crenezumab (RG7412) / AC Immune - LARVOL DELTA

Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial. (PubMed, Lancet Neurol) - P2 | "Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials."

Clinical • Journal • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APOE

Drug Development. (PubMed, Alzheimers Dement) - "We characterize distinct tau accumulation patterns and amyloid-tau interactions, particularly in ADAD mutation carriers, offering valuable insights into early disease progression. We tested our model assumptions and methods, further strengthening the framework for advancing therapeutic research and understanding the neurodegenerative mechanisms underlying both ADAD and sporadic AD."

Clinical • Journal • Alzheimer's Disease • CNS Disorders

Drug Development. (PubMed, Alzheimers Dement) - "Patients undergoing anti-amyloid therapy are at risk of developing ARIAs, particularly those carrying the ApoE4 genotype. ARIAs are generally asymptomatic, do not necessitate treatment discontinuation, and show differing courses depending on the subtype: ARIA-E resolves spontaneously, while ARIA-H persists. Aducanumab was associated with the highest frequency of ARIA events. These findings underscore the importance of regular MRI monitoring and patient-specific management strategies to mitigate complications and optimize therapy outcomes."

Journal • Observational data • Retrospective data • Alzheimer's Disease • Cardiovascular • CNS Disorders • Hematological Disorders • APOE

Developing Topics. (PubMed, Alzheimers Dement) - "The minimal differences between treatment and placebo-relative to the wide scoring scales-suggest that targeting amyloid plaques may be insufficient as a disease-modifying approach. These findings underscore the urgent need for alternative strategies. One such approach is NA-831, Biomed's novel small-molecule therapy based on neurogenesis and neuroprotection. Unlike amyloid-targeted antibodies, NA-831 aims to restore neuronal function and cognition by stimulating endogenous brain repair mechanisms. These emerging strategies may better align with the complex pathophysiology of AD and represent a promising new frontier in treatment."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia

Developing Topics. (PubMed, Alzheimers Dement) - P2 | "This study illustrates the ability to use longitudinal biomarker data to characterize the onset of biomarker changes and impact of putative disease modifiers like APOE4 in ADAD mutation carriers."

Journal • Alzheimer's Disease • CNS Disorders

Basic Science and Pathogenesis. (PubMed, Alzheimers Dement) - "This research enhances our understanding of ARIA-H and may guide future monoclonal antibody drug development, which may improve the cognition and overall prognosis of Alzheimer's disease patients."

Journal • Review • Alzheimer's Disease • CNS Disorders • Hematological Disorders

Directed evolution of drug-like Aβ conformation-specific antibodies. (PubMed, Front Immunol) - "Notably, we find that this approach yields robust isolation of IgGs with higher affinity, higher conformational specificity, and lower off-target binding than multiple clinical-stage Aβ antibodies, including aducanumab and crenezumab. This antibody engineering platform can be readily applied to generate conformational antibodies against diverse types of peptide and protein aggregates linked to human diseases."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

NEW DISCOVERIES IN AMYLOID-RELATED IMAGING ABNORMALITIES WITH HEMORRHAGE AND ANTI-AMYLOID BETA MONOCLONAL ANTIBODIES (WCN 2025) - "(5)Amyloid Beta Clearance Rate. The risk of ARIA-H, from highest to lowest, is as follows: Donanemab, Aducanumab, Bapineuzumab, Lecanemab, Gantenerumab, Crenezumab, Solanezumab. This research enhances our understanding of ARIA-H and may guide future monoclonal antibody drug development, which may improve the cognition and overall prognosis of Alzheimer's disease patients."

Alzheimer's Disease • CNS Disorders

EFFICACY OF ANTI-AMYLOID-Β ANTYBODIES IN ALZHEIMER'S DISEASE: A NETWORK META-ANALYSIS OF COGNITIVE AND FUNCTIONAL OUTCOMES (WCN 2025) - "Background and Aims: Monoclonal antibodies against amyloid-β in Alzheimer's disease (AD) treatments show variable efficacy. Although Donanemab shows the highest cognitive and functional decline delay, it is not significant due to the low number of study. Solanezumab, gantenerumab 510 mg, and aducanumab demonstrates cognitive improvements on the ADAS-Cog 13-item scale. No anti-Aβ antibody showed a significant benefit in slowing functional decline."

