{"id":25093,"date":"2025-02-12T19:00:00","date_gmt":"2025-02-12T13:30:00","guid":{"rendered":"https:\/\/www.delveinsight.com\/blog\/?p=25093"},"modified":"2025-02-27T15:49:43","modified_gmt":"2025-02-27T10:19:43","slug":"alzheimers-disease-treatment-and-clinical-trials","status":"publish","type":"post","link":"https:\/\/www.delveinsight.com\/blog\/alzheimers-disease-treatment-and-clinical-trials","title":{"rendered":"Challenges in the Pursuit of Alzheimer\u2019s Disease Treatment Breakthroughs: Drug Clinical Trial Failures"},"content":{"rendered":"\n

Alzheimer\u2019s,<\/em><\/strong> the most common type of dementia, particularly with an increasing geriatric population, presents a major global crisis. The disease mostly occurs in sexagenarians, but it may manifest in quadragenarians. It is one of the most prevalent neurodegenerative disorders with a multifactorial pathogenesis. It is characterized by a gradual decline in cognitive and functional abilities, with individuals eventually losing their capability to undertake everyday tasks and function independently. Alzheimer\u2019s disease is one of the top ten leading causes of death in the US and the fifth leading cause of death among adults aged 65 years or older.<\/p>\n\n\n\n

\n

\u201cAccording to DelveInsight\u2019s epidemiology analysis, the age cohort 75\u250084 years accounted for the highest, nearly 44% (approximately 7 million) of the total <\/em>diagnosed prevalent cases of Alzheimer\u2019s disease<\/em><\/a> in the 7MM.\u201d<\/em><\/em><\/strong><\/p>\n\n\n\n

\"Alzheimer's-Disease-Epidemiology-Insights-(2023)\"<\/figure>\n<\/blockquote>\n\n\n\n

It is widely known that the progressive cognitive decline as a result of Alzheimer\u2019s disease is associated with the accumulation of amyloid-beta and tau proteins, leading to the formation of two underlying pathological hallmarks, extracellular amyloid beta plaques and intracellular neurofibrillary tangles. These disrupt communication between brain cells, leading to their degeneration.<\/p>\n\n\n\n

However, advancements in the comprehensive understanding of disease pathophysiology and the discovery of novel signaling pathways have revolutionized disease diagnosis, making it more personalized, timely, and reliable. Initiating early treatment is a basic tenant to slow disease progression.<\/p>\n\n\n\n

The current Alzheimer\u2019s disease treatment regime<\/a> is not curative and mostly includes symptomatic therapies. The Alzheimer\u2019s disease treatment market has made considerable progress, with new developments, especially in the past five years, with more amyloid beta-proteins targeted monoclonal antibodies<\/strong> entering the Alzheimer\u2019s disease treatment market, besides the more common acetylcholinesterase inhibitors<\/strong> (AChEIs) and NMDA receptor antagonists.<\/strong><\/p>\n\n\n\n

The recent approval of monoclonal antibodies is a glimmer of hope in the Alzheimer\u2019s disease emerging drug landscape<\/a> littered with failures in recent years. In the chase to enter the lucrative Alzheimer\u2019s market, many drugs that were deemed game changers have failed in late stages. Recent failures include phase III studies across targets such as \u03b3-secretase inhibitors, \u03b2 secretase inhibitors, monoclonal antibodies, and intravenous immunoglobulins in patients with early-stage, mild, or mild to moderate Alzheimer\u2019s. Additionally, some tau aggregation inhibitors have also failed in the late stage.<\/p>\n\n\n\n

The list of failures is long, but the crucial ones to drop out of the race from 2023 to 2024<\/strong> include Eli Lilly\u2019s LY3372689, Athira Pharma\u2019s Fosgonimeton, Sage Therapeutics\u2019 Dalzanemdor, Avanir Pharmaceuticals\u2019 Deudextromethorphan, Roche\/Chugai\u2019s gantenerumab, Merck\u2019s verubecestat, Eli Lilly\u2019s solanezumab, AstraZeneca and Eli Lilly\u2019s lanabecestat, Novartis and Amgen\u2019s CNP520 (umibecestat), Johnson & Johnson\u2019s atabecestat, <\/strong>among others.<\/p>\n\n\n\n

