Alzheimer Disease Pipeline Boasts Promise With Investigational Agents


With the FDA is set to decide on the possible approval of aducanumab in June, the remaining pipeline for Alzheimer therapies is loaded with potential for the future.

Alzheimer disease (AD) has long presented a challenge for the clinical development of drugs due to its complex pathology and difficulty in early identification, among other issues. This challenge has been on display for quite some time, with a number of clinical trials failing to show the efficacy of potential therapies to treat AD—including those of 2 investigational therapies, troriluzole and atabecestat, just this year.1,2

Although, a number of positives have been recently brought to light in spite of these failures. As of now, there are more than 100 agents being evaluated in clinical trials for the treatment of AD, of which 29 had reached phase 3 and 65 had reached phase 2. In total, 97 of these treatments are in disease-modification trials. A review of the pipeline by Cummings et al. last year suggested that this ongoing innovation is present across the pathology spectrum in AD, with all pathways other than amyloid and tau increasing the number of agents in the pipeline compared to 2019.3

Now, in just the first few months of 2021, pharmaceutical companies and research institutions have made announcements, read out new data, and initiated clinical trials of therapies for AD—all while Biogen and Eisai await word from the FDA about their investigational agent aducanumab. This influx of therapies comes in tandem with advances made in diagnostics and biomarkers, and, according to Stephen Salloway, MD, MS, director of neurology and of the Memory and Aging Program, Butler Hospital, the possibility of an approval in the first half of the year may motivate the clinical community to become even more engaged.


In early January 2021, Athira Pharma was awarded a $15 million grant from the National Institute of Aging (NIA) to support its phase 2 randomized, placebo-controlled ACT-AD trial (NCT04491006) investigating ATH-1017 for mild-to-moderate AD, after the first patient was dosed in December 2020. The small-molecule therapeutic promotes the activity of Hepatocyte Growth Factor (HGF) and its receptor, MET, which are expressed in the central nervous system, in order to enhance brain health and function.4,5

Co-investigator Charles Bernick, MD, MPH, clinical professor of neurology, University of Washington School of Medicine, University of Washington Alzheimer’s Disease Research Center, and director of clinical trials, UW Medicine Memory & Brain Wellness Center, said in a statement that “this AD treatment approach is innovative and novel. As part of the study design, the use of quantitative electroencephalogram (qEEG) and Event-Related-Potential (ERP 300) as physiological outcome measures and indicators of improved function in brain networks could be highly valuable to the field as a whole."


The NIA and the Alzheimer’s Drug Discovery Foundation (ADDF) in late January awarded 5-year grants to scientists from Cleveland Clinic’s Lou Ruvo Center for Brain Health to examine the therapeutic potential of lenalidomide, an FDA-approved cancer therapy, in early-stage AD and mild cognitive impairment (MCI). The project is comprised of 2 studies and is led by Marwan Sabbagh, MD, and Boris Decourt, PhD. The investigators will be tasked with identifying whether the drug reduces inflammation and other disease-related neuropathological features, as well as if there’s an impact on cognition of those living with MCI, with a strategy targeting multiple AD neuropathologies at once, a relatively unknown and uncommon approach.6

The 2 lenalidomide studies, which will be dual assessments, are aiming to recruit participants with early-stage AD/MCI at the Lou Ruvo Center for Brain Health. The first study is funded by the NIH and is a 20-month phase 2 investigation evaluating the effect of long-term use of lenalidomide on cognition, along with safety and tolerability. The second study, supported by ADDF funding, is a 6-month phase 2 study examining the short-term use of lenalidomide in 45 participants, with a focus on safety and effects on blood and cerebrospinal fluid biomarkers.

Sabbagh told NeurologyLive in March that the reason they chose this class of medicine “is because they have a dual mechanism of action that inhibits both TNF alpha and inflammation in the non-COX pathway, but also in the TNF alpha pathway. These also have potent effects on both amyloid and base.”


In the first days of February, Cassava Sciences announced the results of an open-label study of its investigational, oral small molecule treatment for AD, simufilam, showing it was associated with the improvement of cognition and behavior in individuals with AD without any reported safety issues. Cassava noted that in combination with prior clinical trial results, these results support the advancement of simufilam into a phase 3 clinical program in AD—a trial that is currently expected to begin in the second half of 2021.7

The study, funded by the National Institutes of Health (NIH), showed that after 6 months of treatment with the altered filamin A (FLNA) restoration agent that cognition scores measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) improved by 1.6 points from baseline scores of 15.5, equivalent to a 10% mean improvement. Additionally, dementia-related behavior—including anxiety, delusions, and agitation—improved by 1.3 points from baseline scores of 4.5 on the Neuropsychiatric Inventory (NPI). This improvement equaled a 29% mean improvement at 6 months.

“We could not be more pleased with these interim results,” Remi Barbier, chief executive officer and president, Cassava, said in a statement at the time. “We would have been satisfied to show simufilam stabilizes cognition in patients over 6 months. An improvement in cognition and behavior tells us this drug candidate has [the] potential to provide lasting treatment effects for people living with Alzheimer’s disease. It’s an exciting development.”


Alector announced in mid-February 2021 that the first patient had been dosed in its randomized, double-blind, placebo-controlled, dose-ranging, phase 2 INVOKE-2 study (NCT04592874) evaluating the investigational agent AL002 in patients with early AD. INVOKE-2 will enroll approximately 265 participants with early AD at up to 90 sites globally and will measure disease progression using the Clinical Dementia Rating Sum Boxes (CDR-SB) as well as fluid and imaging biomarkers.8

AL002 targets the triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane receptor protein expressed on some immune cells and microglia. Some large-scale, genome-wide studies have demonstrated its genetic links to sporadic AD, and other literature suggests that impacted function of TREM2 may lead to AD and dementia.

