Lanabecestat misses the mark for treating early or mild AD

Takeaway

• In 2 randomized controlled trials, lanabecestat (an inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1) did not slow cognitive or functional decline among patients with early or mild Alzheimer’s disease (AD).

Why this matters

• Lack of effective prevention and treatment options.

 Key results

• Both trials stopped early because of futility.
• Least-squares mean change (worsening) in 13-item Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog₁₃) score:
  • AMARANTH trial:
    • 10.3 with placebo.
    • 9.4 with lanabecestat 20 mg.
    • 10.7 with lanabecestat 50 mg.
  • DAYBREAK-ALZ trial:
    • 6.4 with placebo.
    • 8.9 with lanabecestat 20 mg.
    • 6.3 with lanabecestat 50 mg.
• No consistent, reproducible dose-related benefits identified.
• Drug generally well-tolerated.
• Lanabecestat vs placebo group more likely to develop:
  • Psychiatric adverse events (14.8%-33.5% vs 13.3%-24.5%).
  • Weight loss ≥7% (9.5%-24.9% vs 6.3%-12.7%).
  • Hair color changes (0.3%-2.9% vs 0%-0.1%).
• Accompanying author audio interview.

Study design

• 2 global randomized controlled trials among patients aged 55-85 years, with testing of 2 doses:
  • AMARANTH: phase 2/3 trial, 2218 patients with early AD, 104 weeks;
  • DAYBREAK-ALZ: phase 3 trial, 1722 patients with mild AD, 78 weeks.
• Main outcome: change on ADAS-Cog₁₃.
• Funding: Eli Lilly and Company; AstraZeneca.

Limitations

• Possible failure to detect smaller treatment effects.
• Amyloid positivity required for inclusion.