Retrospective data • Alzheimer's Disease • CNS Disorders

Use of monoclonal antibodies in Alzheimer's disease - a systematic review of phase III clinical trials (ECNP 2025) - "Current pharmacological treatments available in Portugal include cholinesterase inhibitors: Rivastigmine, Galantamine, Donepezil, and the N-methyl-D-aspartate (NMDA) receptor antagonist Memantine (2). There was insufficient evidence to conclusively determine the effectiveness of monoclonal antibodies in significantly delaying AD progression. While Aducanumab has shown some promise at higher doses in specific trials, inconsistencies across studies highlight the need for further investigation. The failure of Crenezumab, Gantenerumab, and Solanezumab to achieve meaningful clinical benefits underscores the challenges of targeting amyloid beta in AD therapy."

Clinical • P3 data • Review • Alzheimer's Disease • CNS Disorders • Dementia • Psychiatry

Structural and Functional Determinants of ARIA-H Risk in Anti-Amyloid Monoclonal Antibodies: A Comparative Mechanistic Framework for Alzheimer's Immunotherapy Development. (PubMed, Curr Neuropharmacol) - "These findings establish a mechanistic framework for ARIA-H risk and provide concrete molecular predictors to guide antibody engineering strategies. Prioritizing mAbs with controlled amyloid clearance, C-terminal binding domains, and IgG1 frameworks may enhance therapeutic safety, advancing precision immunotherapy for Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Hematological Disorders

The structural foundations of anti-amyloid-β immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment. (PubMed, J Alzheimers Dis) - "BackgroundAnti-amyloid-β (Aβ) immunotherapies are emerging as treatments for Alzheimer's disease (AD).ObjectiveThis review examines the structure-activity relationships of anti-Aβ therapeutics tested in phase 3 trials.MethodsWe analyzed crystallographic data and molecular models to elucidate the Aβ binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.ResultsLecanemab recognizes minimally degraded Aβ missing 1-2 residues, avoiding common Aβ in circulation and further degraded material sequestered in plaques. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Vascular Neurology • APOE

The Efficacy of Anti-amyloid Monoclonal Antibodies in Early Alzheimer's Dementia: A Systematic Review. (PubMed, Ann Indian Acad Neurol) - "Our findings highlight the need to consider the complex pathophysiology of AD in treatment development. Focusing solely on the amyloid-beta hypothesis may be inadequate; further research is necessary to understand the underlying mechanisms and develop treatments for the multifactorial nature of the disease."

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

New Discoveries in Amyloid-Related Imaging Abnormalities with Hemorrhage (ARIA-H) and Anti-Amyloid Beta Monoclonal Antibodies (ISC 2025) - "For monoclonal antibodies targeting Aβ clearance, we selected seven: Aducanumab, Bapineuzumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, and Solanezumab. Besides, ARIA-H is associated with the characteristics of mAb. (1)More mature Aβ clearance is associated with a higher risk of ARIA-H.(2)Lower clearance of Aβ oligomers is associated with a higher risk of ARIA-H.(3)Aβ clearance closer to the N-terminus is associated with a higher risk of ARIA-H.(4)mAb with an IgG4 structure are more likely to cause ARIA-H than those with an IgG1 structure.(5)Faster achievement of Aβ clearance thresholds is associated with a higher risk of ARIA-H.CONCLUSION This research enhances our understanding of ARIA-H and may guide future monoclonal antibody drug development, which may improve the cognition and overall prognosis of Alzheimer's disease patients."

Alzheimer's Disease • CNS Disorders • Hematological Disorders

Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives. (PubMed, Transl Neurodegener) - "First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation

Developing Topics. (PubMed, Alzheimers Dement) - "The cumulative mean changes for CDR-SB were -0.08; for ADAS-Cog it was -0.53, with both 95%CI including zero. The score range for CDR-SB is 0 to 18; the range for ADAS-Cog is 0 to 70/90. These mean differences across the many trials conducted cannot be considered to be either clinically or statistically significant."