“Alzheimer’s is a devastating disease that robs a person of their identity, and a family of their loved one. We are hopeful that AL002 may one day be a treatment option for the millions of people diagnosed with this disease,” said Michael Gold, MD, vice president, Development Neurosciences, AbbVie, in a February statement. “We are pleased that the study was initiated rapidly and look forward to data from the phase 2 study that will inform a potential pivotal clinical development program for AL002.”


On March 8, 2021, AB Science announced that newly published data on its investigational AD agent masitinib reflected the agent’s ability to block hemichannels on mast cells pose as a promising novel strategy for slowing the progression of neurodegenerative diseases such as AD, according to a recently published peer-reviewed study.9,10

This independent publication came on the heels of a December 2020 announcement that the oral agent met the primary end point in its phase 2b/3 study (NCT01872598) in patients with mild and moderate AD. In that study, treatment with masitinib 4.5 mg/kg/day (n = 182) generated a significant treatment effect on the primary endpoint of change from baseline in the ADAS-Cog compared to those in the control arm (n = 176; P = .0003). In addition to the effect on cognition and memory, masitinib 4.5 mg/kg/day generated a significant change from baseline in the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) score, an instrument that assesses self-care and activities of daily living (P = .0381).11


Just recently, new data from the phase 2 TRAILBLAZER-ALZ study (NCT03367403) of donanemab were published in the New England Journal of Medicine and presented at AD/PD 2021 which suggest that treatment with the therapy results in better composite scores for cognition and ability to perform activities of daily living after 76 weeks compared to placebo in patients with early AD.12,13

The primary outcome was the change from baseline in the score on the Integrated Alzheimer’s Disease Rating Scale (iADRS), which ranged from 0 to 144, with lower scores indicating greater cognitive and functional impairment. At baseline, iADRS score was 106 in both the donanemab (n = 131) and placebo (n = 126; 1 participant was excluded from the modified intent-to-treat population) groups. After 76 weeks, the treatment group’s scores changed by –6.86 points while the placebo group’s changed by −10.06 (difference, 3.20; 95% CI, 0.12-6.27; P = .04). This change was equivalent to a 32% difference in slowing decline for the treatment group, a significant difference that was identifiable by month 9.

"We are confident in the results of the TRAILBLAZER-ALZ study," said Daniel Skovronsky, MD, PhD, chief scientific officer, and president, Lilly Research Laboratories, Eli Lilly and co., donanemab’s developer, in a statement at the time. "This is the first late-stage study in Alzheimer's disease to meet its primary endpoint at the primary analysis. Donanemab has the potential to become a very important treatment for Alzheimer's disease. We were pleased to see not only slowing of cognitive and functional decline, but also very substantial clearance of amyloid plaques and slowing of spread of tau pathology."

1. Biohaven provides update on phase 2/3 trial and Alzheimer's Disease program. News release. January 18, 2021. Accessed March 22, 2021.
2. Sperling R, Henley D, Aisen PS, et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: A truncated randomized phase 2b/3 clinical trial. JAMA Neurol. Published online January 19, 2021. doi:10.1001/jamaneurol.2020.4857
3. Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer's disease drug development pipeline: 2020. Alz Dementia Trans Research Clin Inter. 2020;6(1):e12050. doi: 10.1002/trc2.12050.
4. Athira Pharma awarded $15 million grant from National Institute on Aging to support ACT-AD clinical trial in Alzheimer's disease. News release. December 8, 2020. Accessed March 22, 2021.
5. Athira Pharma announces initiation of patient dosing for ACT-AD clinical trial of ATH-1017, small molecule HGF/MET activator, for treatment of mild-to-moderate Alzheimer’s disease. News release. December 1, 2020. Accessed March 22, 2021.
6. Cleveland Clinic Lou Ruvo Center for Brain Health Receives NIH and ADDF Grants, Totaling $4.6 Million to Study FDA-Approved Cancer Drug Lenalidomide in Alzheimer’s Disease. News release. January 27, 2021. Accessed March 22, 2021.
7. Cassava Sciences’ Simufilam Improves Cognition and Behavior in Alzheimer’s Disease in Interim Analysis of Open-label StudyCassava Sciences’ Simufilam Improves Cognition and Behavior in Alzheimer’s Disease in Interim Analysis of Open-label Study. News release. February 2, 2021. Accessed February 2, 2021.
8. Alector announces first participant dosed in phase 2 study evaluating AL002 in individuals with early Alzheimer’s disease. News release. January 25, 2021. Accessed March 22, 2021.
9. AB Science announces that a new independent publication confirms the role of masitinib as a potential therapy in neurodegenerative disorders including Alzheimer disease. News release. March 8, 2021. Accessed March 22, 2021.
10. Harcha PA, Garcés P, Arredondo C, Fernández G, Sáez JC, van Zundert B. Mast cell and astrocyte hemichannels and their role in Alzheimer’s disease, ALS, and harmful stress conditions. Int J Mol. Published online February 15, 2021. doi: 10.3390/ijims22041924
11. AB Science announces that phase 2b/3 study evaluating oral in Alzheimer’s disease met its primary endpoint. News release. December 16, 2020. Accessed March 22, 2021.
12. Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N J Med. Published online March 13, 2021. doi: 10.1056/NEJMoa2100708.
13. Lilly's donanemab slowed Alzheimer's disease progression in Phase 2 trial: full data presented at AD/PD 2021 and published in NEJM. News release. March 13, 2021. Accessed March 22, 2021.
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