Research Highlights from Padmaja Genesh (December 2020)

Published: Jan 04, 2021

Last Patient Finishes ALZT-OP1 Combo Therapy Trial; Results Expected Early 2021 

The COGNITE trial (NCT02547818) was designed to evaluate ALZT-OP1’s safety and effectiveness in people, ages 55 to 79, with early Alzheimer’s disease. A total of 620 patients were recruited at more than 100 clinical sites clinical sites across the U.S., Canada, Australia, and Europe. 

ALZT-OP1 is a proprietary combination of two previously approved small molecules that have been re-engineered and optimized to reach the brain and provide a daily dose that could potentially suppress the neuroinflammation that leads to neuronal death in Alzheimer’s patients. 

Designed to be a convenient and easy-to-use inhaled and oral delivery kit for once-daily home use, ALZT-OP1 consists of a dry-powder inhaler containing cromolyn (designated ALZT-OP1a) and oral pills containing ibuprofen (designated ALZT-OP1b). 

As such, ALZT-OP1’s multi-modal approach is expected to lower neuroinflammation and potentially slow or halt disease progression in people with early-stage Alzheimer’s. 

The last participant has completed all predefined assessments in the Phase 3 COGNITE clinical trial, which is assessing the safety and effectiveness of AZTherapies’ treatment candidate ALZT-OP1 for people with early Alzheimer’s disease

The trial’s top-line results are expected in the first months of 2021. The biopharmaceutical company hopes its investigational therapy will be found to slow or even stop the progression of Alzheimer’s. 

Preclinical studies have shown that cromolyn, used to treat asthma, can halt the formation of toxic amyloid-beta clumps — one of Alzheimer’s hallmarks that contributes to neuroinflammation — and reduce the release of pro-inflammatory molecules.

The participants were randomly assigned to receive one of four combination treatments: ALZT-OP1 (ALZT-OP1a and ALZT-OP1b), ALZT-OP1a with an oral placebo, inhaled placebo with ALZT-OP1b, or both inhaled and oral placebos. Treatment was given for 72 weeks (about 17 months). 

COGNITE’s main goal is to assess changes in the Clinical Dementia Rating Scale Sum of Boxes from the study’s start to end, or from zero-to-72 weeks of treatment. 



Cortexyme’s COR388 GAIN Trial Advances to Endpoint; Results Expected Late 2021 

Cortexyme’s ongoing Phase 2/3 GAIN clinical trial, which is evaluating the investigational treatment COR388 (Atuzaginstat) in people with mild to moderate Alzheimer’s disease, has been approved to continue as planned to its one-year endpoint, the company said. Topline results from the study, testing whether COR388 can lessen dementia and neurodegeneration in Alzheimer’s, are expected on time in December 2021. 

GAIN (NCT03823404), which now has enrolled 643 participants ages 55 to 80, is a randomized, placebo-controlled study evaluating 40 and 80 mg of COR388, or a placebo, given twice daily to people with confirmed mild to moderate Alzheimer’s disease.  

COR388 is designed to block enzymes secreted by the bacteria P. gingivalis, called gingipains, found in more than 90% of post-mortem brain samples from Alzheimer’s patients. These enzymes also have been shown to trigger Alzheimer’s pathology and neurodegeneration in animal models. 

Following a six-week screening period, COR388 treatment continues for a total of 48 weeks (nearly one year).

There are two primary endpoints in GAIN. One is a mean change in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11), which measures cognitive and non-cognitive functions such as mood and behavior. The other goal is a change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which measures dementia severity. 

Secondary and exploratory endpoints include a change in the Activities of Daily Living (ADCS-ADL) assessment, Neuropsychiatric Inventory (behavioral disturbances), Mini-Mental State Examination (cognitive function), and a Winterlight speech assessment (a speech-based cognitive assessment). 

The trial also includes a sub-study to evaluate the clinical benefit of COR388 in the treatment of periodontitis, an infection of the gums that is caused by P. gingivalis and gingipains. Of the patients enrolled so far in this sub-study, more than 90% had moderate to severe periodontitis at the beginning of the trial. 



