Efavirenz for Patients With Alzheimer's Disease

Summary

This will be a two-center, placebo controlled blinded clinical trial to evaluate the safety and tolerability of efavirenz (EFV) in 36 clinically stable subjects with mild cognitive impairment/early dementia due to Alzheimer's Disease (AD) age ≥55 years. Of these 36 total subjects, 18 will be recruited by MGH and 18 will be recruited by UH. A subset of the subjects at MGH only will also participate in a Stable Isotope Labeling Kinetics (SILK) protocol with deuterated water (a nonhazardous substance), designed to more precisely measure EFV effects on CNS cholesterol turnover. Each respective site's 18 total recruited individuals will be divided into 3 groups: these 3 groups will represent two particular dosages of EFV and a placebo group, respectively. In a double-blind fashion, participants will be receiving either a capsule of EFV or placebo daily for 20 weeks. At MGH only, 12 individuals (4 from each of the two EFV groups and placebo) will participate in the unique "heavy water" SILK protocol assessing the kinetics of deuterium enrichment in plasma 24-hydroxycholesterol (24-OHC). All study participants at both sites will have their blood, cerebral spinal fluid, and urine analyzed at various points throughout the study. All participants will have their DNA genotyped for APOE isoforms (E2, E3 or E4) and single nucleotide polymorphisms (SNPs) in CYP46A1 (rs754203) and CYP2B6 (rs3745274) to be used for post-hoc analysis.

