Lanabecestat misses the mark for treating early or mild AD

  • Wessels AM & al.
  • JAMA Neurol
  • 25 Nov 2019

  • International Clinical Digest
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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.