Journal • Review

A systematic review of the efficacy and safety of anti-amyloid beta monoclonal antibodies in treatment of Alzheimer's disease. (PubMed, Expert Opin Biol Ther) - "According to CDR-SB measurements, lecanemab showed effectiveness in reducing brain amyloid and cognitive decline, with a change from baseline of 1.21. Aducanumab resulted in a decrease of -0.39 (-22%). Bapineuzumab showed no significant benefit, with scores of 2.4 (2.8). Gantenerumab, scoring 1.69 (1.37, 2.01), reduces amyloid, particularly in early Alzheimer's stages. Crenezumab was ineffective, with a score of 3.61...Further research is needed, highlighting the necessity of AD therapeutic research to alter AD's trajectory and provide reliable treatment. www.crd.york.ac.uk/prospero identifier is CRD42024504358."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia

Limitations and potential strategies of immune checkpoint blockade in age-related neurodegenerative disorders. (PubMed, J Physiol Sci) - "Lately, disease-modifying therapies (DMTs) that can alter the pathophysiology that underlies AD with anti-Aβ monoclonal antibodies (MAbs) (e.g., aducanumab, lecanemab, gantenerumab, donanemab, solanezumab, crenezumab, tilavonemab). Similarly, in Parkinson's disease (PD), DMTs utilizing anti-αSyn (MAbs) (e.g., prasinezumab, cinpanemab,) are progressively being developed and evaluated in clinical trials. These therapies are based on the hypothesis that both AD and PD may involve systemic impairments in cell-dependent clearance mechanisms of amyloid-beta (Aβ) and alpha-synuclein (αSyn), respectively, meaning the body's overall inability to effectively remove Aβ and αSyn due to malfunctioning cellular mechanisms. In this review we will provide possible evidence behind the use of immunotherapy with MAbs in AD and PD and highlight the recent clinical development landscape of anti-Aβ (MAbs) and anti-αSyn (MAbs) from these clinical trials in order to better investigate..."

Checkpoint block • Checkpoint inhibition • Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial. (PubMed, Clin Trials) - "Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Novel Coronavirus Disease

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders. (PubMed, Int J Mol Sci) - "This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively."

Journal • Review • Alzheimer's Disease • CNS Disorders

A Review of Recent Advances in the Management of Alzheimer's Disease. (PubMed, Cureus) - "The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab...Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers...The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Diabetes • Inflammation • Insomnia • Metabolic Disorders • Sleep Disorder

Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities. (PubMed, Sci Rep) - "Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aβ present. The findings of this study support the proposal that Aβ antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aβ-based immunotherapies."

Journal • Alzheimer's Disease • CNS Disorders

Native ion mobility-mass spectrometry reveals the binding mechanisms of anti-amyloid therapeutic antibodies. (PubMed, Protein Sci) - "Here, we present a high-resolution native ion-mobility mass spectrometry (nIM-MS) method to investigate complexes formed between a variety of Aβ oligomers and three Aβ-specific IgGs, namely two antibodies with relatively high conformational specificity (aducanumab and A34) and one antibody with low conformational specificity (crenezumab). Through collision induced unfolding (CIU) analysis, our data indicate that antibody stability is increased upon Aβ binding and, surprisingly, this stabilization involves the Fc region. Together, we conclude that nIM-MS and CIU enable the identification of Aβ antibody binding stoichiometries and provide important details regarding antibody binding mechanisms."

Journal

Passive immunotherapy for Alzheimer's disease: challenges & future directions. (PubMed, J Transl Med) - "(N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aβ peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aβ antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects...However, other anti-Aβ antibodies, such as lecanemab (a humanized mAb binds to soluble Aβ protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aβ peptides) and aducanumab (a human mAb binds to the aggregated form of Aβ), have been shown to slow the decline of cognitive functions in early stage AD patients...There are several challenges and limitations of passive immunotherapy using anti-Aβ antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both..."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Evaluation of Patient-Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules. (PubMed, Clin Pharmacol Ther) - "The study drugs, doses, and routes of administration included: crenezumab (15 mg/kg, intravenous infusion), etrolizumab (210 mg, subcutaneous), GDC-X (oral), and hydroxychloroquine (HCQ, 200 mg, oral). A baseline hematocrit correction and/or linear regression-based correction was effective for GDC-X, but not for HCQ. Additionally, the study evaluated the bioanalytical data quality and comparability from the various collection methods, as well as patient preference for the devices."

Journal • PK/PD data