Timeline

Start

2018-05-05

Primary completion

2022-01-28

Completion

2022-01-28

Publications

• Background Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res. 2004 Aug;45(8):1375-97. doi: 10.1194/jlr.R400004-JLR200.
• Background Lutjohann D, Breuer O, Ahlborg G, Nennesmo I, Siden A, Diczfalusy U, Bjorkhem I. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9799-804. doi: 10.1073/pnas.93.18.9799.
• Background Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem. 2003 Jun 20;278(25):22980-8. doi: 10.1074/jbc.M303415200. Epub 2003 Apr 9.
• Background Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7238-43. doi: 10.1073/pnas.96.13.7238.
• Background Ramirez DM, Andersson S, Russell DW. Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol. 2008 Apr 10;507(5):1676-93. doi: 10.1002/cne.21605.
• Background Meaney S, Bodin K, Diczfalusy U, Bjorkhem I. On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function. J Lipid Res. 2002 Dec;43(12):2130-5. doi: 10.1194/jlr.m200293-jlr200.
• Background Leoni V, Caccia C. 24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases. Biochimie. 2013 Mar;95(3):595-612. doi: 10.1016/j.biochi.2012.09.025. Epub 2012 Oct 3.
• Background Bretillon L, Lutjohann D, Stahle L, Widhe T, Bindl L, Eggertsen G, Diczfalusy U, Bjorkhem I. Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J Lipid Res. 2000 May;41(5):840-5.
• Background Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, Crawford DC, Linsenbardt AJ, Shu HJ, Izumi Y, Mennerick SJ, Zorumski CF. The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. J Neurosci. 2013 Oct 30;33(44):17290-300. doi: 10.1523/JNEUROSCI.2619-13.2013.
• Background Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW. Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3869-74. doi: 10.1073/pnas.0600316103. Epub 2006 Feb 27.
• Background Maioli S, Bavner A, Ali Z, Heverin M, Ismail MA, Puerta E, Olin M, Saeed A, Shafaati M, Parini P, Cedazo-Minguez A, Bjorkhem I. Is it possible to improve memory function by upregulation of the cholesterol 24S-hydroxylase (CYP46A1) in the brain? PLoS One. 2013 Jul 16;8(7):e68534. doi: 10.1371/journal.pone.0068534. Print 2013.
• Background Hudry E, Van Dam D, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P, Cartier N. Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther. 2010 Jan;18(1):44-53. doi: 10.1038/mt.2009.175. Epub 2009 Aug 4.
• Background Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E, Seidah NG, Oddo S, LaFerla FM, Spencer TA, Hickey WF, Chang TY. ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3081-6. doi: 10.1073/pnas.0913828107. Epub 2010 Jan 26.
• Background Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, Bjorkhem I. On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett. 2001 Nov 13;314(1-2):45-8. doi: 10.1016/s0304-3940(01)02277-7.
• Background Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol Cell. 2004 Jul 23;15(2):259-68. doi: 10.1016/j.molcel.2004.06.019.
• Background Lutjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring RD, Schlegel U, Jessen F, Rao ML, von Bergmann K, Heun R. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res. 2000 Feb;41(2):195-8.
• Background Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T. Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem. 2009;78:1017-40. doi: 10.1146/annurev.biochem.78.072407.103859.
• Background Mast N, Norcross R, Andersson U, Shou M, Nakayama K, Bjorkhem I, Pikuleva IA. Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003 Dec 9;42(48):14284-92. doi: 10.1021/bi035512f.
• Background Mast N, Andersson U, Nakayama K, Bjorkhem I, Pikuleva IA. Expression of human cytochrome P450 46A1 in Escherichia coli: effects of N- and C-terminal modifications. Arch Biochem Biophys. 2004 Aug 1;428(1):99-108. doi: 10.1016/j.abb.2004.05.012.
• Background White MA, Mast N, Bjorkhem I, Johnson EF, Stout CD, Pikuleva IA. Use of complementary cation and anion heavy-atom salt derivatives to solve the structure of cytochrome P450 46A1. Acta Crystallogr D Biol Crystallogr. 2008 May;64(Pt 5):487-95. doi: 10.1107/S0907444908004046. Epub 2008 Apr 19.
• Background Mast N, White MA, Bjorkhem I, Johnson EF, Stout CD, Pikuleva IA. Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9546-51. doi: 10.1073/pnas.0803717105. Epub 2008 Jul 9.
• Background Mast N, Saadane A, Valencia-Olvera A, Constans J, Maxfield E, Arakawa H, Li Y, Landreth G, Pikuleva IA. Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease. Neuropharmacology. 2017 Sep 1;123:465-476. doi: 10.1016/j.neuropharm.2017.06.026. Epub 2017 Jun 24.
• Background Liao WL, Dodder NG, Mast N, Pikuleva IA, Turko IV. Steroid and protein ligand binding to cytochrome P450 46A1 as assessed by hydrogen-deuterium exchange and mass spectrometry. Biochemistry. 2009 May 19;48(19):4150-8. doi: 10.1021/bi900168m.
• Background Mast N, Liao WL, Pikuleva IA, Turko IV. Combined use of mass spectrometry and heterologous expression for identification of membrane-interacting peptides in cytochrome P450 46A1 and NADPH-cytochrome P450 oxidoreductase. Arch Biochem Biophys. 2009 Mar 1;483(1):81-9. doi: 10.1016/j.abb.2009.01.002. Epub 2009 Jan 10.
• Background Mast N, Charvet C, Pikuleva IA, Stout CD. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J Biol Chem. 2010 Oct 8;285(41):31783-95. doi: 10.1074/jbc.M110.143313. Epub 2010 Jul 28.
• Background Mast N, Linger M, Clark M, Wiseman J, Stout CD, Pikuleva IA. In silico and intuitive predictions of CYP46A1 inhibition by marketed drugs with subsequent enzyme crystallization in complex with fluvoxamine. Mol Pharmacol. 2012 Nov;82(5):824-34. doi: 10.1124/mol.112.080424. Epub 2012 Aug 2.
• Background Mast N, Zheng W, Stout CD, Pikuleva IA. Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response. J Biol Chem. 2013 Feb 15;288(7):4613-24. doi: 10.1074/jbc.M112.438754. Epub 2013 Jan 3.
• Background Mast N, Zheng W, Stout CD, Pikuleva IA. Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1. Mol Pharmacol. 2013 Jul;84(1):86-94. doi: 10.1124/mol.113.085902. Epub 2013 Apr 19.
• Background Mast N, Li Y, Linger M, Clark M, Wiseman J, Pikuleva IA. Pharmacologic stimulation of cytochrome P450 46A1 and cerebral cholesterol turnover in mice. J Biol Chem. 2014 Feb 7;289(6):3529-38. doi: 10.1074/jbc.M113.532846. Epub 2013 Dec 18.
• Background Fanara P, Wong PY, Husted KH, Liu S, Liu VM, Kohlstaedt LA, Riiff T, Protasio JC, Boban D, Killion S, Killian M, Epling L, Sinclair E, Peterson J, Price RW, Cabin DE, Nussbaum RL, Bruhmann J, Brandt R, Christine CW, Aminoff MJ, Hellerstein MK. Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration. J Clin Invest. 2012 Sep;122(9):3159-69. doi: 10.1172/JCI64575. Epub 2012 Aug 27.
• Background Lam TN, Hui KH, Chan DP, Lee SS. Genotype-guided dose adjustment for the use of efavirenz in HIV treatment. J Infect. 2015 Nov;71(5):607-9. doi: 10.1016/j.jinf.2015.07.005. Epub 2015 Jul 18. No abstract available.
• Background Apostolova N, Funes HA, Blas-Garcia A, Galindo MJ, Alvarez A, Esplugues JV. Efavirenz and the CNS: what we already know and questions that need to be answered. J Antimicrob Chemother. 2015 Oct;70(10):2693-708. doi: 10.1093/jac/dkv183. Epub 2015 Jul 22.
• Background Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994 Dec;44(12):2308-14. doi: 10.1212/wnl.44.12.2308.
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• Background Mast N, Reem R, Bederman I, Huang S, DiPatre PL, Bjorkhem I, Pikuleva IA. Cholestenoic Acid is an important elimination product of cholesterol in the retina: comparison of retinal cholesterol metabolism with that in the brain. Invest Ophthalmol Vis Sci. 2011 Feb 1;52(1):594-603. doi: 10.1167/iovs.10-6021. Print 2011 Jan.
• Background Kotti T, Head DD, McKenna CE, Russell DW. Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11394-9. doi: 10.1073/pnas.0805556105. Epub 2008 Aug 6.
• Results Lerner AJ, Arnold SE, Maxfield E, Koenig A, Toth ME, Fortin B, Mast N, Trombetta BA, Denker J, Pieper AA, Tatsuoka C, Raghupathy S, Pikuleva IA. CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease. Alzheimers Res Ther. 2022 Dec 29;14(1):198. doi: 10.1186/s13195-022-01151-z.
• Gascon-Bayarri J, Simon PC, Llop R, Carnaval T, Ledesma MD, Rico I, Sanchez-Castaneda C, Campdelacreu-Fumado J, Calvo-Malvar N, Cos M, de Lama E, Cortes-Romera M, Rodriguez-Bel L, Perez-Sousa C, Cerdan Sanchez M, Muelas N, Sevillano MD, Mir P, Lopez de Munain A, Ferrer A, Videla S. Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment. Medicine (Baltimore). 2022 Dec 2;101(48):e31471. doi: 10.1097/MD.0000000000031471.

Drugs

Indications

No indication recorded.