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FDA grants approval to anti-amyloid monoclonal antibody donanemab for the treatment of Alzheimer’s disease

On July 2, 2024, the U.S. Food and Drug Administration (FDA) approved donanemab-azbt (Kisunla) for the treatment of Alzheimer’s disease (AD) based on evidence of clinically meaningful benefit in the Phase III TRAILBLAZER-ALZ 2 trial. The disease-modifying agent is available as an intravenous infusion for patients with mild cognitive impairment (MCI) due to AD.

Alzheimer’s disease

AD is a neurodegenerative disorder marked by protein aggregates in the brain, specifically neurofibrillary tangles and amyloid plaques, which disrupt normal neuronal function and cause neurodegeneration. MCI is the prodromal stage to AD dementia, where patients initially start experiencing cognitive symptoms.1

Donanemab

Donanemab is a humanized IgG1 monoclonal antibody targeting amyloid plaques. It binds to Aβp3-X, a truncated amyloid beta peptide with N-terminal pyro-glutamate modifications found only in deposited plaques.2 This characteristic sets donanemab apart from other anti-amyloid monoclonal antibodies that bind various soluble or insoluble species to prevent plaque development, instead clearing the established amyloid burden. Early phase trials over the past decade have shown rapid reductions in amyloid deposits in response to donanemab treatment, as well as slowed cognitive decline.2,3

We spoke with Marwan Sabbagh, MD, Lou Ruvo Center for Brain Health, Las Vegas, NV, at the AD/PD™ 2021 conference, who delved deeper into the mechanism of anti-amyloid monoclonal antibodies. He highlighted, ‘We clearly think that the production and presence of amyloid drives other changes in the brain: synapse loss, cytotoxicity, inflammation, tau spread, etc. So, a lot of people have said “lets target amyloid” because it makes sense to remove’.

 

The TRAILBLAZER-ALZ 2 trial

The safety and efficacy of donanemab were evaluated in the Phase III TRAILBLAZER-ALZ 2 study (NCT04437511), a double-blind, placebo-controlled, parallel-group trial involving patients with confirmed amyloid pathology and MCI. A total of 1,736 patients were randomized to receive either 700mg of donanemab every four weeks for the first three doses, followed by 1,400 mg every four weeks, or a placebo, for up to 72 weeks. Amyloid levels were measured using positron emission tomography (PET) at weeks 24, 52, and 76.1

The primary outcome of the trial was the change in the Integrated Alzheimer’s Disease Rating Scale (iADRS) from baseline to week 76. Patients treated with donanemab showed 2.92-point less decline (-10.19 vs -13.11; p=0.0001) in mean iADRS score compared to those who received the placebo, suggesting that donanemab helped slow clinical decline. Additionally, patients treated with donanemab performed better on the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (1.72 vs 2.42; p<0.001).4

Regarding the safety of donanemab, amyloid-related imaging abnormalities (ARIA) of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group.4 Consequently, the prescribing information includes a boxed warning for ARIA. ARIA is more prevalent in patients who are ApoE ε4 homozygotes, so determining ApoE ε4 status is recommended before starting treatment.1 There were also three deaths in the donanemab group and one in the placebo group that were considered treatment related.4

A study extension is ongoing, aiming to improve the long-term understanding of donanemab, including its amyloid clearance properties beyond 76 weeks. Several additional trials are also underway, including TRAILBLAZER-ALZ 3 (NCT05026866), a Phase III decentralized prevention study of donanemab in preclinical AD; TRAILBLAZER-ALZ 5 (NCT05508789), an additional Phase III trial recruiting from over 100 sites outside the US; and TRAILBLAZER-ALZ 6 (NCT05738486), which is assessing the effect of different donanemab dosing regimens on the frequency and severity of ARIA-E in people with early AD.

Donanemab versus other anti-amyloid antibodies

The Phase III TRAILBLAZER-ALZ 4 trial (NCT05108922) compared donanemab to aducanumab, another anti-amyloid antibody approved in 2021, in patients with early symptomatic AD. Assessment of amyloid-PET scans at 6 months revealed that 37.9% donanemab-treated versus 1.6% aducanumab-treated participants achieved amyloid clearance (p< 0.001). 62.0% of donanemab-treated and 66.7% of aducanumab-treated participants reported an adverse event (AE). There were no serious AEs due to ARIA in donanemab arm and 1.4% serious AEs (one event) due to ARIA were reported in aducanumab arm. This study provides evidence for the superior amyloid plaque clearance achieved with donanemab versus aducanumab.5

Access and implications

The approval of donanemab adds a third anti-amyloid antibody to the AD treatment armamentarium, potentially offering greater efficacy compared to current therapies. Patients’ out-of-pocket costs for donanemab depend on treatment duration and insurance coverage, with Medicare providing coverage and reimbursement for donanemab under a National Coverage Determination with Coverage with Evidence Development.6 This agent offers hope to slow AD progression in patients with early-stage disease.

Written by Hannah Elkheir

Reviewed by Juliet Lawrence

References

  1. U.S. Food and Drug Administration. FDA approves treatment for adults with Alzheimer’s disease. FDA News Release. [Press Release]. 2nd July 2024. Accessed 9th July 2024.
  2. Lowe SL, Willis BA, Hawdon A, et al. Donanemab (LY3002813) dose-escalation study in Alzheimer’s disease. Alzheimers Dement (N Y). Feb 2021; 7(1):e12112.
  3. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. May 2021;384(18):1691-1704.
  4. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. Aug 2023; 330(6):512-527.
  5. Salloway S, Lee E, Papka M, Pain A, et al. TRAILBLAZER-ALZ 4: Topline Study Results Directly Comparing Donanemab to Aducanumab on Amyloid Lowering in Early, Symptomatic Alzheimer’s Disease. BJPsych Open. Jul 2023; 9(Suppl 1):S67.
  6. Eli Lilly and Company. Lilly’s Kisunla™ (donanemab-azbt) approved by FDA for treatment of early Alzheimer’s disease. Lilly Investor Relations. [Press Release] 2nd July 2024. Accessed 9th July 2024.