Verubecestat worsens cognition in prodromal Alzheimer’s disease

  • Egan MF & al.
  • N Engl J Med
  • 11 Apr 2019

  • International Clinical Digest
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Takeaway

  • The β-secretase inhibitor verubecestat was associated with potential worsening of cognition when used to treat prodromal Alzheimer’s disease.

Why this matters

  • Unmet medical need for interventions to slow/halt disease progression.

Key results

  • Trial stopped early for futility.
  • Estimated mean change at week 104 in Clinical Dementia Rating Scale–Sum of Boxes (CDRS-SB) score:
    • 1.58 with placebo,
    • 1.65 with 12 mg (P=.67 vs placebo), and
    • 2.02 with 40 mg (P=.01 vs placebo).
  • Estimated rate of progression to Alzheimer’s disease dementia (per 100 patient-years):
    • 19.3 events with placebo,
    • 24.5 events with 12 mg, and
    • 25.5 events with 40 mg (HR vs placebo, 1.38; 97.51% CI, 1.07-1.79).
  • Verubecestat groups had more rash/dermatitis/urticaria (19.9% and 20.9% vs 12.8%), sleep disturbance (7.9% and 9.1% vs 4.5%).
  • Findings similar in interim analysis of EARLY phase 2b/3 randomized controlled trial of atabecestat among 557 patients with preclinical Alzheimer’s disease.

Expert comment

  • In an editorial, David S. Knopman, MD, writes, “The dissociation between Aβ lowering and cognitive benefits with both BACE-1 inhibition and antiamyloid antibody therapy is troubling. To be blunt, Aβ lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”

Study design

  • Phase 3 randomized controlled trial among 1454 patients having memory impairment and elevated brain amyloid levels, but not meeting case definition of dementia (APECS trial).
  • Randomization: verubecestat (12 or 40 mg daily) vs placebo.
  • Main outcome: change in CDRS-SB score.
  • Funding: Merck & Co., Inc., Kenilworth, NJ, USA.
    .

Limitations

  • Lack of active comparator.
  • Few patients in cerebrospinal fluid biomarker study.

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