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%.
Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention
Disclosures: K.D. Rynearson reported a patent to US 2020/0055840 A1 issued. D. Galasko reported being a consultant to Biogen, Fujirebio, and Amprion and on the DSMB for Cognition Therapeutics. S.K. Duddy reported Integrated Nonclinical Development Solutions, Inc. is a private consulting group which supports nonclinical pharmaceutical development for a broad range of organizations, both privately and publicly funded, covering a broad spectrum of indications including those affecting the central nervous system. W.C. Mobley reported personal fees from Annovis Bio, other from Alzheon, personal fees from Samumed, personal fees from Cortexyme, grants from AC Immune, other from Curasen, personal fees from Pfizer, and personal fees from AC Immune outside the submitted work; in addition, W.C. Mobley had a patent to the University of California, San Diego hold patent on GSM pending and serves on the SAB for Alzheon. Stock options were granted for this. Alzheon has a planned clinical trial in AD of a compound. R.E. Tanzi reported a patent to US2020/0055840 A1 issued to the University of California, San Diego/Massachusetts General Hospital, and has received equity and/or personal fees from Neurogenetic Pharmaceuticals, AZTherapies, Amylyx, Annoys, Chromadex, Promis, Cerevance, Takeda, and FujiFilm. R.E. Tanzi is a shareholder of a privately held company (Neurogenetic Pharmaceuticals) that holds rights to a GSM previously in clinical development (NGP555).
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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; Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J Exp Med 5 April 2021; 218 (4): e20202560. doi: https://doi.org/10.1084/jem.20202560
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