Donanemab (Kisunla™): A Comprehensive Clinical and Pharmacological Review of a Second-Generation Amyloid-Targeting Therapy for Alzheimer's Disease

Introduction: A New Therapeutic Modality for Alzheimer's Disease

Contextualizing the Challenge

Alzheimer's disease (AD) stands as one of the most significant public health crises of the 21st century. It is a relentless, progressive neurodegenerative disorder characterized by a gradual decline in memory, thinking, and reasoning skills, ultimately leading to a complete loss of independence and death. For decades, the therapeutic landscape for AD was dominated by symptomatic treatments, primarily cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists.[1] While these agents provide modest and temporary relief of cognitive symptoms by modulating neurotransmitter systems, they do not alter the underlying pathological processes that drive the disease forward. Consequently, they fail to slow, halt, or reverse the inexorable course of neurodegeneration, leaving a profound unmet medical need for therapies that can modify the disease itself.[2]

The Amyloid Cascade Hypothesis as a Therapeutic Target

The scientific pursuit of disease-modifying therapies for AD has been largely guided by the amyloid cascade hypothesis. First proposed over three decades ago, this hypothesis posits that the initiating pathological event in AD is the abnormal processing of the amyloid precursor protein (APP), leading to the excessive production and impaired clearance of amyloid-beta (Aβ) peptides.[4] These peptides, particularly the 42-amino-acid form (Aβ42), are prone to misfolding and aggregation, first into soluble oligomers and protofibrils, and eventually into the insoluble, dense-core amyloid plaques that are a defining neuropathological hallmark of the disease.[4] According to this model, the accumulation of Aβ triggers a downstream cascade of devastating events, including the hyperphosphorylation and aggregation of tau protein into neurofibrillary tangles, synaptic dysfunction, neuroinflammation, and widespread neuronal death, which collectively manifest as the clinical syndrome of dementia.[4] This hypothesis has provided a compelling and durable rationale for the development of therapeutic agents designed to reduce the brain's Aβ burden.[3]

The journey to validate this hypothesis has been arduous, marked by numerous high-profile clinical trial failures of anti-amyloid agents. These setbacks led to considerable skepticism and debate within the scientific community regarding the centrality of Aβ to AD pathogenesis. However, the recent successes of a new generation of monoclonal antibodies, including donanemab, suggest that the hypothesis is not fundamentally flawed, but rather that the timing and specificity of therapeutic intervention are of paramount importance. The emerging evidence indicates that intervening at earlier stages of the disease—before the downstream pathological cascade is irrevocably established—and with agents that potently engage their specific Aβ targets is critical for achieving a clinical benefit. This realization has catalyzed a fundamental paradigm shift in AD research and clinical practice, moving the field toward an era of biologically-defined disease and biomarker-guided intervention.

Emergence of Disease-Modifying Immunotherapies

Within this evolving landscape, donanemab (LY3002813), developed by Eli Lilly and Company, has emerged as one of the most prominent and promising second-generation, disease-modifying immunotherapies.[3] Sold under the brand name Kisunla™, donanemab is a humanized monoclonal antibody engineered to target and clear established amyloid plaques from the brain.[8] Its development and subsequent regulatory approvals represent a landmark achievement, signifying a critical transition from purely symptomatic treatments to therapies that directly engage the core pathology of AD.[2] The approval of donanemab, following that of lecanemab, has not only provided clinicians with a new tool to combat the disease but has also served as a powerful validation of the amyloid hypothesis as a viable therapeutic target. This report provides an exhaustive review of donanemab, detailing its unique molecular profile, dissecting the evidence from its comprehensive clinical development program, critically evaluating its complex safety profile, chronicling its global regulatory journey, and positioning it within the competitive and rapidly advancing therapeutic armamentarium for Alzheimer's disease.

Molecular Profile and Pharmacological Characteristics

Structural and Biochemical Properties

Donanemab, also identified by the research code LY3002813, is a biotech therapeutic classified as a humanized immunoglobulin G1 (IgG1) monoclonal antibody.[5] As a humanized antibody, its protein structure is predominantly derived from human antibody sequences, with only the small, antigen-binding regions (complementarity-determining regions) originating from a non-human source. This design minimizes the potential for immunogenicity in human subjects.[12] Specifically, donanemab was developed from a murine parent monoclonal antibody, mE8-IgG2a, which demonstrated high specificity for its target epitope in preclinical studies.[12]

The molecular structure of donanemab is complex, consistent with other IgG1 antibodies. Its chemical formula is C6452H10038N1708O2013S42, and it possesses an average protein weight of approximately 145 kilodaltons (kDa), with some sources specifying a molecular weight of 145.36 kDa.[5] This large molecular size necessitates parenteral administration, as it would not survive digestion or be absorbed if taken orally.

