Five Promising Alzheimer's Disease Clinical Trials to Watch in 2024

Alzheimer's disease (AD) is often considered the graveyard of drug development for pharmaceutical giants.

For a long time, the AD field has been a disaster area for new drug development. Between 2004 and 2021, nearly 100 AD drugs in development worldwide failed in Phase II or Phase III clinical trials.¹, including pharmaceutical giants such as Johnson & Johnson, Pfizer, Eli Lilly, Merck, and Roche.

According to the World Health Organization, approximately 55 million people worldwide are living with AD, and the number of patients is increasing at a rate of nearly 10 million new cases per year. It is projected that by 2050, this figure will rise to 139 million. AD, along with other forms of dementia, has become the seventh leading cause of death globally and one of the primary causes of disability and dependency among the elderly population worldwide.

But the speed of drug development cannot keep up with the continuously growing treatment needs of AD patients. According to incomplete statistics, currently, only 10 AD treatment drugs have been approved by the FDA for marketing. However, they can only improve patient symptoms and do not reduce the pathological changes of AD, nor can they reverse or slow down the progression of the disease.

Among them, Aduhelm, the first drug approved by the U.S. FDA in nearly 20 years, is also a highly controversial Alzheimer's disease (AD) drug. Due to doubts about its efficacy, its sales have been dismal, with revenue in the first nine months of 2023 falling below $11 million. As a result, it was successively abandoned by Eisai and Biogen. In addition, Roche recently announced the discontinuation of two AD drugs—Crenezumab and Semorinemab.

However, after decades of setbacks and failures, there is once again good news in the field of AD treatment drugs.

In July 2023, Leqembi, another Alzheimer's disease (AD) drug jointly developed by Biogen and Eisai, was approved for marketing by the FDA, becoming the first new AD drug to receive full FDA approval in 20 years. In January 2024, China's National Medical Products Administration announced that Leqembi had been approved in China and is expected to be launched domestically by mid-July this year for the treatment of mild cognitive impairment and mild dementia caused by AD. Eli Lilly's AD drug donanemab showed significant effects in Phase III clinical trials, and the company resubmitted a new drug application for donanemab to the FDA in the second quarter of 2023.

In 2024, the AD field will once again unleash tremendous potential. As many companies are developing candidate drugs targeting the challenges of AD, such as Triggering Receptor Expressed on Myeloid cells-2 (TREM2) and the Hepatocyte Growth Factor (HGF) system, a large number of AD candidate drugs have entered clinical trials. Data shows that, as of January 2023, there were a total of 187 clinical trials evaluating 141 drugs for the treatment of AD.². The results of these clinical trials will be released successively, and the field will also generate some interesting clinical data.Biospace Released the Clinical Trials of 5 AD Candidate Drugs to Watch in 2024.

AL002 is a humanized monoclonal antibody under development by Alector, designed to enhance microglial activity and induce their proliferation by activating TREM2 signaling, thereby promoting the phagocytosis of β-amyloid (Aβ) to delay the progression of Alzheimer's disease (AD). Results from its Phase I clinical trial showed that AL002 can increase microglial phagocytosis of Aβ, reducing the number, volume, and coverage of dystrophic neurons in plaques.

AL002, jointly developed by Alector and AbbVie, is currently in the Phase II INVOKE-2 trial. INVOKE-2 is a randomized, double-blind, placebo-controlled, dose-ranging, multi-center Phase II clinical trial being conducted at multiple sites across 11 countries. Patients with early AD are randomly assigned to receive either AL002 or a placebo intravenously every four weeks, with the primary endpoint being disease progression measured by the Clinical Dementia Rating Scale–Sum of Boxes (CDR®-SB).

Data from INVOKE-2 is expected to be released in the fourth quarter of 2024., If the results are sufficiently convincing, AbbVie will have full option rights for the third phase of development of the drug.

Fosgonimeton is a potential first-in-class small molecule designed to modulate the HGF system and activate neuroprotective and anti-inflammatory pathways in the central nervous system, thereby achieving neuroprotection, neurotrophic effects, and suppression of neuroinflammation in the central nervous system.

