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 donanemab

  1. Eli Lilly and Company
  2. Anti-Aβ N3pG MAb
  3. Intravenous infusion every 4 weeks for the treatment of MCI due to Alzheimer’s disease and mild Alzheimer’s disease
  4. ~40 million people with Alzheimer’s disease globally
  5. >35% expected increase in total prevalent cases of early Alzheimer’s disease in the G7 markets by 2031 due to aging population

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. Phase 3 studies (TRAILBLAZER-ALZ-2 and TRAILBLAZER-ALZ-3) are ongoing in patients with early Alzheimer’s disease and preclinical Alzheimer’s disease, respectively. Data from TRAILBLAZER-ALZ-2 are expected in the first half of 2023.
  2. Phase 2 efficacy results showed a reduction in decline from baseline on the Integrated AD Rating Scale (iADRS) and other metrics at week 76; rapid, deep reduction in amyloid plaques; and lower risk of ARIA-E (27%) than with ADUHELM (35%).
  3. A small phase 3 trial (TRAILBLAZER-ALZ-4) comparing donanemab with ADUHELM head-to-head on the superiority of amyloid plaque clearance in early Alzheimer’s disease patients is ongoing, with data expected in late 2022.
  4. A global, placebo-controlled phase 3 trial (TRAILBLAZER-ALZ-5) evaluating the safety and efficacy of the drug in patients with early AD and tau pathology is ongoing, with completion expected in the first half of 2027.

Review and approval status

June 2021:
• Breakthrough Therapy designation: U.S. FDAAugust 2022:
• BLA accepted and priority review for accelerated approval granted: U.S. FDA

Expected launch:
2023: United States
2025: Japan and Europe
Patents estimated to expire beginning in 2031

How will donanemab 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 donanemab 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
probability of success for
donanemab in the United States.

Drug Timeline & Success Rates

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