Table 1: Donanemab Drug Profile Summary

Characteristic	Detail	Source(s)
Generic Name	donanemab-azbt	8
Brand Name	Kisunla™	5
Developer	Eli Lilly and Company	7
DrugBank ID	DB16647	5
CAS Number	1931944-80-7	11
Type	Biotech; Humanized IgG1 Monoclonal Antibody	5
Target	N-terminal pyroglutamate amyloid-beta (N3pG)	5
Mechanism	Promotes microglial-mediated phagocytosis of established amyloid plaques	5
Administration	Intravenous (IV) Infusion	7
Dosing	Monthly (every 4 weeks)	16
Elimination Half-Life	Approximately 10–12 days	4
Metabolism	Proteolytic degradation	16

Mechanism of Action (Pharmacodynamics)

The therapeutic rationale and clinical profile of donanemab are defined by its highly specific and unique mechanism of action, which distinguishes it from other amyloid-targeting antibodies.

Unique Target Epitope

Donanemab's primary pharmacological distinction lies in its selective binding to a modified form of Aβ that is found almost exclusively within the dense core of established brain amyloid plaques.[6] This target is the N-terminal pyroglutamate-modified form of amyloid-beta, often abbreviated as AβpE3, Aβp3-x, or N3pG.[5] This modification, a cyclization of the glutamate residue at the third position of the Aβ peptide, renders the peptide more hydrophobic and prone to aggregation, making it a key component of insoluble plaque deposits.[5] By targeting this specific epitope, donanemab is designed to be a "plaque-buster," focusing its activity on the existing amyloid burden rather than on soluble, circulating forms of Aβ such as monomers or protofibrils, which are the primary targets of other antibodies like lecanemab.[22] This high degree of specificity for deposited plaque is believed to be central to its potent amyloid-clearing effects observed in clinical trials.[12]

Mechanism of Plaque Clearance

Upon intravenous administration and passage across the blood-brain barrier, donanemab binds with high affinity to the N3pG epitope on amyloid plaques.[5] The Fc (fragment crystallizable) region of the donanemab IgG1 antibody is then thought to engage Fc receptors on microglia, the resident immune effector cells of the central nervous system.[5] This engagement activates the microglia, triggering them to recognize the antibody-coated plaques as foreign and clear them from the brain parenchyma through a process known as microglial-mediated phagocytosis.[5] This mechanism is designed to actively remove and eliminate the existing amyloid burden, which is hypothesized to be a necessary step for any AD therapy to be effective.[13]

The very mechanism responsible for donanemab's potent amyloid clearance, however, is also intrinsically linked to its primary safety concern. The rapid and aggressive removal of established plaques, which are often deeply integrated into the cerebral vasculature in a condition known as cerebral amyloid angiopathy (CAA), can lead to transient inflammation and a compromise of blood vessel integrity. This structural disruption of the neurovascular unit is the direct pathophysiological cause of the vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H) frequently observed on magnetic resonance imaging (MRI) scans of treated patients.[7] This recognition—that the therapeutic action and the main adverse effect are two sides of the same coin—profoundly influenced the clinical development strategy for donanemab. It led to the innovative inclusion of a "stop-dosing" paradigm in the pivotal clinical trials, wherein treatment is discontinued once a predefined threshold of amyloid clearance is achieved.[19] This approach represents a strategic attempt to mitigate the long-term risks of continued drug exposure by removing the therapeutic agent once its target has been eliminated, a feature not present in the protocols for other approved amyloid-targeting antibodies.

Biomarker Effects

The pharmacodynamic effect of donanemab is most directly and dramatically observed through neuroimaging and fluid biomarkers. Clinical studies have consistently demonstrated that treatment leads to a rapid, robust, and dose-dependent reduction in brain amyloid plaque levels, as quantified by amyloid positron emission tomography (PET) imaging.[5] In some patients, complete or near-complete amyloid clearance (defined as falling below the threshold for amyloid positivity, typically <24.1 Centiloids) can be achieved within 6 to 12 months of treatment.[12] In addition to its effects on Aβ, donanemab has also been shown to reduce plasma levels of phosphorylated tau at position 217 (p-tau217), a highly specific fluid biomarker of AD pathology.[5] This effect on a downstream marker suggests that by removing the upstream amyloid trigger, donanemab may modulate the subsequent tau-related pathology, a key tenet of the amyloid cascade hypothesis.

Pharmacokinetics and Metabolism

The pharmacokinetic profile of donanemab dictates its dosing regimen and informs its potential for drug interactions.

