What evidence supports the efficacy and safety of donanemab for Alzheimer disease?

Introduction
Alzheimer disease (AD) is a neurodegenerative disorder that primarily affects older adults, and is the most common cause of dementia and the fifth leading cause of death in adults aged 65 years and older in the United States.1 Alzheimer disease is characterized by a gradually progressive dementia that affects cognition, behavior, and functional status, with mild cognitive impairment (MCI) often preceding dementia.2

Diagnosis
There is no known cause of AD, however its key neuropathologic features are diffuse brain plaques characterized by extracellular amyloid beta, neurofibrillary tangles, and intracellular buildup of hyperphosphorylated tau (p-tau) protein.2,3 Alzheimer disease is diagnosed through clinical evaluation (ie, assessing cognitive decline, particularly memory and reasoning), neuroimaging (ie, identifying amyloid plaques and tau tangles), and sometimes cerebrospinal fluid biomarkers.1 Progression of disease can be measured with mental status scales such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clinical Dementia Rating (CDR) scale, the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), and/or any other questionnaire measuring independent daily function.1 Multiple studies have found that patients decline on average 3 to 3.5 points on the MMSE each year, though there is significant heterogeneity across studies and between patients. Moreover, the MMSE has not been developed for longitudinal assessments, suggesting that only large declines in points (≥3 points) seem to be meaningful.1,4

Alzheimer disease therapies
Approved therapies for AD include cholinesterase inhibitors (donepezil, rivastigmine, galantamine), an N-methyl-D-aspartate (NMDA) receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (lecanemab and donanemab).2 Of these therapies, only the anti-amyloid monoclonal antibodies are classified as “disease modifying agents”. Donanemab (Kisunla) is a humanized monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta plaques in the brain which is indicated for use in patients with mild cognitive impairment or the mild dementia stage of AD.5 Lecanemab (Leqembi) is the only other anti-amyloid antibody currently on the market.6 Aducanumab (Aduhelm) was previously available but has been discontinued by the manufacturer.7

Literature review
The efficacy and safety of donanemab in early AD was evaluated in 2 randomized, double-blind, placebo-controlled, multicenter clinical trials, TRAILBLAZER 1 (Phase 2) and TRAILBLAZER 2 (Phase 3), which led to its Food and Drug Administration (FDA) approval in July 2024.8,9 TRAILBLAZER 1 was conducted in the United States and Canada, while TRAILBLAZER 2 was conducted in 8 countries. Both trials are compared in Table 1 below.

Table 1. Donanemab clinical trials.8,9 *
TRAILBLAZER 1TRAILBLAZER 2
Intervention and study durationN=257 patients were randomized 1:1 to receive IV donanemab (700 mg for the first 3 doses, then 1400 mg thereafter) or IV placebo every 4 weeks for up to 72 weeks.

Patients were switched to placebo if their amyloid plaque level was <11 to 25 centiloids on PET scans.		N=1736 patients were randomized 1:1 to receive IV donanemab (700 mg for the first 3 doses, then 1400 mg thereafter) or IV placebo every 4 weeks for up to 72 weeks

