lecanemab (Leqembi)

Indications

• treatment of Alzheimer's disease (FDA-approved)*
  • may not benefit women or patients < 65 years
    • treatment effect may be smaller in men than women
• European drug agency rejects lecanemab due to issues of efficacy & safety
• benefits too small to justify cost (NICE)

* first beta-amyloid monoclonal antibody to receive traditional approval from the US Food & Drug Administration (FDA)

* unlike aducanumab,there was no formal FDA advisory committee meeting on lecanemab prior to approval

Contraindications

• 2 groups of patients not likely to benefit*
  • amyloid-negative patients
  • amyloid-positive with a high plasma phospho-tau burden

* plasma ptau217 useful for identifying patients unlikely to benefit

Dosage

• bi-weekly intravenous infusion of 10 mg/kg
• subcutaneous dosing investigational

Injection for intravenous infusion: 500 mg/5 mL & 200 mg/2 mL single use vials

* it takes a multidisciplinary team to administer lecanemab

• this team should include:
  • a behavioral neurologist who can distinguish mild cognitive impairment from depression
  • a neuropsychologist to interpret cognitive testing & make the correct diagnosis
  • a neuroradiologist to look for cerebral microbleeds at baseline
  • a social worker to handle financial issues

Adverse effects

• infusion-related reactions (24%)
• amyloid-related imaging abnormality-edema or effusions (ARIA-E) 12.6%
  • patients homozygous for apo E4 are > 6 times more likely to experience symptomatic ARIA with edema or effusions & 3 times more likely to experience cerebral microhemorrhages than those homozygous for apo E3

* Black-box warning:

• rare cases of serious & life-threatening events

• drug adverse effects of anti-Alzheimer monoclonal antibody
• drug adverse effects of pharmaceutical monoclonal antibodies

Drug interactions

• concurrent use of lecanemab & SSRI may increase risk of intracerebral hemorrhage within the first 30 days of combination therapy
• antiplatelet drugs increase risk intracerebral hemorrhage
• anticoagulants increase risk of intracerebral hemorrhage
• thrombolytic agents increase risk of intracerebral hemorrhage

Mechanism of action

• humanized IgG1 monoclonal antibody
• binds with high affinity to amyloid-beta soluble protofibrils

Complications

• complications of ARIA manifested as headache the day after infusion may not be recognized by emergency medicine physicians at a local hospital
  • even if they do, they not not be able to facilitate an emergency MRI
  • thus the importance of 24/7 access to a multidisciplinary team as described above (see Dosage: section)

Clinical trials

• small phase 2b trial
  • reportedly completely clears amyloid within 18 months in 80% patients with early Alzheimer's disease
  • granted breakthrough therapy designation
• small but significant reduction in cognitive decline in early Alzheimer's disease in a phase III trial
  • the National Institute on Aging (NIA) eagerly awaits publication of this data in a peer-reviewed scientific journal
• volunteer died during the study; unclear if death caused by lecanemab
• a 2nd death in a lecanemab trial participant occurred
  • lecanemab may have interacted with tissue plasminogen activator used to treat a stroke in this participant with cerebral amyloid angiopathy
• lecanemab associated with lower increase in Clinical Dementia Rating - Sum of Boxes score at 18 months than placebo (1.21 vs 1.66, baseline 3.2) in patients with early Alzheimer's disease, but associated with adverse events
• Institute for Clinical & Economic Review (ICER) found lecanemab failed to show benefit compared to supportive care for adults with early Alzheimer' disease

* summary of 3 deaths in lecanemab trial participants

Notes

• Eisai & Biogen
• list price for lecanemab (Leqembi)...would be $26,500 per year
• Medicare says it would cover much of its cost
• treatment expense & complexity may preclude traditionally marginalized populations
• apoE genotype was not revealed to any patients, insurance companies, employers, families or other doctor treating the patients
  • thus no dislosure of added risk of apoE genotype for ARIA-E

More general terms

• anti-Alzheimer monoclonal antibody

Additional terms

• investigational therapies for treatment of Alzheimer's disease