Administration and Dosing

Donanemab is administered via intravenous (IV) infusion over approximately 30 minutes.[4] The approved dosing regimen in the United States begins with three initial doses of 700 mg administered every 4 weeks, followed by a maintenance dose of 1400 mg every 4 weeks.[16] This titration is designed to gradually introduce the drug and potentially temper the initial immune response. Based on findings from the TRAILBLAZER-ALZ 6 study, which demonstrated that a slower titration schedule could significantly reduce the risk of ARIA-E, an updated label with a new recommended titration dosing schedule was approved in July 2025.[26] As noted, treatment can be discontinued if amyloid PET imaging confirms that the plaque burden has been reduced to minimal or no levels.[16]

Distribution and Half-Life

Following IV administration, donanemab exhibits a bi-exponential decline in serum concentrations with dose-proportional and time-linear kinetics.[18] It has a terminal elimination half-life of approximately 10 to 12 days.[4] Like other large-molecule antibodies, its volume of distribution is primarily confined to the plasma and extracellular fluid. It is capable of crossing the blood-brain barrier to reach its target in the central nervous system, though this passage is limited, resulting in a cerebrospinal fluid (CSF) to serum concentration ratio of approximately 0.2%.[20] Population pharmacokinetic analyses have indicated that maintaining a serum concentration above a threshold of 4.43 μg/mL is associated with optimal amyloid plaque reduction.[4]

Metabolism and Elimination

As a therapeutic protein, donanemab is not metabolized by the cytochrome P450 (CYP450) enzyme system in the liver, which is the primary pathway for the metabolism of most small-molecule drugs.[1] This characteristic is clinically significant as it confers a very low potential for pharmacokinetic drug-drug interactions, a desirable feature for a medication intended for long-term use in an elderly population that is often on multiple concomitant medications.[2] Instead, donanemab is expected to be degraded into its constituent amino acids and small peptides through general protein catabolism pathways, primarily via cell-mediated endocytosis and clearance by the reticuloendothelial system.[16] Because these clearance mechanisms are not organ-specific, dose adjustments are not considered necessary for patients with mild to moderate renal or hepatic impairment.[4]

Clinical Development Program: The TRAILBLAZER Trials

The clinical evidence supporting the efficacy and safety of donanemab is derived from a series of meticulously designed studies known as the TRAILBLAZER-ALZ program. This program has been instrumental not only in establishing the drug's therapeutic profile but also in advancing the methodology of Alzheimer's disease clinical trials.

Phase 2 Study (TRAILBLAZER-ALZ, NCT03367403)

The TRAILBLAZER-ALZ study served as the crucial proof-of-concept trial for donanemab, providing the first robust evidence of its clinical potential.

Design and Innovation in Patient Selection

Published in the New England Journal of Medicine, TRAILBLAZER-ALZ was a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial that enrolled 257 participants with early symptomatic AD.[6] A key innovation of this study was its pioneering use of tau PET imaging as a primary tool for patient selection and stratification. The trial was designed to test the hypothesis that an anti-amyloid therapy would be most effective in patients who had established amyloid pathology but had not yet developed widespread tau pathology. Consequently, the study specifically enrolled participants with intermediate levels of tau protein deposition on PET scans, excluding those with very low or very high tau loads.[6] This enrichment strategy was a significant departure from previous AD trials and represented a more targeted, biologically-driven approach to patient selection.

Efficacy and Biomarker Outcomes

The trial successfully met its primary endpoint. At 76 weeks, participants treated with donanemab showed a statistically significant 32% slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS), a composite measure of cognition and function, compared to those receiving placebo. The absolute difference in the change from baseline was 3.20 points in favor of donanemab (p=0.04).[6]

While the primary outcome was met, the results for secondary endpoints were mixed, with no statistically significant differences observed between the groups on other widely used scales such as the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) or the Mini-Mental State Examination (MMSE).[28]

The biomarker results, however, were striking and unambiguous. Treatment with donanemab led to a profound and rapid clearance of amyloid plaques. At 6 months, 40% of treated participants had achieved amyloid negativity on PET scans, a figure that rose to 68% by 18 months.[25] The mean reduction in amyloid plaque level was 85.06 centiloids greater with donanemab than with placebo at 76 weeks.[29]

Safety Profile

The primary safety signal identified in the trial was the occurrence of amyloid-related imaging abnormalities with edema (ARIA-E). This adverse event was observed in 26.7% of participants in the donanemab group, the majority of whom were asymptomatic.[1] These findings established ARIA as the principal risk associated with donanemab, setting the stage for the intensive safety monitoring protocols that would be implemented in the subsequent Phase 3 study.

Pivotal Phase 3 Study (TRAILBLAZER-ALZ 2, NCT04437511)

Building on the promising results of the Phase 2 study, TRAILBLAZER-ALZ 2 was designed as the definitive, large-scale pivotal trial to confirm the efficacy and safety of donanemab and support global regulatory submissions.

Design and Patient Population

Published in the Journal of the American Medical Association, TRAILBLAZER-ALZ 2 was a global, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 1,736 participants with early symptomatic AD (mild cognitive impairment or mild dementia) and biomarker-confirmed amyloid and tau pathology.[7] The study retained the use of tau PET to stratify the population into a low-medium tau group (n=1182), which served as the primary analysis population, and a high tau group (n=552).[33] Participants received either donanemab or placebo intravenously every 4 weeks for up to 18 months, with the provision to stop dosing if amyloid clearance was achieved.[30]

Efficacy Outcomes

The trial was a resounding success, meeting its primary endpoint and all key secondary endpoints. The results provided compelling evidence that the clinical benefit derived from amyloid removal is highly dependent on the underlying pathological stage of the disease, with the greatest benefit observed when intervention occurs before the extensive spread of tau pathology.

