Kisunla (donanemab-azbt) / Eli Lilly - LARVOL DELTA

Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease. (PubMed, Alzheimers Dement) - "Anti amyloid beta therapeutics are compared by their diffusible aggregate binding characteristics. In-vitro and brain-derived aggregates are tested using single-molecule detection. Lecanemab shows therapeutic success by binding to aggregates formed in early disease. Lecanemab binds to these aggregates with high affinity and coats them better."

Journal • Alzheimer's Disease • CNS Disorders

Data-Driven Modeling of Amyloid-beta Targeted Antibodies for Alzheimer's Disease. (PubMed, Res Sq) - "The results indicate that Donanemab achieves the most significant reduction in fibrils. These findings provide a quantitative basis for optimizing AD treatments, providing valuable insight into the balance between therapeutic efficacy and safety."

Journal • Alzheimer's Disease • CNS Disorders

Clinical efficacy of anti-amyloid antibodies in apolipoprotein E ε4 homozygotes: A Bayesian reanalysis of lecanemab and donanemab phase 3 results. (PubMed, Alzheimers Dement (N Y)) - "The most likely explanation for our results is the lack of a treatment effect for lecanemab and donanemab in ApoE ε4 homozygotes. This could reflect inadequate exposure to the antibody due to more severe side effects, subsequent treatment interruptions, and lower dosing or a biologically driven lack of efficacy in a genetically determined disease. Our results support the view that excluding these cases from treatment is justifiable because of the higher risk of side effects and the lack of clinical efficacy."

Journal • P3 data • Alzheimer's Disease • CNS Disorders • Dementia • APOE

ALADDIN: Amyloid Lowering for Alzheimer's in Down's With Donanemab Investigation (clinicaltrials.gov) - P4 | N=60 | Not yet recruiting | Sponsor: Michael Rafii, MD, PhD

New P4 trial • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Genetic Disorders

Clinical Benefits and Risks of Antiamyloid Antibodies in Sporadic Alzheimer Disease: Systematic Review and Network Meta-Analysis With a Web Application. (PubMed, J Med Internet Res) - "Our results showed that donanemab is more effective and has a safety profile similar to aducanumab and lecanemab, highlighting the need for treatment options with improved safety. Potential bias may have been introduced in the included trials due to unblinding caused by frequent cerebral edema and microbleeds, as well as the impact of the COVID-19 pandemic."

Clinical • Journal • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Dementia • Infectious Disease • Novel Coronavirus Disease

Towards Identifying an Optimal Time for Amyloid Assessment with Donanemab Treatment (S23.004). (PubMed, Neurology) - "Dr. Mintun has received personal compensation for serving as an employee of Eli Lilly & Co."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

ARIA Risk Factors and Management Experience in Donanemab Clinical Trials in Early Symptomatic Alzheimer's Disease (AAN 2025) - P2, P3 | "Applying T2*GRE-based inclusion criteria to SWI scans in randomized participants (n=840) yielded similar results for trial inclusion (38 participants [4.5%] would not have met criteria). Conclusions Donanemab trials have identified factors for managing ARIA risk including identifying higher risk patients prior to treatment and a modified titration dosing regimen."

Clinical • Late-breaking abstract • Alzheimer's Disease • CNS Disorders • Hematological Disorders • APOE

Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. (PubMed, Alzheimers Dement) - P3 | "In TRAILBLAZER-ALZ 6, the amyloid-related imaging abnormalities-edema/effusions (ARIA-E) frequency was 13.7% in the modified titration arm compared to 23.7% in the standard arm at week 24. The modified titration arm met the primary endpoint of ARIA-E relative risk reduction at 24 weeks versus the standard arm. The modified titration versus standard arm at week 24 had comparable non-ARIA-E related safety profile, amyloid reduction, plasma phosphorylated tau217 reduction, cumulative exposure, and pharmacokinetics. Data at week 52 were consistent with week 24 results."

Clinical • Journal • Alzheimer's Disease • CNS Disorders

AMPLIFYING EFFICIENCY AND ACCURACY IN DEMENTIA DRUG DEVELOPMENT (ADPD 2025) - "Recent FDA approvals of amyloid targeting treatments like aducanumab, lecanemab, and donanemab highlight ongoing challenges related to efficacy, cost, and patient access. This initiative aims to enhance the discovery, validation, and regulatory adoption of novel diagnostic and therapeutic techno logies, ultimately fostering more accurate, cost -effective, and personalized treatment interventions for dementia. The workgroup identifies up challenges and proposes the research questions for wider public to answer"

Alzheimer's Disease • CNS Disorders • Dementia

EFFEROCYTOSIS -DRIVEN NEUROINFLAMMATION REDUCTION BY NOVEL GAS6 FUSION PROTEIN (GAIA) IN ANTI -AΒ IMMUNOTHERAPIES (ADPD 2025) - "Recent FDA approvals of antibody therapeutics like Lecanemab and Donanemab have demonstrated significant reductions in A β burden and deceleration of cognitive decline, reinforcing A β as a viable therapeutic target. GAIA-Aβ effectively clear amyloid plaques and induce anti -inflammatory responses, with favorable pharmacokinetic profiles. These findings suggest that GAIA -Aβ may offer comparable therapeutic benefits in reducing A β burden while improving safety profiles by mitigating issues like vascular damage and ARIA associated with current immunotherapies."