Patients were switched to placebo if their amyloid plaque level was <11 to 25 centiloids on PET scans.
Patient population
  • Aged 60 to 85 years with early symptomatic Alzheimer disease (prodromal Alzheimer) or mild Alzheimer with dementia with an MMSE score of 20-28
  • Enrolled patients had an average baseline iADRS scorea of 106, MMSE scoreb of 23, and an amyloid plaque level of 104 centiloids
  • 72% of enrolled patients completed the trial
  • Aged 60 to 85 years with early symptomatic Alzheimer disease (MCI or Alzheimer disease with mild dementia) with an MMSE score of 20-28, and who had low/medium or high tau pathology
  • Enrolled patients had an average baseline iADRS scorea of 104, MMSE scoreb of 22, more than 80% of patients had mild Alzheimer disease, and an amyloid plaque level of 102 centiloids
  • 76% of enrolled patients completed the trial
Outcomes
  • Primary
    • Change from baseline in the iADRS score at 76 weeks was -6.86 in the donanemab group and -10.06 in the placebo group (difference, 3.2; 95% CI, 0.12 to 6.27; p=0.04)
  • Secondary
    • No substantial difference in the ADCS-iADL and MMSE scores between groups
    • Lack of statistically significant difference between groups in the CDR-SB score, therefore no conclusion can be drawn about the change in the ADAS-Cog score
    • Amyloid plaque reduction was 85.06 centiloids more in the donanemab group than in the placebo group
  • Primary
    Low/medium tau population:
    • Change from baseline in the iADRS score at 76 weeks was -6.02 in the donanemab group and -9.27 in the placebo group (difference, 3.25; 95% CI, 1.88 to 4.62; p<0.001), representing a 35.1% slowing of disease progression
    Combined tau population:
    • Change from baseline in the iADRS score at 76 weeks was -10.19 in the donanemab group and -13.11 in the placebo group (difference, 2.92; 95% CI, 1.51 to 4.33; p<0.001), representing a 22.3% slowing of disease progression
  • Secondary
    • No substantial difference between groups in MMSE or ADCS-iADL scores
    • Amyloid plaque level decreased by 88 centiloids with donanemab and increased by 0.2 centiloids with placebo in the low/medium tau population
    • Amyloid plaque level decreased by 87 centiloids with donanemab and decreased by 0.67 centiloids with placebo in the combined tau population
Safety
  • AEs that led to drug discontinuation: 30.5% donanemab vs 7.2% placebo (p≥0.001)
  • AEs that led to trial discontinuation: 15.3% donanemab vs 4.8% placebo (p=0.007)
  • ARIA-E or ARIA-H: 38.9% donanemab vs 8% placebo
  • 3 deaths in the donanemab group and 1 death in the placebo group were considered related to treatment
  • AEs that led to drug discontinuation: 13.1% donanemab vs 4.3% placebo
  • AEs that led to trial discontinuation: 8.1% donanemab vs 3.7% placebo
  • ARIA-E or ARIA-H: 24% and 19.7%, respectively with donanemab vs 1.9% and 7.4%, respectively with placebo
Limitations
  • Small sample size
  • Predominately White patient population
  • Heterogeneity in doses of donanemab received
  • Occurrence of ARIA-E may have led to unblinding
  • Slowing disease progression by half was not achieved (which was the basis for the power calculation)
  • Predominantly White patient population
  • Analysis of the high tau population alone was done post hoc
  • Occurrence of ARIA-E may have led to unblinding
  • Donanemab only achieved a clinically meaningful difference on the iADRS scale in the low/medium tau population (not in the total population)
Abbreviations: ADAS-Cog=Alzheimer Disease Assessment Scale-cognitive subscale; ADCS-iADL=Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living Inventory; AEs=adverse events; ARIA-E=amyloid-related imaging abnormalities with edema or effusions; ARIA-H=amyloid-related imaging abnormalities with hemosiderin deposits; CI=confidence interval; CDR-SB=Clinical Dementia Rating scale-Sum of Boxes; iADRS=Integrated Alzheimer Disease Rating Scale; IV=intravenously; MCI=mild cognitive impairment; MMSE=Mini-Mental State Examination; PET=positron emission tomography.
aThe iADRS score is a composite score of the ADAS-Cog score and the ADCS-iADL score, ranging from 0-144, with lower scores indicating a greater cognitive deficit and greater impairment in performing activities of daily living.9 A change of 5 (patients with MCI) to 9 points (patients with mild AD) is considered clinically meaningful.10
bMMSE scores range from 0-30, with ≥30 for no cognitive impairment, 26-29 for questionable impairment, 21-25 for mild impairment, 11-20 for moderate impairment, and 0-10 for severe dementia.9
*The TRAILBLAZER 4 trial compared donanemab to aducanumab. However, since aducanumab is currently off the market, that trial is not discussed herein.

Ongoing clinical trials, entitled TRAILBLAZER 3, 5, and 6, are seeking to evaluate the safety and efficacy of donanemab in participants with preclinical AD, to assess the safety and efficacy of donanemab in early AD for up to 93 weeks, and to investigate different donanemab dosing regimens and their effect on the frequency and severity of amyloid-related imaging abnormalities with edema or effusions (ARIA-E) in adults with early AD, respectively.11-13

Alzheimer disease therapeutics
A few meta-analyses have compared the monoclonal antibodies used for early AD. A Bayesian meta-analysis of Phase 3 trials with aducanumab, lecanemab, donanemab, and high-dose gantenerumab (no longer in development) in prodromal and mild AD found that while there was heterogeneity across studies in terms of statistically significant results, there was moderate evidence in favor of a treatment effect across studies for the monoclonal antibodies.14 Another meta-analysis of 33 randomized controlled trials involving 8 different monoclonal antibodies for cognitive decline in AD found that while donanemab performed better than other therapies in ADAS-cog scores, lecanemab slowed decreases in the Alzheimer’s Disease Cooperative Study-Activities of Daily Living score (ADAS-ADL).15 The analysis also concluded that lecanemab had a higher risk of serious adverse events during treatment than donanemab, but lecanemab had a lower risk than donanemab of amyloid-related imaging abnormalities. Lastly, a network meta-analysis of donanemab, lecanemab, aducanumab, and lithium in mild AD found that donanemab and lecanemab were significantly more effective than placebo on the ADAS-cog and the Clinical Dementia Rating scale-Sum of Boxes score (CDR-SB), but there was no difference between the 2 agents on the ADAS-cog.16 According to another analysis, both lecanemab and donanemab were significantly less tolerable and acceptable than placebo.17 Table 2 compares donanemab and lecanemab across multiple variables that may be relevant in clinical practice.

