Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Bristol-Myers Squibb
This arylsulfonamide γ-secretase inhibitor was reported to selectively block processing of the enzyme's APP substrate, relatively sparing Notch processing. Notch is a transmembrane receptor whose signaling is important for cell-fate decisions in the intestine and in lymphocyte maturation. In preclinical models, Notch acts as a tumor suppressor in the skin. Notch inhibition is thought to have caused side effects that forced the termination of the previous clinical compound semagacestat; consequently, subsequent drug-development programs have aimed to achieve a greater separation between APP and Notch inhibition.
This drug has been reported to have 137-fold selectivity for APP over Notch in cell culture, and to robustly reduce CSF Aβ levels without causing Notch-related toxicity in rats and dogs. Other research has challenged the selectivity of this compound (Albright et al., 2013; Crump et al., 2012). Preclinical toxicology studies reported effects on fertility, fetal development, and other side effects in rats and dogs, that are consistent with inhibition of Notch processing (Sivaraman and Sanderson, 2023; Simutis et al., 2018).
About a dozen Phase 1 trials evaluated avagacestat's safety and pharmacology in healthy volunteers and people with Alzheimer's disease. In particular, drug interaction studies were conducted with cholinesterase inhibitors, blood thinners, and a range of other drugs commonly used in aging populations, including skin anti-infectives.
In 2009, two Phase 2 trials were started, of which one was completed, and the other was terminated. The first trial was a multinational, six-month, dose-ranging study comparing 25, 50, 100, and 125 mg/day to placebo in 209 people with mild to moderate Alzheimer's disease. The two lower doses led to similar discontinuation rates as placebo, the two higher doses to more discontinuations than placebo. Most patients dropped out due to gastrointestinal and dermatological side effects such as diarrhea, nausea, vomiting, rash, and itching skin; nonmelanoma skin cancers were also seen. The trial generated dose-dependent pharmacodynamic effects on CSF biomarkers in some patients, but at the two higher doses cognition trended toward a worsening compared with placebo (see Coric et al., 2012). This trial was further notable for raising awareness that amyloid-related imaging abnormalities (ARIA) can occur not only with immunotherapy but also with γ-secretase inhibition (see Jul 2011 news).
In this study, patients started out on 125 mg/day of study drug but were switched to 50 mg/day when high-dose intolerability in the dose-ranging study became apparent. Participants were assessed for brain imaging and fluid biomarkers, as well as cognition. An interim analysis conducted when the trial had enrolled 263 participants showed similar results as the prior trial in mild to moderate AD. In the prodromal population, too, avagacestat increased the rate of nonmelanoma skin cancers such as squamous- and basal-cell carcinoma. Diarrhea, nausea, vomiting, and rash were more common in the treatment group. These side effects were attributed to the study drug. On efficacy, patients on avagacestat progressed to dementia at similar rates as patients on placebo. CSF analysis showed a small reduction in amyloid with treatment; volumetric MRI results showed slightly more atrophy with treatment, i.e., modest evidence of target engagement. Results were published after peer review (Coric et al., 2015).
In November 2012, Bristol-Myers Squibb terminated this trial and announced its decision to end further development of avagacestat (see company news release). Experts in the field consider the benefit of this study to be that it validated a new trial design for prodomal AD (see Dec 2012 news story) and that Phase 2 signals were read correctly, avoiding a costly Phase 3 failure.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 10 May 2023
- Paris: Renamed ARIA, Vasogenic Edema Common to Anti-Amyloid Therapy
- Drug Company Halts Development of γ-Secretase Inhibitor Avagacestat
- Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM. Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease. Arch Neurol. 2012 Aug 13;:1-12. PubMed.
- Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, Curtis C, Soininen H, Thein S, Shiovitz T, Pilcher G, Ferris S, Colby S, Kerselaers W, Dockens R, Soares H, Kaplita S, Luo F, Pachai C, Bracoud L, Mintun M, Grill JD, Marek K, Seibyl J, Cedarbaum JM, Albright C, Feldman HH, Berman RM. Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial. JAMA Neurol. 2015 Nov;72(11):1324-33. PubMed.
- Albright CF, Dockens RC, Meredith JE, Olson RE, Slemmon R, Lentz KA, Wang JS, Denton RR, Pilcher G, Rhyne PW, Raybon JJ, Barten DM, Burton C, Toyn JH, Sankaranarayanan S, Polson C, Guss V, White R, Simutis F, Sanderson T, Gillman KW, Starrett JE, Bronson J, Sverdlov O, Huang SP, Castaneda L, Feldman H, Coric V, Zaczek R, Macor JE, Houston J, Berman RM, Tong G. Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat. J Pharmacol Exp Ther. 2013 Mar;344(3):686-95. PubMed.
- Crump CJ, Castro SV, Wang F, Pozdnyakov N, Ballard TE, Sisodia SS, Bales KR, Johnson DS, Li YM. BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry. 2012 Sep 18;51(37):7209-11. PubMed.
- Sivaraman L, Sanderson T. Gamma secretase inhibition: Effects on fertility and embryo-fetal development in rats. Toxicol Appl Pharmacol. 2023 Jun 15;469:116512. Epub 2023 Apr 6 PubMed.
- Simutis FJ, Sanderson TP, Pilcher GD, Graziano MJ. Nonclinical Safety Assessment of the γ-Secretase Inhibitor Avagacestat. Toxicol Sci. 2018 Jun 1;163(2):525-542. PubMed.
- Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Tong G. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012 Oct 1;51(10):681-93. PubMed.
- Tong G, Castaneda L, Wang JS, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright C, Dockens RC. Effects of Single Doses of Avagacestat (BMS-708163) on Cerebrospinal Fluid Aβ Levels in Healthy Young Men. Clin Drug Investig. 2012 Sep 14; PubMed.
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- Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012 Mar;34(3):654-67. PubMed.
- Gu H, Deng Y, Wang J, Aubry AF, Arnold ME. Development and validation of sensitive and selective LC-MS/MS methods for the determination of BMS-708163, a gamma-secretase inhibitor, in plasma and cerebrospinal fluid using deprotonated or formate adduct ions as precursor ions. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2319-26. PubMed.
- Simutis FJ, Sanderson TP, Pilcher GD, Graziano MJ. Investigations on the Relationship Between Ovarian, Endocrine, and Renal Findings in Nonclinical Safety Studies of the γ-Secretase Inhibitor Avagacestat. Toxicol Sci. 2019 Sep 1;171(1):98-116. PubMed.
- Yang G, Zhou R, Guo X, Yan C, Lei J, Shi Y. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell. 2021 Jan 21;184(2):521-533.e14. Epub 2020 Dec 28 PubMed.
- Gertsik N, Am Ende CW, Geoghegan KF, Nguyen C, Mukherjee P, Mente S, Seneviratne U, Johnson DS, Li YM. Mapping the Binding Site of BMS-708163 on γ-Secretase with Cleavable Photoprobes. Cell Chem Biol. 2017 Jan 19;24(1):3-8. Epub 2017 Jan 5 PubMed.
- Nishioka H, Tooi N, Isobe T, Nakatsuji N, Aiba K. BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer's disease models. Sci Rep. 2016 Sep 19;6:33427. PubMed.
- Penninkilampi R, Brothers HM, Eslick GD. Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2016 Jul 6;53(4):1395-404. PubMed.
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