Preclinical Validation of a Potent γ-secretase Modulator for Alzheimer's Disease Prevention

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2021 Mar 2

PMID 33651103

Citations 36

Authors

Kevin D Rynearson

Moorthi Ponnusamy

Olga Prikhodko

Yuhuan Xie

Can Zhang

Phuong Nguyen

Brenda Hug

Mariko Sawa

Ann Becker

Brian Spencer

Jazmin Florio

Michael Mante

Bahar Salehi

Carlos Arias

Douglas Galasko

Brian P Head

Graham Johnson

Jiunn H Lin

Steven K Duddy

Robert A Rissman

William C Mobley

Gopal Thinakaran

Rudolph E Tanzi

Steven L Wagner

Affiliations

Soon will be listed here.

Abstract

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.

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References

Mortelmans K, Riccio E . The bacterial tryptophan reverse mutation assay with Escherichia coli WP2. Mutat Res. 2000; 455(1-2):61-9. DOI: 10.1016/s0027-5107(00)00076-2. View

Green R, Schneider L, Amato D, Beelen A, Wilcock G, Swabb E . Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009; 302(23):2557-64. PMC: 2902875. DOI: 10.1001/jama.2009.1866. View

Kwart D, Gregg A, Scheckel C, Murphy E, Paquet D, Duffield M . A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019; 104(2):256-270.e5. DOI: 10.1016/j.neuron.2019.07.010. View

Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E . Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006; 27(7):686-95. DOI: 10.1002/humu.20336. View

Henley D, Raghavan N, Sperling R, Aisen P, Raman R, Romano G . Preliminary Results of a Trial of Atabecestat in Preclinical Alzheimer's Disease. N Engl J Med. 2019; 380(15):1483-1485. DOI: 10.1056/NEJMc1813435. View

McDade E, Wang G, Gordon B, Hassenstab J, Benzinger T, Buckles V . Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology. 2018; 91(14):e1295-e1306. PMC: 6177272. DOI: 10.1212/WNL.0000000000006277. View

Sunderland T, Linker G, Mirza N, Putnam K, Friedman D, Kimmel L . Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 2003; 289(16):2094-103. DOI: 10.1001/jama.289.16.2094. View

Rynearson K, Buckle R, Barnes K, Herr R, Mayhew N, Paquette W . Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme. Bioorg Med Chem Lett. 2016; 26(16):3928-37. DOI: 10.1016/j.bmcl.2016.07.011. View

Ward K, Stelman G, Morgan J, Zeigler K, Azzarano L, Kehler J . Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey. Drug Metab Dispos. 2004; 32(2):172-7. DOI: 10.1124/dmd.32.2.172. View

10.

Salloway S, Sperling R, Fox N, Blennow K, Klunk W, Raskind M . Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014; 370(4):322-33. PMC: 4159618. DOI: 10.1056/NEJMoa1304839. View

11.

Gilman S, Koller M, Black R, Jenkins L, Griffith S, Fox N . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005; 64(9):1553-62. DOI: 10.1212/01.WNL.0000159740.16984.3C. View

12.

Kounnas M, Durakoglugil M, Herz J, Comer W . NGP 555, a γ-secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses. Alzheimers Dement (N Y). 2020; 5:458-467. PMC: 6944734. DOI: 10.1016/j.trci.2019.06.006. View

13.

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

14.

Kounnas M, Danks A, Cheng S, Tyree C, Ackerman E, Zhang X . Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron. 2010; 67(5):769-80. PMC: 2947312. DOI: 10.1016/j.neuron.2010.08.018. View

15.

Qiu C, Kivipelto M, von Strauss E . Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009; 11(2):111-28. PMC: 3181909. View

16.

Doody R, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S . A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013; 369(4):341-50. DOI: 10.1056/NEJMoa1210951. View

17.

Egan M, Kost J, Tariot P, Aisen P, Cummings J, Vellas B . Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med. 2018; 378(18):1691-1703. PMC: 6776074. DOI: 10.1056/NEJMoa1706441. View

18.

Prikhodko O, Rynearson K, Sekhon T, Mante M, Nguyen P, Rissman R . The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer's Disease. J Alzheimers Dis. 2020; 73(4):1541-1554. DOI: 10.3233/JAD-190442. View

19.

Sevigny J, Chiao P, Bussiere T, Weinreb P, Williams L, Maier M . The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016; 537(7618):50-6. DOI: 10.1038/nature19323. View

20.

Hardy J, Higgins G . Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992; 256(5054):184-5. DOI: 10.1126/science.1566067. View