• Primary Analysis (Low/Medium Tau Population): In the prespecified primary analysis group, donanemab demonstrated a robust clinical effect. Treatment slowed the rate of clinical decline by 35% on the iADRS (difference vs. placebo: 3.25; p<0.001) and by 36% on the CDR-SB (difference vs. placebo: -0.67; p<0.001) over 76 weeks.[4] The consistency across these two distinct primary and secondary endpoints strengthened the validity of the findings. Furthermore, nearly half (47%) of the participants in this group who received donanemab showed no clinical progression at one year (defined as a CDR-SB score change of 0), compared to only 29% of those on placebo.[36] Treatment also reduced the risk of progressing to the next clinical stage of the disease by 39% over the 18-month trial period.[8]
• Overall Population (Including High Tau): When the analysis was expanded to include the entire amyloid-positive study population (n=1736), the treatment effect, while still highly statistically significant, was attenuated. In this combined group, donanemab slowed decline by 22% on the iADRS (difference: 2.92; p<0.001) and by 29% on the CDR-SB (difference: -0.7; p<0.001).[12] The dilution of the effect size in the overall population strongly supports the conclusion that by the time a patient has developed high tau pathology, the neurodegenerative process may have become partially independent of the initial amyloid trigger, thus limiting the benefit of amyloid removal alone.
• Subgroup Analyses: Further analyses reinforced the "earlier is better" hypothesis. Within the low-medium tau group, the benefit was greatest in those at the earliest clinical stage. Participants with mild cognitive impairment (MCI) experienced a remarkable 60% slowing of decline on the iADRS, whereas those who had already progressed to mild dementia saw a more modest 30% slowing.[36] A similar pattern was observed based on age, with patients younger than 75 years deriving a greater benefit than those 75 and older.[33]
• Biomarker Outcomes: As in the Phase 2 study, donanemab produced profound amyloid clearance. Across all participants, treatment reduced brain amyloid plaque on average by 84% at 18 months, compared to a 1% decrease in the placebo group.[8]

This body of evidence strongly suggests the existence of an optimal "therapeutic window" for anti-amyloid therapies. The data imply that intervention is most impactful after amyloid pathology is established but before tau pathology has become widespread and the associated neurodegeneration has become self-sustaining. This has profound implications for clinical practice, underscoring the urgent need for early and accurate diagnosis, including the routine use of biomarkers like amyloid and tau PET, to identify patients who are most likely to benefit from treatment.

Table 2: Summary of Key TRAILBLAZER-ALZ 2 Efficacy Outcomes (76 Weeks)

Efficacy Outcome	Low/Medium Tau Population (n=1182)	Overall Amyloid-Positive Population (n=1736)
iADRS Change from Baseline
Difference vs. Placebo	3.25 (p < 0.001)	2.92 (p < 0.001)
% Slowing of Decline	35%	22%
CDR-SB Change from Baseline
Difference vs. Placebo	-0.67 (p < 0.001)	-0.70 (p < 0.001)
% Slowing of Decline	36%	29%
Data sourced from.34 iADRS: Integrated Alzheimer's Disease Rating Scale; CDR-SB: Clinical Dementia Rating Scale-Sum of Boxes. A positive difference in iADRS and a negative difference in CDR-SB indicate a benefit for donanemab.

Safety Profile

The safety findings from TRAILBLAZER-ALZ 2 were consistent with the Phase 2 study but provided more precise estimates of risk due to the larger population. ARIA remained the most significant adverse event. ARIA-E occurred in 24.0% of participants in the donanemab group, with 6.1% experiencing symptoms. ARIA-H was observed in 31.4% of the donanemab group compared to 13.6% in the placebo group.[36] Critically, there were three treatment-related deaths in the donanemab arm, two of which were attributed to serious ARIA, underscoring the potentially severe nature of this side effect.[37]

Ancillary and Ongoing Studies

The donanemab clinical development program extends beyond the pivotal efficacy trials, with several ongoing studies designed to answer critical remaining questions.

• TRAILBLAZER-ALZ 3 (NCT05026866): This is a large-scale Phase 3 prevention trial testing donanemab in individuals who are cognitively unimpaired but have evidence of AD brain pathology (preclinical AD).[42] This study is the logical culmination of the "earlier is better" hypothesis and will be crucial for determining if intervention before the onset of symptoms can delay or even prevent cognitive decline. Its results are highly anticipated and could reshape the future of AD treatment.
• TRAILBLAZER-ALZ 4 (NCT05108922): This Phase 3 study is a head-to-head active comparator trial designed to directly compare the amyloid plaque clearing ability of donanemab versus aducanumab.[44] Early results have already shown donanemab's superiority on this biomarker endpoint.[12]
• TRAILBLAZER-ALZ 6 (NCT05738486): This Phase 3 safety study was specifically designed to address the challenge of ARIA. It is investigating whether different, slower titration dosing regimens can reduce the incidence and severity of ARIA while preserving the drug's efficacy.[45] Positive results from this study have already led to an updated dosing recommendation on the drug's label, demonstrating a commitment to optimizing the benefit-risk profile.[26]

Safety and Tolerability Profile

The clinical utility of donanemab is defined by a careful balance between its demonstrated efficacy and its significant safety considerations. While generally considered well-tolerated for a majority of patients, the drug carries notable risks that require stringent monitoring and careful patient selection. The safety profile is dominated by amyloid-related imaging abnormalities (ARIA), a class effect of potent amyloid-clearing antibodies.