Alzheimer's Disease • CNS Disorders • Inflammation • AXL • GAS6 • MERTK

USING PLASMA P -TAU FOR PRIMARY EFFICACY IN A 1 -YEAR PHASE 1B PROOF -OF-CONCEPT STUDY BASED ON PREDICTION OF CLINICAL BENEFIT (ADPD 2025) - " Aducanumab, donanemab, and lecanemab data for plasma p -tau biomarkers and clinical assessments were obtained from the literature. Our analysis suggests that the linear correlation between p -tau and clinical outcome GST can be utilized to facilitate trial design and even to estimate clinical benefit based on treatment effects on ptau -217."

Clinical • P1 data • Alzheimer's Disease • CNS Disorders

COMPARISON OF BINDING SPECIFICITY OF ANTI -AMYLOID -BETA ANTIBODIES IN SERIAL SECTIONS OF APPNL-F/NL-F; APOE4 MOUSE BRAINS (ADPD 2025) - "Aims: Immunotherapy is the leading treatment strategy for Alzheimer's disease (AD), with the FDA approving anti-amyloid-beta (Aβ) monoclonal antibodies (mAbs), lecanemab and donanemab, for early -stage AD... Immunoreactivity of recombinant lecanemab (r -lecanemab), recombinant murine lecanemab precursor (r -mAb158), and sabirnetug (ACU193) mAbs was quantitatively characterized in serial sections from briefly fixed 20 -month-old APPNL -F/NL-F; ApoE4fl/fl mice... The observed differences in binding affinities suggest that antibody selectivity may play a role in ARIA prevalence. High -magnification analyses will further clarify these differences, potentially revealing whether antibodies linked to higher ARIA show increased binding to vascular amyloid and how binding profiles vary with concentration. Funding_1R01NS136122 -01_CAL."

Preclinical • Alzheimer's Disease • CNS Disorders

SIMULATED AMYLOID TRAJECTORIES FOLLOWING DONANEMAB TREATMENT (ADPD 2025) - "Conclusions ERM-based simulation is a promising approach to translate amyloid reduction associated with donanemab treatment from clinical trials into routine practice and provides insight on the expected rate of amyloid reduction and treatment duration. Simulations suggest that amyloid reduction rate decreased and proportion of patients who reached the amyloid threshold of <24.1 CL plateaued over time."

Alzheimer's Disease • CNS Disorders

DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF INITIAL PATIENTS RECEIVING AMYLOID-TARGETING TREATMENTS IN THE U.S. AFTER FDA APPROVAL (ADPD 2025) - "Aims Three amyloid targeting treatments for Alzheimer's disease have been approved in the U.S.: aducanumab (Jun 7, 2021), lecanemab (July 6, 2023) and donanemab (July 2, 2024). However, disadvantaged populations appear underrepresented in spite of their higher disease burden, given that 8% of the 65+ Medicare population are low-income dually eligible, and 9% and 7.5% are Black and Hispanic beneficiaries, respectively. Future data need to be examined to determine whether those disparities persist."

Clinical • Alzheimer's Disease • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Coronary Artery Disease • Depression • Diabetes • Dyslipidemia • Heart Failure • Hypertension • Metabolic Disorders • Nephrology • Otorhinolaryngology • Psychiatry • Renal Disease

ARE ANTI-AMYLOID ANTIBODIES IN APOE EPSILON 4 HOMOZYGOTES NOT ONLY DANGEROUS BUT ALSO INEFFECTIVE? – A BAYESIAN REANALYSIS AND METAANALYSIS (ADPD 2025) - "Methods Data were derived from supplementary analyses in the regulatory studies Clarity (lecanemab) and TRAILBLAZER-ALZ2 (donanemab). This could reflect inadequate exposure to the antibody due to more severe side effects, subsequent treatment interruptions, and lower dosing, or a biologically driven lack of efficacy in a genetically determined disease. Our Results support the view that excluding these cases from treatment is ethically justifiable not only because of the higher risk of side effects but also because of the lack of clinical efficacy."

Retrospective data • Alzheimer's Disease • CNS Disorders • Dementia • APOE

RELATIONSHIP BETWEEN AMYLOID REDUCTION AND CLINICAL OUTCOMES FOLLOWING DONANEMAB THERAPY: INSIGHTS FROM THE TRAILBLAZER-ALZ 2 PHASE 3 CLINICAL TRIAL (ADPD 2025) - P3 | "In general, lower observed amyloid burden correlated with slower decline on combined cognitive and functional assessments. Conclusions Strong correlations were observed between lower post-baseline amyloid values and slower cognitive and functional decline, supporting the disease-modifying effect of donanemab treatment for participants with early symptomatic AD and amyloid PET imaging as a surrogate biomarker."