Athira Pharma stated that although Fosgonimeton did not meet the primary endpoint expected in the Phase II SHAPE trial for Parkinson's disease dementia and Lewy body dementia in December last year, when Athira Pharma narrowed the scope of the modified intent-to-treat population to five patients, there was a statistically significant improvement in cognitive scores. The final results showed that Fosgonimeton demonstrated good safety and tolerability.

Currently, Athira Pharma has completed patient enrollment for the Phase II/III LIFT-AD trial of Fosgonimeton in patients with mild to moderate AD. LIFT-AD is a 26-week randomized, double-blind, placebo-controlled trial in which approximately 315 patients with mild to moderate AD receive either a once-daily subcutaneous injection of 40 mg Fosgonimeton or placebo. The primary endpoint is the Global Statistical Test (GST), while key secondary and exploratory endpoints include changes in plasma biomarkers related to neurodegeneration, protein pathology, and neuroinflammation.The main data of the trial is expected to be released in the second half of this year.

Craig Suvannavejh, senior analyst of biopharmaceuticals and biotechnology research at Mizuho, stated that despite the controversy surrounding the currently collected data, Fosgonimeton is "interesting," and HGF is a unique drug target that has the potential to improve neuronal function and can be used in combination with anti-amyloid or anti-tau therapies.

ALZ-801 is an oral anti-amyloid small molecule drug candidate and a prodrug of tramiprosate (homotaurine), designed to prevent the formation of amyloid oligomers. The primary results of its Phase II clinical trial showed that, in over 2,000 AD patients, ALZ-801 demonstrated good safety and did not increase the risk of amyloid-related imaging abnormalities (ARIA). In 2017, ALZ-801 received Fast Track designation from the FDA.

Currently,ALZ-801 is in Phase III clinical trials to evaluate its efficacy in early AD patients with APOE4/4, and the study results are expected to be announced in the middle of this year.。

PRX012 is an anti-Aβ antibody that targets a key epitope at the N-terminus of Aβ and represents a new generation of high-binding-valence antibodies. Unlike Leqembi and donanemab, which are administered intravenously, PRX012 is delivered subcutaneously. Preclinical data show that, in the central nervous system, PRX012 administered subcutaneously can achieve concentrations capable of clearing both pyroglutamate-modified and unmodified Aβ plaques in brain tissue. In April 2022, PRX012 received Fast Track designation from the FDA.

PRX012 is currently in Phase I ASCENT trial to evaluate its use in treating adults aged 55-85 with mild AD, with results expected to be announced this year.。

AXS-05 is a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity for the treatment of depression and other central nervous system (CNS) disorders, composed of dextromethorphan and bupropion. Unlike the four previously mentioned drugs, AXS-05 is not a disease-modifying drug for AD but a candidate for treating AD-related symptoms. Axsome Therapeutics is currently testing its efficacy against agitation associated with AD symptoms.

The core characteristics of agitation include restlessness, excessive or purposeless activity, irritability, increased reactivity to internal and external stimuli, and instability in the course of the disease. Axsome stated that currently about 70% of AD patients suffer from agitation, which is associated with a decline in cognitive function, earlier admission to nursing homes, and increased mortality.

Despite the FDA approval of Otsuka Pharmaceutical/Lundbeck's Rexulti (Brexpiprazole) for a new indication in 2023, used to treat agitation associated with Alzheimer’s disease (AD), making it the first FDA-approved drug for AD agitation, Rexulti carries a black box warning for elderly patients with dementia-related psychosis. The drug may increase the risk of death in such patients.

Previously, Axsome presented the Phase III ACCORD trial data of AXS-05 for the treatment of agitation in Alzheimer's disease (AD) at the 2023 Clinical Trials on Alzheimer's Disease (CTAD) conference. The results showed that, compared with placebo, AXS-05 significantly delayed the recurrence of agitation symptoms and demonstrated good safety and tolerability, with no new safety signals identified during the trial.

AXS-05 is currently being tested in a second pivotal Phase III clinical trial, with results expected to be announced in the second quarter of 2024.。

References:

1. Kim, C. Kwon et al. ‘Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures. 1 Jan. 2022 : 83-100.

2. Alzheimer's disease drug development pipeline: 2023.