twice daily or placebo for 10 weeks, in a within-subject crossover design. They will be evaluated on change in hippocampal function as assessed by a virtual human Morris Water Maze. Secondary outcomes include the CANTAB paired associates learning task and safety. Both trials will run through mid-2020.

In November 2019, the FDA granted fast-track designation to neflamapimod for DLB.

On October 6, 2020, EIP Pharma announced that the AscendD-LB trial had met its primary endpoint (see company press release). According to results presented that November at CTAD, patients on neflamapimod three times daily improved on the cognitive composite compared to those on twice-daily dosing, or placebo. The gains were observed after four weeks treatment, and maintained at 16 weeks. Treatment resulted in improvement on the secondary endpoint of the Timed Up and Go Test, which measures mobility and cognition. Other secondary endpoints of the NPI, CDR-sb, and International Shopping List Test trended toward improvement (Nov 2020 conference news). Results on the remaining secondary endpoints—MMSE and quantitative EEG—were not reported. The study enrolled 91 patients at 24 sites and had no withdrawals due to drug-related events, and no reported drug-related adverse events.

For trials on this compound, see clinicaltrials.gov.

Clinical Trial Timeline