Clinical • Clinical data • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

MODIFIED TITRATION OF DONANEMAB REDUCED ARIA-E RISK AND MAINTAINED AMYLOID REDUCTION: 12-MONTH RESULTS FROM TRAILBLAZER-ALZ 6 (ADPD 2025) - P3 | "Serious adverse events, discontinuations or treatment-related adverse events in the modified titration arm were largely comparable to the standard dosing arm. Conclusions Consistent with the 24-week Results , the 52-week data shows that a more gradual titration of dose significantly reduced ARIA-E risk while demonstrating comparable pharmacodynamics compared to standard dosing."

APOE

PRE-RECORDED: SAFE USE OF AMYLOID-LOWERING ANTIBODIES (ADPD 2025) - "Appropriate Use Recommendations (AUR) for lecanemab have been published and an AUR is being prepared for donanemab by a group of dementia experts to help guide the safe introduction of these treatments into clinical practice. This presentation will review the key criteria for patient selection and ARIA management to optimize treatment and limit serious adverse events."

Alzheimer's Disease • CNS Disorders • Dementia

Donanemab: Appropriate use recommendations. (PubMed, J Prev Alzheimers Dis) - "Surveillance MRIs to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, prior to the 12th dose in higher risk individuals, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET, typically obtained 12-18 months after initiating treatment."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APOE

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 24-27 March 2025 (European Medicines Agency) - "The European Medicines Agency has recommended the refusal of the marketing authorisation for Kisunla, a medicine intended for the treatment of early Alzheimer’s disease. The Agency issued its opinion on 27 March 2025. The company that applied for authorisation, Eli Lilly Nederland B.V., may ask for a re-examination of the opinion within 15 days of receiving the opinion."

European regulatory • Alzheimer's Disease

Coverage Gaps: Do U.S. Commercial Health Plans Have Concordant Alzheimer's Disease Therapy & Testing Policies? (ISPOR 2025) - "These policies were effective from 1/1/2024 through 12/31/2024 and included FDA-approved therapies (lecanemab and donanemab) and testing for amyloid pathology (cerebrospinal fluid [CSF] biomarker assays and amyloid positron emission tomography [PET] scans). Although there's often alignment between amyloid targeting therapies and testing policies, inconsistencies remain. As new technologies like plasma-based biomarkers become available, it's essential for health plans to ensure policy concordance to minimize access variability for AD patients."

Discordant • HEOR • Alzheimer's Disease • CNS Disorders

Cost-Effectiveness of Delaying Progression of Alzheimer's Disease with Novel Monoclonal Antibodies: A Societal Perspective (ISPOR 2025) - "This research aims to estimate the cost impact and cost-effectiveness of Aducanumab, Donanemab, and Lecanemab in delaying progression in early AD patients. A Markov simulation model was used incorporating literature and a prior cost-impact model of delaying AD progression. New monoclonal AD treatments were estimated to add substantial costs with modest clinical benefits, with Donanemab adding the highest cost. The cost-effectiveness of the agents is substantially influenced by the patient's age at treatment initiation, treatment efficacy in slowing disease progression, and the cost of medications."

Cost effectiveness • HEOR • Alzheimer's Disease • CNS Disorders

The Unseen Progress: How PROs May Overlook the Value of Slowing Degenerative Decline (ISPOR 2025) - "This study examines the relationship between clinical outcomes and PROs in degenerative diseases, focusing on patient perceptions of treatments that slow progression. The pivotal trials of recent Food and Drug Administration (FDA)-approved treatments for degenerative diseases were analyzed; these included nintedanib for idiopathic pulmonary fibrosis (IPF), tofersen for amyotrophic lateral sclerosis (ALS), ocrelizumab for primary-progressive multiple sclerosis (PPMS), and donanemab-azbt for Alzheimer's disease (AD). PROs may not detect the benefit of treatment for degenerative diseases. A potential explanation is misalignment in patient expectations. Future research is needed to evaluate how treatment benefits can be appropriately captured by patient experience data."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Idiopathic Pulmonary Fibrosis • Immunology • Multiple Sclerosis • Pulmonary Disease • Respiratory Diseases

Adverse Events Associated With Recently Approved Alzheimer's Drugs: A Real-World Pharmacovigilance Study (ISPOR 2025) - "Aducanumab, lecanemab, and donanemab were recently approved therapies targeting beta-amyloid removal in the brain. FDAERs provide a rapid understanding of Real-world safety signals for AD therapies which demonstrated similar overall organ-level adverse effects, however distinct differences in specific events were noted."

Adverse events • Clinical • Real-world • Real-world evidence • Alzheimer's Disease • Cerebral Hemorrhage • CNS Disorders • Fatigue • Hematological Disorders • Pain

Generalizability of trial criteria on amyloid-lowering therapy against Alzheimer's disease to individuals with mild cognitive impairment or early Alzheimer's disease in the general population. (PubMed, Eur J Epidemiol) - "We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab, and applied these to participants with MCI and early clinical AD dementia from the population-based Rotterdam Study. Findings from recent RCTs reporting protective effects of monoclonal antibodies against amyloid-β are applicable to less than 15% of community-dwelling individuals with MCI or early AD. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with MCI/AD in routine clinical practice."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Depression • Mood Disorders • Psychiatry • APOE