Table 2. Major points of comparison between donanemab and lecanemab.5,6,8,9,18,19
DonanemabLecanemab
Approved populationMCI or mild dementia stage of AD
Dosing700 mg every 4 weeks for 3 doses, then 1400 mg every 4 weeks administered IV over 30 minutes

Donanemab can be discontinued if amyloid plaques decrease to minimal levels.		10 mg/kg once every 2 weeks administered IV over 1 hour
Monitoring requirementsMRI required before the 2nd, 3rd, 4th, and 7th infusions to monitor for ARIA. Directions for suspending dosing if ARIA occurs are available in the package insert.MRI required before the 5th, 7th, and 14th infusions to monitor for ARIA. Directions for suspending dosing if ARIA occurs are available in the package insert.
Immunogenicity
  • 87% (691/792) of patients developed anti-donanemab-azbt antibodies
  • Of those, 100% were neutralizing antibodies
  • 40.9% (63/154) of patients developed anti-lecanemab-irmb antibodies
  • Of those, 25.4% were neutralizing antibodies
Major safety differences
  • ARIA-E was observed in 24% of patients on donanemab vs 14% of patients on placebo
  • ARIA-H was observed in 31% of patients on donanemab vs 13% of patients on placebo
  • MRI resolution occurred in 63% of patients by 12 weeks, 80% by 20 weeks, and 83% overall
  • 9% of patients on donanemab reported infusion related reactions vs 0.5% on placebo
  • ARIA-E was observed in 13% of patients on lecanemab vs 2% of patients on placebo
  • ARIA-H was observed in 17% of patients on lecanemab vs 9% of patients on placebo
  • MRI resolution occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall
  • 26% of patients on lecanemab reported infusion related reactions vs 7% on placebo
Primary outcomes in clinical trialsTRAILBLAZER 1 and TRAILBLAZER 2: change in iADRS score from baseline to 76 weeksStudy 1: change from baseline on a weighted composite score consisting of selected items from the CDR-SB, MMSE, and ADAS-Cog 14 scores at week 53
Study 2: change from baseline at 18 months in the CDR-SB score
StorageStore in a refrigerator at 2°C to 8°C (36°F to 46°F) and in the original carton to protect from light. Do not freeze or shake. May be stored at room temperature for up to 3 days.Store in a refrigerator at 2°C to 8°C (36°F to 46°F) and in the original carton to protect from light. Do not freeze or shake.
Abbreviations: AD=Alzheimer disease; ADAS-Cog 14=Alzheimer Disease Assessment Scale–Cognitive Subscale 14; AEs=adverse events; ARIA-E=amyloid-related imaging abnormalities with edema or effusions; ARIA-H=amyloid-related imaging abnormalities with hemosiderin deposits; CDR-SB=Clinical Dementia Rating scale-Sum of Boxes; iADRS=integrated Alzheimer’s Disease Rating Scale; IV=intravenous; MCI=mild cognitive impairment; MMSE=Mini-Mental State Examination; MRI=magnetic resonance imaging.

Conclusion
Monoclonal antibodies for the treatment of early AD represent a major shift in therapy; however, clinical benefits and harms must be weighed before their use. Although amyloid-targeting monoclonal antibodies (including donanemab) have modest benefits on cognitive and functional scales in patients with AD, these improvements may not represent clinically important differences and are associated with clinically meaningful harm.20,21 Medicare coverage of amyloid-targeting monoclonal antibodies and patient demand may drive prescribing, but further guidance from professional organizations and longer-term follow-up are needed to justify widespread use in practice.22,23

References

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  11. U.S. National Library of Medicine. A donanemab (LY3002813) prevention study in participants with Alzheimer’s disease (TRAILBLAZER-ALZ 3). Updated July 2024. https://clinicaltrials.gov/study/NCT05026866. Accessed August 15, 2024.
  12. U.S. National Library of Medicine. A study of donanemab (LY3002813) in participants with early symptomatic Alzheimer’s disease (TRAILBLAZER-ALZ 5). Updated July 2024. Updated July 2024. https://clinicaltrials.gov/study/NCT05508789. Accessed August 15, 2024.
  13. U.S. National Library of Medicine. A study of different donanemab (LY3002813) dosing regimens in adults with early Alzheimer’s disease (TRAILBLAZER-ALZ 6). Updated July 2024. https://clinicaltrials.gov/study/NCT05738486. Accessed August 15, 2024.
  14. Teipel SJ, Temp AGM, Lutz MW. Bayesian meta-analysis of phase 3 results of aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer’s disease. Alzheimers Dement (N Y). 2024;10(1):e12454. doi:10.1002/trc2.12454
  15. Qiao Y, Gu J, Yu M, Chi Y, Ma Y. Comparative efficacy and safety of monoclonal antibodies for cognitive decline in patients with Alzheimer’s disease: a systematic review and network meta-analysis. CNS Drugs. 2024;38(3):169-192. doi:10.1007/s40263-024-01067-2
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  22. Center for Medicare and Medicaid Services. CMS Finalizes Medicare Coverage Policy for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. April 2, 2022. https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment. Accessed August 2024.
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Prepared by:
Elma Abdulbaki, PharmD Candidate Class of 2025
University of Illinois Chicago College of Pharmacy

September 2024

The information presented is current as of July 16, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.