AlzeCure’s Lead Therapy Candidate Entering Phase 1 Testing in Sweden 

AlzeCure Pharma is preparing to launch a Phase 1 clinical trial in Sweden to evaluate the tolerability and safety of ACD856, one of its therapy candidates for Alzheimer’s disease, the company announced. 

The trial follows the release of the first positive clinical results, in which ACD856 showed a good pharmacokinetic profile (how the body affects a medicine), and was found suitable for further clinical development as an oral medication for Alzheimer’s. 

 ACD856 is the lead therapy candidate for AlzeCure Pharma’s NeuroRestore drug development platform, which is focused on improving cognition by stimulating key pathways in the central nervous system (brain and spinal cord). The platform is made up of three experimental treatments aimed at reducing the symptoms of cognitive dysfunction in Alzheimer’s, traumatic brain injury, sleep apnea, and Parkinson’s disease. 

Specifically, NeuroRestore is designed to improve cognition by enhancing neurotrophin signaling (neutrophins are proteins that regulate the development, maintenance, and functions of the nervous system), whose levels are impaired in diseases like Alzheimer’s.

Moreover, neurotrophins, such as the brain-derived neurotrophic factor (BDNF), function as neurotransmitters — substances produced in response to nerve signals that act as chemical messengers and are key mediators of nerve cell communication. When these neurotransmitters fail to function properly, the communication between nerve cells is impaired, giving rise to cognitive disabilities. 

In preclinical studies, ACD856 was found to significantly increase the levels of key neurotransmitters in the hippocampus of rats, and improved memory in mice.



IGC Starts Phase 1 Study of Low-dose Cannabinoid in Alzheimer’s Patients 

A Phase 1 trial is enrolling patients with mild to severe dementia from Alzheimer’s disease to test IGC-AD1, an investigational cannabis-based treatment being developed by India Globalization Capital (IGC) Pharma, a subsidiary of IGC, according to a recent press release

In the placebo-controlled study, 12 participants will receive the medication over three 14-day periods, with the dose increasing in each period. 

The study primarily aims to assess the safety of IGC-AD1. The company will also monitor the patients’ dementia-related behavioral aspects to help guide later trial phases. 

IGC-AD1 combines small doses of cannabinoids — chemicals derived from cannabis — with other compounds into a formulation designed to help with Alzheimer’s.

The potential therapy is based on the discovery, made at the University of Southern Florida, that low doses of THC — the component of marijuana associated with psychological effects, or getting “high” — bind to amyloid plaques (believed to play a key role in cognitive decline) and prevent them from aggregating, or clumping, in neurons. 

THC interacts with the body through several known pathways, including anti-oxidative effects, and by binding to the CB1 receptor in the central nervous system, among others. Cannabinoids have increasingly attracted attention as potential therapies for treating Alzheimer’s. 

 IGC expects to complete the Phase 1 study during the first half of calendar 2021. 



Dosing Starts in Athira’s Phase 2 ACT-AD Trial Testing ATH-1017: Enrollment Ongoing 

Athira Pharma has begun dosing patients in its Phase 2 clinical trial evaluating ATH-1017, an investigational small molecule for the treatment of mild to moderate Alzheimer’s disease

Clinical efficacy will be demonstrated by improvements in cognition and functional assessments among participants, compared with a placebo. 

Called ACT-AD, the randomized, double-blind trial (NCT04491006) will evaluate the safety and efficiency of ATH-1017 (previously known as NDX-1017), compared with a placebo, in the treatment of mild to moderate Alzheimer’s. 

ATH-1017 is a small molecule specifically designed to enhance the activity of the hepatocyte growth factor (HGF, also known as scatter factor), and its receptor protein MET, which are expressed in the central nervous system, in order to promote brain health and function.

