Background

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).

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 (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.

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