Challenges in the Pursuit of Alzheimer’s Disease Treatment Breakthroughs: Drug Clinical Trial Failures

Alzheimer’s, 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’s 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.

“According to DelveInsight’s epidemiology analysis, the age cohort 75─84 years accounted for the highest, nearly 47% (approximately 7 million) of the total diagnosed prevalent cases of Alzheimer’s disease in the 7MM.”

It is widely known that the progressive cognitive decline as a result of Alzheimer’s 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.

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.

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

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

The list of failures is long, but the crucial ones to drop out of the race include Roche/Chugai’s gantenerumab, Merck’s verubecestat, Eli Lilly’s solanezumab, AstraZeneca and Eli Lilly’s lanabecestat, Novartis and Amgen’s CNP520 (umibecestat), Johnson & Johnson’s atabecestat, among others.

Inhibitors of γ-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, while 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.

The past decade has appeared optimistic for finding disease-modifying therapies for Alzheimer’s, as a result of the understanding of the “amyloid hypothesis”, 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. Not a single BACE inhibitor is currently listed in any company’s pipeline for experimental or clinical development.

BACE1 inhibitor, lanabecestat, a collaborative therapy of AstraZeneca and Eli Lilly, having skipped Phase II trials and directly begun Phase III, was discontinued in 2018, and the trials were put to end for futility, as they were not likely to meet the primary endpoints upon completion. Janssen’s atabecestat, 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. 

Merck’s verubecestat and Biogen and Eisai’s elenbecestat, also BACE1 inhibitors, were dropped from the pipeline, as Phase III results demonstrated no benefits in mitigating cognitive/functional decline in patients with Alzheimer’s. 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. 

Novartis and Amgen’s umibecestat was discontinued due to reports of safety issues, and Eli Lilly’s LY3202626 abandoned due to the low likelihood of statistically significant treatment effect.

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 – until recently.

Eli Lilly, solanezumab, an Aβ-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’s symptoms in clinical trials. 

Roche’s Genentech and AC Immune’s drug, crenezumab, 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, pushing the company to bid adieu to the drug in 2022, after a decade of efforts. 

Another big blow was Roche (Genentech’s) gantenerumab, 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. 

Most of these failures can be attributed to:

• Inadequate understanding of the complex pathophysiology of Alzheimer’s disease that has led to the incorrect selection of treatment targets and inappropriate drug dosages
• Insufficient evidence for initiating pivotal trials and testing for clinical efficacy, as drugs advanced into the pivotal phase III trial for Alzheimer’s disease with far less efficacy testing than generally accepted in standard practice
• Studies relied on and accepted changes in biomarker levels (Aβ or tau) as surrogate clinical endpoints, without evidence of confirmatory changes in cognitive, functional, and global performance when deciding to advance to the pivotal trial
• Pivotal trial design issues such as poor choice of primary clinical outcome measures, inclusion of non-Alzheimer patients, insufficient accounting for Alzheimer’s subtype, and late intervention administration further added to the troubles.

Despite high failure rates, companies are holding on to hope and tirelessly seeking the key to unlock effective treatments and renewed possibilities for Alzheimer’s disease, to change the treatment paradigm in the years to come. 

“Every step we take towards better Alzheimer’s disease treatment is a step closer to a brighter tomorrow for millions of families touched by this disease.”

The US FDA’s accelerated approval of Biogen and Eisai‘s ADUHELM is a glimmer of hope amidst the successive chain of failures. Though the approval was not without controversy, given that the data it was based on was less than solid, yet, the decision left the door ajar for further approvals based on surrogate biomarker data. 

The recent US FDA conversion of Biogen and Eisai’s LEQEMBI’s (lecanemab) accelerated approval to a traditional one is an classic example of grit and persistence.  Despite a few initial hiccups, the approval along with a CMS go-ahead with Medicare covering the therapy for Alzheimer’s appropriate patient segment has provided much relief. This approval besides garnering support for Biogen and Eisai, and helping them drive past the ADUHELM stumble, has opened the gates for a plethora of therapies that are in different stages of development. 

Late-stage trial results of Eli Lilly’s donanemab, wherein it slows cognitive decline by 35%, is another unexpected success and is hailed as a ‘turning point’ for Alzheimer’s disease treatment. Both these provide strong evidence that removing amyloid from the brain can slow down Alzheimer’s disease, and the amyloid hypothesis, whose potential had been uncertain after dozens of drug failures, actually has disease-modifying potential.

Drugs are being developed to address disease heterogeneity, its complexity, and its multifaceted nature. The multi-target intervention has more potential compared to a single target. A systems approach that considers the human system holistically would yield better results, as it incorporates the complexity and involvement of multiple physiological pathways and brain-body interactions, thus overcoming the overreliance on single pathways and single target approaches. 

Further quantitative systems pharmacology model combined with artificial intelligence could identify gaps in our knowledge of the disease, generate new biological or pharmacological hypotheses, and aid in the design of in vitro and in vivo experiments to investigate and validate the model insights.  Scientists have begun to apply modeling approaches to Alzheimer’s with encouraging results. For example, AI models have shown great accuracy in diagnosing Alzheimer’s patients.

Various therapies by Anavex Life Sciences, Alzheon, Athira Pharma, Annovis Bio, Eli Lilly, BioVie, AB Science, Novo Nordisk, Cassava Sciences, TauRx Therapeutics, KeifeRx, AriBio, Cerecin, Eisai, others are in late stages of development that have the potential to create a positive shift in the Alzheimer’s disease treatment market. 

The early-stage Alzheimer’s disease pipeline is complete with therapies with novel mechanisms of action, and improved disease pathology has added to this growth of drug development. The early Alzheimer’s pipeline is brimming with biggies like Janssen, AbbVie, Merck, etc., which are also in the race. With several assets being assessed, what is certain is that even though a few might fail, there will be improved treatment, and the Alzheimer’s disease treatment market will grow leaps and bounds in the future.

Severity-specific drugs are also being developed and Companies like Partner Therapeutics, EIP Pharma, Synaptogenix, Alkahest, Stemedica Cell Technologies, and Merck are focusing their research on this unmet need.

Therefore, despite the present challenges, there is a positive force in improving Alzheimer’s disease treatment. With innovative drug development, the path toward a world where memory endures, cognition thrives, and the specter of Alzheimer’s disease is but a distant memory, looks optimistic.