Name: Neflamapimod
Synonyms: VX-745
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Dementia with Lewy Bodies, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Dementia with Lewy Bodies (Phase 2), Huntington's Disease (Phase 2)
Company: EIP Pharma, LLC


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). Previously called VX-745, neflamapimod has been repurposed for evaluation in neurodegenerative diseases. 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.

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., 2011Bachstetter et al., 2011Corrêa 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 has 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)In a rat ischemic stroke model, subacute treatment for six weeks dose-dependently promoted behavior, sensory and motor function recovery, and raised brain-derived neurotrophic factor (BDNF) protein levels (Alam et al., 2020).


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 newsAug 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 (Dec 2019 conference newsslides posted on company website), and published after peer review (Prins et al., 2021).

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 June 2021.

In 2019, EIP Pharma began additional Phase 2 trials in people with dementia with Lewy bodies (DLB) and early Huntington's disease (HD). Called AscenD-LB, 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 was scheduled to take place at 22 sites in U.S. and two in the Netherlands, and run through mid-2020. The second study was to enroll 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. 

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.

In October 2020, the HD trial was terminated before completion, due to Covid19 restrictions (see EU Clinical Trials RegisterEIP Pharma website).

For trials on this compound, see

Clinical Trial Timeline

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031
EIP Pharma, LLC NCT02423200
EIP Pharma, LLC NCT02423122

Last Updated: 04 Aug 2021


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News Citations

  1. Emerging Alzheimer’s Therapies Test the Waters at CTAD
  2. At AAIC, Yet Another Phase 3 Flop While Phase 1 Trials Forge Ahead
  3. At CTAD, Early Failures and Hints of Success, from Small Trials
  4. In Phase 2 Trial, Neflamapimod Aids Cognition in Lewy Body Dementia
  5. New Ideas for Alzheimer’s Treatment: What’s on Offer in 2015?

Research Models Citations

  1. Tg2576

Paper Citations

  1. . An exploratory clinical study of p38 α kinase inhibition in Alzheimer's disease. Ann Clin Transl Neurol. 2018 Apr;5(4):464-473. Epub 2018 Mar 6 PubMed.
  2. . Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer's Disease. J Prev Alzheimers Dis. 2017;4(4):273-278. PubMed.
  3. . A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease. Alzheimers Res Ther. 2021 May 27;13(1):106. PubMed.
  4. . Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014 Jun;13(6):614-29. PubMed.
  5. . Free and cued selective reminding distinguishes Alzheimer's disease from vascular dementia. J Am Geriatr Soc. 2008 May;56(5):944-6. PubMed.
  6. . The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor. ACS Med Chem Lett. 2011 Oct 13;2(10):758-63. Epub 2011 Jul 28 PubMed.
  7. . VX-745. Vertex Pharmaceuticals. Curr Opin Investig Drugs. 2001 Aug;2(8):1070-6. PubMed.
  8. . p38 MAP kinase inhibitors as potential therapeutic drugs for neural diseases. Cent Nerv Syst Agents Med Chem. 2011 Mar 1;11(1):45-59. PubMed.
  9. . Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ). J Neuroinflammation. 2011;8:79. PubMed.
  10. . The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease. J Signal Transduct. 2012;2012:649079. PubMed.
  11. . P38α MAPK Signaling-A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease. Int J Mol Sci. 2020 Jul 31;21(15) PubMed.
  12. . Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models. ACS Chem Neurosci. 2015 Apr 15;6(4):666-80. Epub 2015 Feb 23 PubMed.
  13. . Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats. J Alzheimers Dis. 2015;48(1):219-27. PubMed.
  14. . Continuous administration of a p38α inhibitor during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level. PLoS One. 2020;15(12):e0233073. Epub 2020 Dec 4 PubMed.

External Citations

  1. press release
  2. slides posted
  3. company press release
  4. EU Clinical Trials Register
  5. EIP Pharma website

Further Reading


  1. . Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells. Bioorg Med Chem Lett. 2007 Sep 15;17(18):5107-10. Epub 2007 Jul 13 PubMed.
  2. . X-ray structure of p38α bound to TAK-715: comparison with three classic inhibitors. Acta Crystallogr D Biol Crystallogr. 2012 Aug;68(Pt 8):1041-50. Epub 2012 Jul 17 PubMed.
  3. . Continuous administration of a p38α inhibitor during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level. PLoS One. 2020;15(12):e0233073. Epub 2020 Dec 4 PubMed.