Therapeutics

Avagacestat

Tools

Back to the Top

Overview

Name: Avagacestat
Synonyms: BMS-708163
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

Background

This is an arylsulfonamide γ-secretase inhibitor that 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., 2013Crump et al., 2012).

Findings

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.

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. 

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 storyand 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
Sponsor Clinical Trial 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024
Bristol-Myers Squibb NCT00890890
N=263

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

References

News Citations

  1. Paris: Renamed ARIA, Vasogenic Edema Common to Anti-Amyloid Therapy
  2. Drug Company Halts Development of γ-Secretase Inhibitor Avagacestat

Therapeutics Citations

  1. Semagacestat

Paper Citations

  1. . 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.
  2. . BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry. 2012 Sep 18;51(37):7209-11. PubMed.

Other Citations

  1. Albright et al., 2013

External Citations

  1. company news release

Further Reading

Papers

  1. . 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.
  2. . Effects of Single Doses of Avagacestat (BMS-708163) on Cerebrospinal Fluid Aβ Levels in Healthy Young Men. Clin Drug Investig. 2012 Sep 14; PubMed.
  3. . ACS Chemical Neuroscience Molecule Spotlight on BMS-708163. ACS Chem Neurosci. 2012 Mar 21;3(3):149-50. PubMed.
  4. . A contrast in safety, pharmacokinetics, and pharmacodynamics across age groups after a single 50-mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol. 2012 May 23; PubMed.
  5. . 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.
  6. . 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.