Inhibitors of \u03b3-Secretase abandoned in phase III studies included semagecestat avagacestat and tarenflurbil. Semagecestat was associated with worsening of daily function and increased rates of skin cancer and infection. In contrast, avagacestat was associated with a higher progression rate of the disease and adverse dose-limiting effects like skin cancer, and tarenflurbil was ascribed to low potency and brain penetration.<\/p>\n\n\n\n

The past decade has appeared optimistic for finding disease-modifying therapies for Alzheimer\u2019s as a result of the understanding of the \u201camyloid hypothesis\u201d, especially with several BACE inhibitors in clinical trials. However, what happened could be described as a burial ground for BACE inhibitors, with almost all pharmaceutical companies having abandoned BACE1 inhibitors. No BACE inhibitor is listed in any company\u2019s pipeline for experimental or clinical development.<\/p>\n\n\n\n

BACE1 inhibitor, lanabecestat,<\/strong> a collaborative therapy of AstraZeneca and Eli Lilly<\/strong>, having skipped Phase II trials and directly begun Phase III, was discontinued in 2018. The trials were put to end for futility, as they were not likely to meet the primary endpoints upon completion. Janssen\u2019s atabecestat<\/strong>, despite a long history of clinical trials with promising results, was unable to progress beyond phase II\/III study, due to reports of liver toxicity in test subjects. The drug was discontinued in 2018. <\/p>\n\n\n\n

Merck\u2019s verubecestat<\/strong> and Biogen and Eisai\u2019s elenbecestat<\/strong>, also BACE1 inhibitors, were dropped from the pipeline, as Phase III results demonstrated no benefits in mitigating cognitive\/functional decline in patients with Alzheimer\u2019s<\/a>. Rather, they had unfavorable risk-benefit ratios associated with cognitive worsening, brain volume loss, and multiple treatment-related adverse events, including falls and injuries, suicidal ideation, weight loss, sleep disturbance, skin rash, and hair color change. <\/p>\n\n\n\n

Novartis and Amgen\u2019s umibecestat was discontinued <\/strong>due to reports of safety issues, and Eli Lilly\u2019s LY3202626 abandoned due to the low likelihood of statistically significant treatment effect.<\/p>\n\n\n\n

A multitude of trials were underway for other mechanisms of action, like amyloid-beta-specific monoclonal antibodies, tau-aggregate inhibitors, and tau vaccines, among others. Amyloid-beta targeting drugs were touted as game-changers, however many of these also failed in gaining market entry, casting doubt on the validity of amyloid as a target \u2013 until recently.<\/p>\n\n\n\n

Eli Lilly, solanezumab,<\/strong> an A\u03b2-specific mAb, designed to target soluble forms of amyloid beta, did not clear existing plaques and was abandoned by Lilly in 2016 after it did not slow loss of mental functioning in patients with mild Alzheimer\u2019s symptoms in clinical trials. <\/p>\n\n\n\n

Roche\u2019s Genentech and AC Immune\u2019s drug, crenezumab<\/strong>, failed to prevent early symptoms or slow cognitive decline. There was no significant difference in cognition or the ability to store and retrieve new memories between participants who received the drug and those who got a placebo. After a decade of efforts, the company bid adieu to the drug in 2022. <\/p>\n\n\n\n

Another big blow was Roche (Genentech\u2019s) gantenerumab<\/strong>, as the drug missed the mark, and was unable to slow clinical decline in people with early-stage disease but also did not seem to clear amyloid plaques. <\/p>\n\n\n\n