Amyloid-Related Imaging Abnormalities (ARIA)

ARIA is the most common and clinically significant adverse event associated with donanemab therapy. It is detectable via MRI and manifests in two primary forms.[24]

• ARIA with Edema (ARIA-E): This form is characterized by vasogenic edema or sulcal effusions, representing a localized breakdown of the blood-brain barrier and subsequent fluid shifts into the brain parenchyma. It is believed to be caused by an inflammatory response to the rapid removal of amyloid from cerebral blood vessels.[7]
• ARIA with Hemosiderin Deposition (ARIA-H): This form includes cerebral microhemorrhages (small spots of bleeding) and superficial siderosis (bleeding on the surface of the brain). ARIA-H often occurs in conjunction with ARIA-E.[24]

Incidence and Clinical Presentation

The pivotal TRAILBLAZER-ALZ 2 trial provided robust data on the incidence of ARIA [34]:

• ARIA-E occurred in 24.0% of donanemab-treated participants, a rate substantially higher than the 2.1% observed in the placebo group.
• While most cases of ARIA-E were asymptomatic and detected only on routine surveillance MRI, 6.1% of all treated participants experienced symptomatic ARIA-E. Symptoms can range from mild (headache, dizziness, nausea) to severe (confusion, visual changes, gait difficulty, seizures).[37]
• ARIA-H was observed in 31.4% of participants receiving donanemab, compared to 13.6% in the placebo group.
• Most critically, ARIA can be life-threatening. In TRAILBLAZER-ALZ 2, serious ARIA occurred in 1.6% of participants, and two of the three treatment-related deaths were directly attributed to complications of ARIA.[3] The drug's label now carries a Boxed Warning, the FDA's most stringent, highlighting this risk.[9]

Risk Factors and Management

The risk of developing ARIA is not uniform across all patients. A critical finding from clinical studies is the powerful influence of genetics.

• APOE4 Genotype: The primary genetic risk factor for ARIA is the Apolipoprotein E ε4 (APOE4) allele.[17] Individuals who are homozygous for this allele (carrying two copies) are at the highest risk of developing ARIA, including severe and symptomatic events.[19] This creates a fundamental clinical dilemma, as the APOE4 allele is also the strongest genetic risk factor for developing Alzheimer's disease itself. The population most likely to need the treatment is also the population most at risk from its most dangerous side effect.
• Baseline MRI Findings: Patients with pre-existing evidence of cerebral amyloid angiopathy, such as the presence of more than four cerebral microbleeds on a baseline MRI, are also at an increased risk and were typically excluded from the clinical trials.[19]

This complex risk profile necessitates a rigorous management strategy:

1. Pre-treatment Assessment: Appropriate Use Recommendations developed by expert consensus state that APOE genotyping should be performed for all patients prior to initiating therapy to inform the benefit-risk discussion.[19] A baseline brain MRI obtained within the last 12 months is also mandatory to screen for exclusionary criteria like excessive microbleeds.[19]
2. Shared Decision-Making: The decision to treat must involve a thorough conversation between the clinician, patient, and caregivers, explicitly weighing the statistical probability of slowing cognitive decline against the tangible risk of potentially fatal brain swelling or bleeding.[19]
3. Surveillance Monitoring: A stringent MRI monitoring protocol is required. Surveillance MRIs are recommended prior to the 2nd, 3rd, 4th, and 7th infusions, with additional scans for higher-risk individuals, to detect ARIA early, often before symptoms develop.[19]
4. Risk Mitigation: The development and approval of a slower, modified titration dosing regimen, based on the TRAILBLAZER-ALZ 6 study, is a direct attempt to mitigate ARIA risk. This new regimen was shown to lower the relative risk of ARIA-E by 41% at 24 weeks compared to the original dosing schedule, without compromising amyloid-clearing efficacy.[26]

Table 3: Incidence of Key Adverse Events in TRAILBLAZER-ALZ 2

Adverse Event	Donanemab Group (n=853) (%)	Placebo Group (n=874) (%)
Any ARIA (-E or -H)	36.8%	14.9%
ARIA-E (Any)	24.0%	2.1%
ARIA-E (Symptomatic)	6.1%	0.1%
ARIA-H	31.4%	13.6%
Infusion-Related Reaction	8.7%	0.5%
Any Serious Adverse Event	17.4%	15.8%
Treatment-Related Death	0.4% (3 participants)	0.1% (1 participant)
Data sourced from.36 ARIA: Amyloid-Related Imaging Abnormalities; ARIA-E: ARIA with Edema; ARIA-H: ARIA with Hemosiderin Deposition.

