The U.S. Food and Drug Administration (FDA)’s accelerated approval of ADUHELM™ (aducanumab) for the treatment of early Alzheimer’s disease in 2021 met with controversy, and uptake was curtailed by a lack of clinician support and Medicare coverage. Now, supported by landmark clinical data from a phase 3 trial, next-in-class anti-Aβ monoclonal antibody (MAb) lecanemab has been granted accelerated approval by FDA and appears poised for ex-U.S. launches, marketed under the brand name LEQEMBI™. Donanemab, and others in the class (e.g., Roche’s gantenerumab), may follow suit pending the results of ongoing trials. If approved, differentiation in the areas of adverse events (AEs), convenience and clinical and biomarker efficacy will be key determinants of future uptake.

About lecanemab

  1. Eisai Co Lt and Biogen Inc.
  2. Anti-Aβ protofibril MAb
  3. Intravenous infusion every 2 weeks for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease
  4. Less frequent maintenance dosing intervals and subcutaneous administration also being explored

Why is it a drug to watch?

The U.S. FDA’s accelerated approval of ADUHELM based on biomarker endpoints (i.e., decreased amyloid levels in the brain) opened the gate for U.S. regulatory submission based on similar data from other disease-modifying therapies (DMTs). The phase 3 trial readout for lecanemab validates the clinical efficacy of agents in this class, positions the drug for global regulatory approvals and bodes well for the phase 3 trial results for donanemab, which are still pending.

  1. Both primary and secondary endpoints were met in the global confirmatory phase 3 CLARITY AD trial conducted with patients with early Alzheimer’s disease: treatment led to significant changes in the global cognitive and functional scale (CDR-SB) starting at six months and reaching a 27% reduction in clinical decline at 18 months, compared with placebo. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E) was 12.5% with lecanemab and 1.7% with placebo (35% with ADUHELM and 27% with donanemab, as reported in other studies).
  2. Phase 2 efficacy results showed a reduction in decline from baseline on the Alzheimer’s Disease Composite Score (ADCOMS) and other metrics at 78 weeks and rapid, deep amyloid plaque clearance.
  3. The phase 3 AHEAD 3-45 and phase 2/3 DIAN-TU (in combination with E2814, an anti-tau MAb by Eisai Co Ltd) prevention studies are ongoing in patients with preclinical Alzheimer’s disease and Alzheimer’s disease– causing genetic mutations, respectively.

Review and approval status

June 2021:
• Breakthrough Therapy designation: U.S. FDA

December 2021:
• Fast Track designation: U.S. FDA

March 2022:
• Submission under the “prior assessment consultation”: Pharmaceuticals and Medical Devices Agency (PMDA)

July 2022:
• Biologics License Application (BLA) accepted and priority review granted: U.S. FDA

January 6, 2023:
• Granted accelerated approval: U.S. FDA

Expected launch:
2023: United States
2024: Japan and Europe

Patents estimated to expire beginning in 2025

How will lecanemab impact the market for Alzheimer’s disease?

  1. Until the approval of ADUHELM, symptomatic therapy was the only treatment option for patients with Alzheimer’s disease. Acetylcholinesterase inhibitors and memantine, now generic, have been and will continue to be the standard of care across mild, moderate and severe disease.
  2. Other anti-Aβ DMTs are in late-phase development, including gantenerumab (Roche).
  3. Many more drugs from a range of mechanisms of action (MOAs; e.g., tau-based therapies, sigma-1 receptor inhibitors, glucagon-like peptide 1 [GLP-1] analogues, SIGLEC3 and Trem2 antibodies) are in mid and late-phase trials, with potential for further differentiation (e.g., oral administration) and adjunctive use.
  4. Regulatory success of anti-Aβ MAbs could infuse more investment dollars into dementia and influence companies’ decisions about which drugs to develop; although this could lead to bypassing of other MOAs to develop next-gen anti-amyloid drugs, the existing pipeline is rich, and modest clinical efficacy and AEs of near-to-market agents will sustain the opportunity for many future entrants.
  5. Further trial results supporting the amyloid-beta hypothesis for Alzheimer’s disease causality, as well as improved safety and delivery profiles, could facilitate uptake for lecanemab, donanemab and future anti-Aβ and non-Aβ–targeting drugs.

What gaps in treatment does lecanemab fill?

The most critical need for patients with Alzheimer’s disease has long been safe, effective DMTs that slow cognitive and functional decline. Uptake of ADUHELM is minimal for a multitude of reasons, limiting the patient benefit. Lecanemab and donanemab appear to offer improved risk/benefit profiles over ADUHELM, while additional therapies could eventually provide greater patient choice and the potential for synergistic combinations to maximize outcomes.

What hurdles might it need to overcome to reach blockbuster status?

Backed by positive phase 3 outcomes, blockbuster sales for lecenamab (and other putative DMTs) should easily be within reach based on population size, market demand and pricing. That said, the entry of ADUHELM accomplished little to prime health system preparedness, and questions and challenges remain regarding access, reimbursement and affordability; early patient detection and presentation; seamless specialist referral and diagnosis pathways; infusion infrastructure; and healthcare provider perceptions about the risk/benefit of drugs in the class and their willingness to prescribe. Upcoming regulatory and payer decisions on lecanemab will likely set the precedent for others in the class, and uptake is expected to be slow until reimbursement terms are set.

expected sales in 2027

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