Therapeutics

Efavirenz

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Overview

Name: Efavirenz
Synonyms: Efavirenz
Chemical Name: (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Tau (timeline), Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Approved for: HIV infection

Background

Efavirenz is an FDA-approved anti-retroviral medication used for human immunodeficiency virus infection. A non-nucleoside reverse transcriptase inhibitor, it is taken in pill form. It can cause serious side effects, including changes in mental health, liver toxicity, and severe skin rash and allergic reactions. Interest in repurposing this drug for Alzheimer’s disease stems from the discovery that doses 100 times lower than used for HIV promote cholesterol efflux from the brain. Excess brain cholesterol, and altered cholesterol metabolism, are both implicated in AD.

Low-dose efavirenz lowers brain cholesterol by allosterically activating the enzyme cholesterol 24-hydroxlyase, also known as CYP46A1 (Mast et al., 2014). CYP46A1-mediated modification is the major pathway for eliminating excess cholesterol from the brain. In preclinical work, efavirenz lessened memory loss in 5XFAD mice, and reduced brain amyloid when started early (Petrov et al., 2019; Mast et al., 2017). Treatment was associated with changes in astrocyte and microglial activation, expression of synaptic proteins, and membrane properties (Petrov et al., 2019; Petrov et al., 2020). This work was all done in one lab, but it is supported by previous studies on modulation of Aβ and tau pathology by CYP46A1 and cholesterol metabolism (e.g., see Djelti et al., 2015; Hudry et al., 2010; Burlot et al., 2015).

Efavirenz was independently identified in an unbiased screen for phospho-tau-lowering drugs using neurons derived from Alzheimer’s patient stem cells (Feb 2019 news on van der Kant et al., 2019). In this system, reduction of the abundance of cholesterol esters promoted phospho-tau degradation by the proteasome. The drug also reduced Aβ42 production, but by a different mechanism involving cholesterol binding to the amyloid precursor protein. In another study, efavirenz promoted uptake of tau seeds into cells, by changing the cholesterol makeup of cell membranes (May 2022 news on Tuck et al., 2022).

Efavirenz was reported to diminish the frequency of retinal vascular lesions in AD mice, suggesting a potential use in people with macular degeneration (El-Darzi et al., 2022). It prolonged the survival of prion-infected mice (Ali et al., 2021).

Findings

In May 2018, a Phase 1 trial began at two U.S. hospitals to test target engagement of efavirenz in people with Alzheimer’s disease and mild cognitive impairment or mild dementia. The study planned to enroll 36 patients for a 20-week course of 50 or 200 mg per day, or placebo. For comparison, the standard dose for HIV is 600 mg/day. The primary outcome was change in plasma 24-hydroxycholesterol, the product of CYP46A1 and a biomarker of brain enzyme activity. The study also aimed to assess CYP46A1 activity using "heavy water" Stable Isotope Labeling Kinetics (SILK) of plasma 24-hydroxycholesterol. The trial ended in January 2022, after enrolling only five patients. According to published results, 50 or 200 mg elicited a significant increase in plasma 24-hydroxycholesterol, which reversed after drug was stopped (Lerner et al., 2022). One patient on the 200 mg dose was evaluated with the SILK protocol, and showed evidence of increased brain cholesterol turnover consistent with CYP46A1 activation. The drug caused no serious side effects. One patient on the 50 mg dose withdrew after eight weeks treatment due to a diffuse skin rash, a known and common side effect of efavirenz. Low enrollment was attributed in part to the COVID-19 pandemic.

Investigators in the Netherlands said they are planning a Phase 2 trial to refine dosing based on plasma 24-hydroxycholesterol (see 2022 comment). No such trial has been registered to date.

For details on the Phase 1 trial, see clinicaltrials.gov.

Last Updated: 15 Sep 2023

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References

News Citations

  1. A New PET Tracer Could Track Cholesterol Clearance from the Brain
  2. Cholesteryl Esters Hobble Proteasomes, Increase p-Tau
  3. Membrane Border Patrol: Cholesterol Stymies Tau Uptake, Aggregation

