This article is more than 5 years old. Information may no longer be current.

Avagacestat ineffective for Alzheimer's disease

Study findings in JAMA Neurology indicate no clinically significant effect of avagacestat on cerebrospinal fluid amyloid biomarkers or clinical measures of prodromal Alzheimer’s disease.

“Avagacestat (BMS-708163) is an oral γ-secretase inhibitor designed for the selective inhibition of β-amyloid (Aβ) synthesis relative to processing of Notch substrates. Phase 1 studies demonstrated that avagacestat decreased Aβ40 and Aβ42 levels at dosages expected to be tolerated in patients. Given that Aβ abnormality is an early marker of [Alzheimer’s disease] pathology and seems to change substantially throughout the course of [mild cognitive impairment], avagacestat was advanced into a phase 2 [prodromal Alzheimer’s disease] clinical trial,” Vladimir Coric, MD, of Global Clinical Research, Bristol-Myers Squibb, and colleagues wrote.

To assess the safety of avagacestat for prodromal Alzheimer’s disease and whether cerebrospinal fluid biomarkers can identify this patient population prior to clinical diagnosis, researchers conducted a randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated non-randomized observational cohort of participants negative for cerebrospinal fluid biomarkers. Of the 263 study participants in the treatment phase, 132 were randomly assigned to avagacestat and 131 to placebo. The untreated observational cohort included an additional 102 patients.

At a dose of 50 mg per day, avagacestat was relatively well-tolerated with low discontinuation rates (19.6%), however, a dose of 125 mg per day had higher discontinuation rates (43%) primarily due to gastrointestinal tract adverse events.

Researchers observed increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects among those who received avagacestat.

Individuals who received avagacestat had higher rates of serious adverse events compared with placebo (37.1% vs. 23.7%). This was attributed to higher incidence of nonmelanoma skin cancer.

At 2 years, progression to dementia was more frequent among those with prodromal Alzheimer’s disease compared with those in the observational cohort (30.7% vs. 6.5%). Brain atrophy rates for those with prodromal Alzheimer’s disease were approximately double that of the observational cohort.

Researchers observed no significant treatment differences between the avagacestat and placebo groups regarding key clinical outcomes.

“This trial failed to demonstrate clinically meaningful effects of avagacestat on [cerebrospinal fluid] amyloid biomarkers or clinical outcome measures. Although avagacestat was relatively well-tolerated at 50 mg/d, minimal pharmacodynamic effects on amyloid reduction were observed at that dose. A higher incidence of [adverse events] and untenable discontinuation rates at 125 mg/d precluded evaluation of avagacestat at doses associated with more robust reductions in [cerebrospinal fluid] amyloid,” the researchers wrote. “Although our study failed to demonstrate that avagacestat meaningfully affects the course of [Alzheimer’s disease], the results show the feasibility of prospectively identifying [prodromal Alzheimer’s disease] and enriching a clinical trial population with patients at increased risk of progressing to dementia.” – by Amanda Oldt

Disclosure: Coric, Pilcher, Dockens, Soares, Luo, Cedarbaum, Albright, Feldman, Berman, Colby, Kerselaers and Kaplita report current or previous employment at Bristol-Myers Squibb and owning or previously owning stock in the company. Please see the full study for a list of all authors’ relevant financial disclosures.