Infusion-Related and Hypersensitivity Reactions

Incidence and Presentation

Infusion-related reactions (IRRs) are another common adverse event associated with donanemab. In the TRAILBLAZER-ALZ 2 study, IRRs occurred in 8.7% of participants receiving donanemab, compared to just 0.5% in the placebo group.[36] These reactions typically occur during the infusion or within 30 minutes of its completion, with the majority occurring within the first four infusions.[24] Symptoms can include chills, sweating, nausea, vomiting, headache, changes in blood pressure, and erythema.[24]

Management

If an IRR occurs, the standard procedure is to slow the rate of infusion or temporarily stop it until symptoms resolve. For subsequent infusions, premedication with antihistamines, acetaminophen, or corticosteroids may be considered to reduce the risk of recurrence.[24]

Hypersensitivity Reactions

In addition to IRRs, more severe hypersensitivity reactions, including anaphylaxis and angioedema (swelling of the face, lips, and mouth), have been reported.[24] These are medical emergencies that require immediate discontinuation of the infusion and appropriate medical intervention. Due to this risk, donanemab is contraindicated in any patient with a known history of serious hypersensitivity to the drug or any of its components.[24]

Other Adverse Events of Note

Hepatotoxicity

Concerns about liver toxicity are relevant for many long-term therapies. However, clinical trials of donanemab have not shown a significant hepatotoxic signal. The incidence of serum aminotransferase elevations was infrequent and was not significantly different from the rate observed in the placebo group. To date, donanemab has not been linked to instances of clinically apparent liver injury.[16]

Headache

Headache is listed as a common side effect, occurring in at least 10% of patients.[24] It is important for clinicians to differentiate a simple headache from a headache that may be a symptom of underlying ARIA, which may require neuroimaging to rule out.

Global Regulatory Trajectory and Market Access

The path of donanemab from clinical development to market availability has been a complex and closely watched journey, highlighting differing regulatory philosophies and the challenges of bringing a novel therapy for a high-unmet-need disease to patients worldwide.

U.S. Food and Drug Administration (FDA) Review

The FDA recognized the potential significance of donanemab early in its development, granting it Fast Track, Priority Review, and Breakthrough Therapy designations.[7] These designations are intended to expedite the review of drugs that may offer substantial improvements over existing therapies for serious conditions.

Despite this, the initial regulatory path was not straightforward. An application for Accelerated Approval, based on the Phase 2 biomarker data of amyloid plaque reduction, was met with a Complete Response Letter from the FDA in January 2023.[9] The agency indicated that it required data from a larger number of patients with at least 12 months of drug exposure to adequately assess safety and efficacy.

Following the comprehensive and positive results of the pivotal TRAILBLAZER-ALZ 2 study, Eli Lilly submitted a new application for traditional (full) approval. After a positive recommendation from its advisory committee, the FDA granted full approval for donanemab, under the brand name Kisunla, on July 2, 2024.[5] The indication is for the treatment of Alzheimer's disease in patients with mild cognitive impairment or the mild dementia stage of the disease, the population in which the drug was studied.[9] Subsequently, in July 2025, the FDA approved an updated label for Kisunla to include a new, slower titration dosing regimen based on the TRAILBLAZER-ALZ 6 study, which was shown to reduce the risk of ARIA.[26]

European Medicines Agency (EMA) Assessment

The regulatory review in Europe proved to be more challenging and resulted in a different outcome. In March 2025, the EMA's Committee for Medicinal Products for Human Use (CHMP) issued an initial negative opinion, recommending the refusal of a marketing authorization for donanemab.[7]

Following a request for re-examination by Eli Lilly, the CHMP revisited the data. On July 24, 2025, the committee reversed its initial stance and issued a positive opinion, recommending that a marketing authorization be granted.[50] However, this positive recommendation came with a critical restriction. The CHMP recommended approval only for a specific subpopulation: adult patients with early symptomatic AD who are

APOE4 heterozygotes (one copy of the risk allele) or non-carriers.[50] This decision explicitly excludes patients who are APOE4 homozygotes (two copies of the risk allele), the group known to be at the highest risk for developing severe ARIA.

This divergence between the FDA and EMA decisions reflects a fundamental difference in regulatory philosophy. Both agencies reviewed the identical dataset from the TRAILBLAZER-ALZ 2 trial. The FDA, arguably placing greater weight on the high unmet medical need and physician autonomy, approved the drug for the broad indicated population, leaving the complex benefit-risk calculation for high-risk APOE4 homozygotes to be made by clinicians and patients through shared decision-making. The EMA, in contrast, adopted a more prescriptive and arguably more paternalistic approach. It concluded that for the APOE4 homozygous subgroup, the risk of serious harm from ARIA outweighed the modest potential for clinical benefit, and therefore removed that treatment choice from the table. This schism creates a "two-tiered" system of access based on a patient's genetic makeup and sets a challenging precedent for the future of personalized medicine, potentially leading to significant global disparities in access to treatment.

