Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: EIP Pharma, LLC
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.
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
Last Updated: 18 May 2018
- Emerging Alzheimer’s Therapies Test the Waters at CTAD
- At AAIC, Yet Another Phase 3 Flop While Phase 1 Trials Forge Ahead
- New Ideas for Alzheimer’s Treatment: What’s on Offer in 2015?
Research Models Citations
- Scheltens P, Prins N, Lammertsma A, Yaqub M, Gouw A, Wink AM, Chu HM, van Berckel BN, Alam J. 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.
- Alam J, Blackburn K, Patrick D. 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.
- Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014 Jun;13(6):614-29. PubMed.
- Grober E, Hall C, Sanders AE, Lipton RB. Free and cued selective reminding distinguishes Alzheimer's disease from vascular dementia. J Am Geriatr Soc. 2008 May;56(5):944-6. PubMed.
- Duffy JP, Harrington EM, Salituro FG, Cochran JE, Green J, Gao H, Bemis GW, Evindar G, Galullo VP, Ford PJ, Germann UA, Wilson KP, Bellon SF, Chen G, Taslimi P, Jones P, Huang C, Pazhanisamy S, Wang YM, Murcko MA, Su MS. 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.
- Yasuda S, Sugiura H, Tanaka H, Takigami S, Yamagata K. 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.
- Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ. 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.
- Corrêa SA, Eales KL. The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease. J Signal Transduct. 2012;2012:649079. PubMed.
- Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, Minasov G, Anderson WF, Pelletier JC, Watterson DM. 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.
- Alam JJ. 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.
- Haddad JJ. VX-745. Vertex Pharmaceuticals. Curr Opin Investig Drugs. 2001 Aug;2(8):1070-6. PubMed.
- Bagley MC, Davis T, Dix MC, Rokicki MJ, Kipling D. 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.
- Azevedo R, van Zeeland M, Raaijmakers H, Kazemier B, de Vlieg J, Oubrie A. 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.