The therapy was developed to slow or stop disease progression or even reverse it. In previous preclinical studies, ATH-1017 was shown to be able to regenerate nerve cells and improve cognitive function. 

The trial expects to recruit a total of 75 participants, ages 55 to 85, at several clinical sites across the U.S. and Australia. More information and contacts can be found here

Similar to the company’s LIFT-AD Phase 2/3 trial, participants will be randomly assigned to receive either a low or high dose of ATH-1017 or a placebo, delivered subcutaneously (under the skin) daily for 26 weeks. Neither participants nor researchers will know which patient is given the medication and which the placebo. 

The study will measure quantitative electroencephalography (qEEG), as a biomarker for brain function, and event-related potential (ERP) to assess working memory processing speed and executive function. 



Biogen, Eisai Request Approval of Aducanumab for Alzheimer’s in Japan 

 Biogen and Eisai are seeking approval of Aducanumab (BIIB037) for the treatment of Alzheimer’s disease in Japan, the companies have announced. If approved, Aducanumab will become the first therapy with the potential to slow the clinical decline seen in patients with Alzheimer’s. 

The treatment is under priority review with the U.S. Food and Drug Administration (FDA) with a final decision expected by March 7, 2021. It is also under review with the European Medicines Agency. 

Aducanumab, being developed by Biogen in collaboration with Eisai, is a man-made antibody designed to clear beta-amyloid protein, whose toxic clumps are known to induce the death of neurons in the brain in those with Alzheimer’s. 

The approval requests were based on clinical data from Phase 3 trials — EMERGE (NCT02484547) and ENGAGE (NCT02477800) — which tested aducanumab in people with early Alzheimer’s disease. 

The trials were discontinued after an independent monitoring committee determined that Aducanumab was not likely to produce meaningful benefits. However, an analysis of an additional three months of data, which became available after the trials stopped, showed that EMERGE achieved its main goal: treatment with Aducanumab led to improvements in cognition and function — including memory, orientation, and language, as well as activities of daily living — when compared to a placebo. 

Recently, an advisory arm of the FDA recommended that the available clinical data on Aducanumab does not support the effectiveness of the investigational therapy for Alzheimer’s. 

Out of 11 committee members, eight agreed that the Phase 3 EMERGE data did not provide “strong evidence” of efficacy, while seven members did not agree that the PRIME study showed enough evidence supporting effectiveness. 



Fujirebio Seeks FDA’s Premarket Approval for Diagnostic Test 

Fujirebio Diagnostics has submitted a premarket notification — also known as a 510(k) — to the U.S. Food and Drug Administration (FDA) for its Alzheimer’s diagnostic test, called Lumipulse G β-Amyloid Ratio (1-42/1-40). 

If cleared by the FDA, it will be among the first commercially available lab tests to assess the risk of Alzheimer’s disease in adults with signs of cognitive impairment. 

The new Lumipulse G β [beta]-Amyloid ratio combines two individual tests, the Lumipulse G β-amyloid 1-42 and the Lumipulse G β-amyloid 1-40. Each test measures the levels of a different form of the beta-amyloid protein — beta-amyloid 42 and beta-amyloid 40 — in the cerebral spinal fluid (CSF), which is the liquid surrounding the brain and spinal cord. This fluid is collected using a lumbar puncture procedure, also called a spinal tap. 

Beta-amyloid is the main constituent of amyloid plaques, or clumps, in the brain, one of the main features of Alzheimer’s disease. Evidence suggests that the accumulation of beta-amyloid in the brain disrupts several brain functions and eventually leads to the death of nerve cells (neurons). 

The test output is the ratio of beta-amyloid 1-42/1-40 in the CSF and is intended for use in adults, ages 50 and older, with signs of cognitive impairment, who are being tested for Alzheimer’s disease or other causes of cognitive decline. 

The Lumipulse G β-Amyloid test and tests measuring the levels of the tau protein — whose accumulation is also a hallmark of Alzheimer’s disease — are already approved for use in the European Union.



Compiled by Padmaja Genesh, Learning Specialist