Status in Other Key Markets

Donanemab has also been reviewed and approved in several other major markets. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) granted approval in October 2024.[7] Approvals or marketing authorizations have also been granted in Japan, China, Australia, Brazil, and Mexico, among others. Notably, in most of these other jurisdictions, the approval is for patients with early AD regardless of their ApoE4 status, aligning more closely with the FDA's decision than the EMA's.[51]

Economic Considerations

The introduction of this new class of therapies comes with substantial economic implications. The list price for donanemab in the United States was set at US$32,000 for a one-year course of treatment.[7] This price point, similar to that of lecanemab, raises significant questions about affordability and access for patients and sustainability for healthcare systems, particularly given the large number of individuals affected by Alzheimer's disease. The total cost of care must also account for the necessary ancillary services, including biomarker testing (amyloid PET or CSF analysis), APOE genotyping, and frequent MRI monitoring, all of which add to the overall economic burden.

Comparative Analysis and Clinical Context

The approval of donanemab places it in a new and competitive therapeutic class alongside other amyloid-targeting monoclonal antibodies. For clinicians and patients, the choice of therapy will depend on a nuanced understanding of the relative strengths and weaknesses of each agent, particularly in the domains of efficacy, safety, and administration convenience.

Donanemab vs. Lecanemab (Leqembi™)

Lecanemab is donanemab's most direct competitor and the other leading second-generation anti-amyloid therapy.

• Mechanism: A key difference lies in their primary targets. Donanemab is highly specific for N3pG, a modified form of Aβ found only in established, insoluble plaques.[12] In contrast, lecanemab preferentially targets soluble Aβ protofibrils, which are considered to be highly neurotoxic species that exist upstream of plaque deposition.[12] This mechanistic difference may explain why donanemab appears to clear existing plaque more rapidly, while lecanemab may act earlier in the aggregation cascade.
• Efficacy: In their respective pivotal Phase 3 trials, both drugs demonstrated a similar magnitude of clinical benefit, slowing cognitive and functional decline by approximately 27% to 36% on key scales like the CDR-SB.[8] While direct head-to-head clinical outcome trials are lacking, a network meta-analysis suggested that donanemab might have a slightly greater effect on cognitive outcomes, whereas lecanemab was ranked highest for the biomarker outcome of amyloid PET removal.[22] For practical purposes, their clinical efficacy is generally considered to be in the same range.
• Safety: The safety profile is a critical differentiator. The available data suggest that donanemab is associated with a higher incidence of ARIA. In their respective Phase 3 trials, ARIA-E occurred in 24.0% of donanemab patients versus 12.6% of lecanemab patients, and ARIA-H occurred in 31.4% of donanemab patients versus 17.3% of lecanemab patients.[3] This suggests that lecanemab may offer a more favorable safety profile, particularly for patients at higher risk for ARIA.
• Dosing and Administration: Donanemab offers a significant convenience advantage. It is administered as a monthly (every 4 weeks) intravenous infusion.[23] Lecanemab, by contrast, requires a bi-weekly (every 2 weeks) infusion.[23] Furthermore, donanemab's unique "stop-dosing" protocol, which allows for treatment cessation upon achieving amyloid clearance, is an attractive feature that could reduce long-term treatment burden and cost, though the durability of this effect remains to be fully characterized.

Donanemab vs. Aducanumab (Aduhelm™)

Aducanumab was the first of this class of antibodies to receive FDA approval, though its journey was marked by significant controversy.

• Efficacy: The clinical efficacy data for aducanumab were inconsistent across its two pivotal trials, leading to considerable debate about its clinical benefit. A direct head-to-head study, TRAILBLAZER-ALZ 4, compared the two drugs on the biomarker endpoint of amyloid clearance. The results demonstrated that donanemab was superior, achieving a 65.2% reduction in amyloid plaque at 6 months, compared to just a 17.0% reduction for aducanumab.[12] Aducanumab has since been voluntarily withdrawn from the market by its manufacturer.[2]
• Safety: Both drugs carry a significant risk of ARIA. The discontinuation of aducanumab makes direct safety comparisons less clinically relevant for future decision-making.

Positioning in the Alzheimer's Treatment Paradigm

The availability of donanemab and lecanemab has fundamentally altered the management of early Alzheimer's disease.

