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 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.
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
Research Models Citations
- 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.