Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval (original) (raw)
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Alzheimer's Research & Therapy
Background This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer’s disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration’s approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors a...
Drugs, 2024
Introduction ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD. Methods The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ 42 /Aβ 40) and tau pathology (p-tau 181) were enrolled, with serial CSF and plasma levels of Aβ 42 and Aβ 40 measured over 104 weeks. Longitudinal changes of CSF Aβ 42 , plasma Aβ 42 /Aβ 40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex. Results A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ 42 level and plasma Aβ 42 /Aβ 40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26). Conclusions In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD. Trial Registry https:// clini caltr ials. gov/ study/ NCT04 693520.
Lessons Learnt from the Second Generation of Anti-Amyloid Monoclonal Antibodies Clinical Trials
Dementia and Geriatric Cognitive Disorders, 2020
Background: Alzheimer disease (AD) is a chronic neurodegenerative disorder with complex pathophysiology that affects over 50 million people worldwide. Most drug therapies, to date, have focused on targeting the amyloid-beta (Aβ) pathway, but clinical outcomes of anti-Aβ antibodies have been unsuccessful and unable to meet their primary endpoints. Similar trends have also been observed in treatments that target the tau pathway. Summary: This paper reviews recent anti-Aβ passive monotherapies, since Bapineuzumab, that have progressed to phase 3 clinical trials. Specifically, we discuss the 4 clinical trial programs of Solanezumab (targets Aβ monomers), Aducanumab (targets Aβ oligomers and plaques), Crenezumab (targets Aβ oligomers), and Gantenerumab (targets Aβ fibrils) which are all exogenous monoclonal antibodies. We conclude with potential reasons for why they have not met their primary endpoints and discuss lessons learnt from these trials. Key Message: Future disease-modifying tr...
Journal of Experimental Pharmacology
Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aβ plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aβ. These treatments include but are not limited to using small molecules to alter the interactions of Aβ monomers, reducing hyperactivation of neuronal circuits altering Aβ's molecular pathway of synthesis, improving degradation of Aβ, employing passive immunity approaches, and stimulating patients' active immunity to target Aβ. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aβ levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aβ pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aβ synthesis.