Paper Citations

  1. 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. PubMed.
  2. 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. Epub 2013 Dec 18 PubMed.
  3. Petrov AM, Lam M, Mast N, Moon J, Li Y, Maxfield E, Pikuleva IA. CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice. Neurotherapeutics. 2019 Jul;16(3):710-724. PubMed.
  4. 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. Epub 2017 Jun 24 PubMed.
  5. Petrov AM, Mast N, Li Y, Pikuleva IA. The key genes, phosphoproteins, processes, and pathways affected by efavirenz-activated CYP46A1 in the amyloid-decreasing paradigm of efavirenz treatment. FASEB J. 2019 Aug;33(8):8782-8798. Epub 2019 May 7 PubMed.
  6. Petrov AM, Mast N, Li Y, Denker J, Pikuleva IA. Brain sterol flux mediated by cytochrome P450 46A1 affects membrane properties and membrane-dependent processes. Brain Commun. 2020;2(1) Epub 2020 Apr 11 PubMed.
  7. Djelti F, Braudeau J, Hudry E, Dhenain M, Varin J, Bièche I, Marquer C, Chali F, Ayciriex S, Auzeil N, Alves S, Langui D, Potier MC, Laprevote O, Vidaud M, Duyckaerts C, Miles R, Aubourg P, Cartier N. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease. Brain. 2015 Aug;138(Pt 8):2383-98. Epub 2015 Jul 2 PubMed.
  8. Hudry E, Van Dam D, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougnères 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. PubMed.
  9. Burlot MA, Braudeau J, Michaelsen-Preusse K, Potier B, Ayciriex S, Varin J, Gautier B, Djelti F, Audrain M, Dauphinot L, Fernandez-Gomez FJ, Caillierez R, Laprévote O, Bièche I, Auzeil N, Potier MC, Dutar P, Korte M, Buée L, Blum D, Cartier N. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology. Hum Mol Genet. 2015 Nov 1;24(21):5965-76. Epub 2015 Sep 10 PubMed.
  10. van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LS. Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons. Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9. Epub 2019 Jan 24 PubMed.
  11. Tuck BJ, Miller LV, Katsinelos T, Smith AE, Wilson EL, Keeling S, Cheng S, Vaysburd MJ, Knox C, Tredgett L, Metzakopian E, James LC, McEwan WA. Cholesterol determines the cytosolic entry and seeded aggregation of tau. Cell Rep. 2022 May 3;39(5):110776. PubMed.
  12. El-Darzi N, Mast N, Buchner DA, Saadane A, Dailey B, Trichonas G, Pikuleva IA. Low-Dose Anti-HIV Drug Efavirenz Mitigates Retinal Vascular Lesions in a Mouse Model of Alzheimer's Disease. Front Pharmacol. 2022;13:902254. Epub 2022 Jun 1 PubMed.
  13. Ali T, Hannaoui S, Nemani S, Tahir W, Zemlyankina I, Cherry P, Shim SY, Sim V, Schaetzl HM, Gilch S. Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice. Acta Neuropathol Commun. 2021 Apr 1;9(1):58. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Anderson KW, Mast N, Hudgens JW, Lin JB, Turko IV, Pikuleva IA. Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity. J Biol Chem. 2016 May 27;291(22):11876-86. Epub 2016 Apr 7 PubMed.
  2. Mast N, Li Y, Pikuleva IA. Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz. Int J Mol Sci. 2022 Jul 11;23(14) PubMed.
  3. Mast N, Petrov AM, Prendergast E, Bederman I, Pikuleva IA. Brain Acetyl-CoA Production and Phosphorylation of Cytoskeletal Proteins Are Targets of CYP46A1 Activity Modulation and Altered Sterol Flux. Neurotherapeutics. 2021 Jul;18(3):2040-2060. Epub 2021 Jul 7 PubMed.
  4. Mast N, El-Darzi N, Petrov AM, Li Y, Pikuleva IA. CYP46A1-dependent and independent effects of efavirenz treatment. Brain Commun. 2020;2(2):fcaa180. Epub 2020 Oct 29 PubMed.
  5. Mast N, Verwilst P, Wilkey CJ, Guengerich FP, Pikuleva IA. In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds. J Med Chem. 2020 Jun 25;63(12):6477-6488. Epub 2019 Nov 3 PubMed.
  6. El-Darzi N, Mast N, Li Y, Dailey B, Kang M, Rhee DJ, Pikuleva IA. The normalizing effects of the CYP46A1 activator efavirenz on retinal sterol levels and risk factors for glaucoma in Apoj-/- mice. Cell Mol Life Sci. 2023 Jul 1;80(7):194. PubMed.
  7. Petrov AM, Pikuleva IA. Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases. Neurotherapeutics. 2019 Jul;16(3):635-648. PubMed.