• Patient Selection: The appropriate candidate for donanemab is a patient in the early symptomatic stages of the disease (MCI or mild dementia) who has biomarker confirmation of amyloid pathology via amyloid PET or CSF analysis.[9] Patients with advanced dementia are not candidates, as the trials have shown minimal to no benefit in later stages.
• Role of Biomarkers: Biomarker testing is no longer just a research tool; it is an essential prerequisite for treatment. Amyloid confirmation is mandatory for eligibility. While not required for treatment initiation, tau PET imaging may play an increasingly important role in prognostication and counseling patients, given the clear data showing that baseline tau levels strongly predict the magnitude of clinical benefit.[19] As discussed, APOE genotyping is also essential for a comprehensive assessment of ARIA risk and for guiding the shared decision-making process.[19]
• Clinical Decision-Making: For eligible patients, the choice between donanemab and lecanemab will likely involve a careful, individualized discussion. The decision will hinge on a trade-off between donanemab's more convenient monthly dosing schedule and its innovative stop-dosing potential versus lecanemab's more favorable ARIA safety profile. This decision must be personalized, taking into account the patient's APOE genotype, baseline MRI findings, comorbidities, tolerance for risk, and personal values and goals of care.[19]

Table 4: Comparative Profile of Amyloid-Targeting Monoclonal Antibodies

Feature	Donanemab (Kisunla™)	Lecanemab (Leqembi™)	Aducanumab (Aduhelm™)
Target Epitope	Deposited Plaque (N3pG)	Soluble Protofibrils	Aggregated Aβ (Oligomers/Fibrils)
Dosing Frequency	Monthly (IV)	Bi-weekly (IV)	Monthly (IV)
Stop-Dosing Protocol	Yes (upon plaque clearance)	No	No
Efficacy (% Slowing on CDR-SB)	29%–36%	~27%	Inconsistent/Controversial
ARIA-E Incidence (%)	24.0%	12.6%	~35%
ARIA-H Incidence (%)	31.4%	17.3%	~19% (microhemorrhage)
FDA Approval Status	Full Approval (July 2024)	Full Approval (July 2023)	Withdrawn from Market (2024)
EMA Approval Status	Positive Opinion (Restricted)	Full Approval	Not Approved
Data compiled from.2 Efficacy and safety data are from respective pivotal Phase 3 trials and are not from direct head-to-head comparisons.

Conclusion and Future Directions

Synthesis of Evidence

Donanemab represents a significant and tangible step forward in the long and arduous fight against Alzheimer's disease. As a potent amyloid-clearing immunotherapy, it has unequivocally demonstrated the ability to alter the underlying pathology of the disease. The evidence from its comprehensive clinical development program confirms that this biological effect translates into a statistically significant and clinically detectable, albeit modest, slowing of cognitive and functional decline for patients in the early symptomatic stages of AD. The success of donanemab, alongside lecanemab, has firmly established anti-amyloid monoclonal antibodies as the first class of disease-modifying therapies for Alzheimer's and has powerfully validated the amyloid cascade hypothesis as a central tenet of the disease's pathogenesis.

The Benefit-Risk Calculus

This therapeutic advance, however, is not without considerable complexity. The clinical benefits of donanemab must be carefully and soberly weighed against a substantial safety profile, which is dominated by the risk of amyloid-related imaging abnormalities. ARIA, particularly in its symptomatic and severe forms, can lead to significant morbidity and, in rare but documented cases, mortality. This benefit-risk calculus is not universal but is highly individualized, heavily influenced by a patient's APOE4 genetic status. The stark reality that the patient population at the highest genetic risk for the disease is also at the highest risk for the treatment's most serious side effect creates a profound clinical and ethical challenge that will define the real-world implementation of this therapy.

Unanswered Questions and Future Research

Despite the landmark nature of its approval, critical questions about donanemab remain. The long-term durability of amyloid clearance after treatment cessation is unknown, as is the potential need for, and safety of, re-treatment if and when plaques begin to reaccumulate.[3] The efficacy and safety of the drug in more diverse racial and ethnic populations, who were underrepresented in the pivotal trials, must be established.

Looking ahead, the future of AD therapy will likely evolve in several key directions. The results of the TRAILBLAZER-ALZ 3 prevention trial will be of paramount importance, as they will determine if this therapeutic approach can be shifted to an even earlier, preclinical stage to prevent the onset of clinical symptoms altogether.[42] Furthermore, it is widely believed that the ultimate strategy for halting a multifaceted disease like Alzheimer's will require combination therapies that target multiple pathological pathways simultaneously. The future may see anti-amyloid agents like donanemab used in conjunction with anti-tau therapies, anti-inflammatory agents, or other novel mechanisms to achieve a more profound and durable clinical effect.[2]

Expert Opinion

The approval of donanemab is a watershed moment in the history of Alzheimer's disease therapeutics. It cements the role of immunotherapy in the AD treatment armamentarium and provides genuine hope to millions of patients and families. However, its implementation in routine clinical practice will be fraught with challenges, requiring a sophisticated healthcare infrastructure capable of delivering early diagnosis, advanced biomarker testing, genetic counseling, and intensive safety monitoring. Donanemab is a significant step forward, but it is not a cure. It represents the end of the beginning in the development of disease-modifying treatments, underscoring the urgent and continued need for research into safer, more effective, and more accessible therapeutic strategies to conquer this devastating disease.

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