In August 2024<\/em>, Eli Lilly<\/strong>, a major player in Alzheimer\u2019s drug development, faced a significant setback. Their experimental anti-tau drug LY3372689<\/strong>, designed to prevent the buildup of tau tangles\u2014one of the disease’s hallmarks\u2014failed in its Phase 2 clinical trial<\/strong>. The trial, which aimed to test whether the drug could slow cognitive decline in early symptomatic Alzheimer\u2019s patients, did not meet its primary endpoint. The disappointment was palpable. Tau pathology has long been considered a critical target in AD, and Lilly had hoped that LY3372689 would be the next big step following the approval of their anti-amyloid drug, Kisunla (donanemab)<\/strong>. But when the data came in, it showed that patients on the drug did no better than those on a placebo. While Lilly remains committed to exploring tau-targeting therapies, this failure left them without a single tau-directed candidate in their clinical-stage pipeline.<\/p>\n\n\n\n

Just a month later, in September 2024<\/em>, Athira Pharma<\/strong> experienced disappointment when fosgonimeton, an investigational treatment, failed to demonstrate significant cognitive improvements in a Phase 2\/3 clinical trial. Fosgonimeton was designed to enhance brain function by targeting neurotrophic pathways. Still, despite being well tolerated, the drug did not lead to meaningful improvements in cognitive skills or daily functioning in patients with mild to moderate Alzheimer\u2019s. Researchers pointed to potential flaws in the trial, such as the relatively short 26-week treatment period<\/strong> and the fact that the placebo group showed little cognitive decline\u2014making it difficult to measure any real benefit. Though the drug showed some minor advantages in select subgroups, such as those carrying the APOE4 gene<\/strong>, the results were not strong enough to justify moving forward.<\/p>\n\n\n\n

Then came another blow in October 2024<\/em>,<\/strong> when Sage Therapeutics<\/strong> announced that it was halting the development of dalzanemdor (SAGE-718)<\/strong> for Alzheimer’s disease. The LIGHTWAVE study<\/strong>, which tested the drug in patients with mild cognitive impairment and early-stage dementia, failed to show any meaningful improvement in cognitive function. Sage had pinned its hopes on dalzanemdor\u2019s ability to enhance NMDA receptor activity<\/strong>, a key player in neural communication and memory formation. However, despite the drug\u2019s promising mechanism of action and favorable safety profile, it ultimately fell short in clinical trials. In the wake of this failure, Sage made the difficult decision to discontinue further research into dalzanemdor for AD<\/strong>, shifting its focus to other neuropsychiatric conditions.<\/p>\n\n\n\n

Even before these recent setbacks, in February 2024<\/em>, Otsuka Pharmaceutical<\/strong> faced its own challenges when its Phase 3 trial of AVP-786 failed to meet its main goal of easing agitation in Alzheimer’s patients. The drug was being evaluated as a potential treatment for agitation associated with dementia, a symptom that can be distressing for both patients and caregivers. Unfortunately, the trial results showed no significant difference between the drug and placebo, and to make matters worse, there was a higher rate of falls among patients receiving AVP-786. While Otsuka has vowed to analyze the data further to see if the drug might still have potential, this failure has cast doubt on AVP-786\u2019s future as an Alzheimer\u2019s treatment.<\/p>\n\n\n\n

These repeated disappointments serve as a stark reminder of how complex and elusive Alzheimer\u2019s disease<\/em> remains. Researchers continue to pursue different therapeutic targets\u2014beta-amyloid plaques, tau tangles, neuroinflammation, and metabolic dysfunction<\/strong>\u2014but the road to an effective treatment is long and unpredictable. For every breakthrough like Leqembi (lecanemab) and Kisunla (donanemab)<\/strong>, multiple failed drugs never make it past clinical trials. Yet, despite these setbacks, the scientific community remains undeterred. The lessons learned from these failures will help refine future research, bringing us one step closer to an effective therapy\u2014or even a cure\u2014for Alzheimer\u2019s disease.<\/p>\n\n\n\n

Most of these failures can be attributed to:<\/strong><\/p>\n\n\n\n