New York City-based Bristol-Myers Squibb recently announced that it will halt all clinical development of its γ-secretase inhibitor avagacestat, including an ongoing trial in people with prodromal Alzheimer’s disease (see company press release). Results from two Phase 2 trials—one completed and the other ongoing—pointed to worsening cognition and greater adverse effects in the treated people compared to those on placebo (see ARF related news story). Termination echoes that of Eli Lilly’s γ-secretase inhibitor semagacestat, which was discontinued in 2010 (see ARF related news story) owing to worsening cognition in treated versus untreated AD patients (see ARF related news story).

Avagacestat’s demise may signal the end of the line for γ-secretase inhibitors that broadly suppress the activity of all types of γ-secretase complex, including cleavage of other substrates besides amyloid precursor protein (APP). Researchers continue to study γ-secretase modulators, which aim to more selectively shift APP processing while allowing the enzyme to cleave its other substrates normally (see ARF related news story and ARF news story). Bristol-Myers Squibb is testing a γ-secretase modulator in Phase 1 trials, according to company spokeswoman Sonia Choi. Several pharmaceutical companies have γ-secretase modulators in Phase 1 or preclinical development, including the Japan-based Eisai Co. Ltd. (see ARF related news story), EnVivo Pharmaceuticals and F. Hoffmann-La Roche Ltd., Basel, Switzerland (see ARF related news story).

Avagacestat site investigators contacted by Alzforum deplored the sudden nature of the trial’s end. They had to call participants and ask them to return study medication. The investigators were not allowed to let patients continue until their next visit, where investigators could have explained the trial’s end to their patients in person. “Our patients were upset,” said one investigator, who declined attribution because (s)he was not authorized to speak publicly. Noting that internal site impressions had hinted at a biomarker response but no cognitive benefit, these investigators essentially felt that the prodromal trial was the right design for the wrong drug.—Gwyneth Dickey Zakaib.


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News Citations

  1. Déjà Vu? AD Patients Again Look Worse on γ-Secretase Inhibitor
  2. Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor
  3. Paris: Semagacestat Autopsy and Other News of Trial Tribulations
  4. New γ-Secretase Modulators Reduce Aβ42, Avoid Notch
  5. Barcelona: Live and Learn—γ-Secretase Inhibitors Fade, Modulators Rise
  6. Barcelona: Allosteric γ Modulation Moves Toward Clinic
  7. Evidence Mounts That Some γ-Secretase Modulators Bind Presenilin

External Citations

  1. company press release
  2. completed
  3. ongoing
  4. EnVivo Pharmaceuticals

Further Reading


  1. . β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell Res. 2013 Mar;23(3):351-65. PubMed.
  2. . Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1. Biochemistry. 2013 Jan 8;52(1):61-9. Epub 2012 Dec 14 PubMed.
  3. . The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation. J Biol Chem. 2013 Jan 25;288(4):2521-31. PubMed.
  4. . β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat Med. 2013 Jan;19(1):43-9. PubMed.