The Alzheimer’s Drug Discovery Foundation (ADDF) announces ten new investments, totaling $13.25 million, to help advance research programs focused on novel therapeutic targets and innovative avenues for the treatment and prevention of Alzheimer’s disease and related dementias.
“Our investment in these studies reflects the ADDF’s venture philanthropy approach supporting companies and academia to accelerate drug research,” said Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF. “It is exciting to see much of the work we’ve funded over the past 20 years is now advancing to later-stage phase 2 trials.”
Several of these new treatments being investigated are focused on targets associated with the biology of aging, such as neuroinflammation, oxidative stress, and hyperactivity in the brain cells. Other programs involve biomarkers, behavioral symptoms associated with Alzheimer’s, and delirium prevention.
Eric Siemers, MD – Vaccinex, Inc.
A pilot pharmacodynamic study of Anti-SEMA4D Antibody (VX15) in early Alzheimer’s disease
In Alzheimer’s disease there is an increase in brain inflammation that contributes to cognitive impairment. Vaccinex Inc. is developing a novel antibody drug that regulates brain inflammation, a very promising therapeutic target for Alzheimer’s. This antibody has been shown to improve neuroinflammation in preclinical studies and showed positive results in a small clinical trial in Huntington’s disease patients. This program will test the Vaccinex drug in a phase 2a clinical trial to assess changes in biomarkers of brain metabolism and neuroinflammation.
Chien-liang Lin, PhD, Ohio State University
Development of small molecule activators of glutamate transporter EAAT2 translation for Alzheimer’s disease
Hyperactivity in brain cells is one of the early pathological events in Alzheimer’s disease. This can be caused by excessive levels of an essential neurochemical called glutamate, which at abnormally high levels can be toxic to nerve cells. Normally, a transporter called EAAT2 removes excess glutamate and prevents damage in the brain. EAAT2 levels decline in Alzheimer’s patients, which is proposed to be an early event in the disease process. Dr. Lin has identified a novel drug that increases the production of EAAT2 protein in order to reduce glutamate and lower hyperactivity. The drug restores memory, improves integrity of nerve cell connections, and reduces amyloid plaques in Alzheimer’s animal models. Dr. Lin was previously selected as an ADDF-Harrington Scholar through a partnership with the Harrington Discovery Institute. Through the award, he received two years of in-kind consulting support from pharma-experienced drug development professionals, providing valuable program guidance. The current funding will enable Dr. Lin and collaborators to perform regulatory toxicology studies required by the FDA for approval to conduct the first human clinical trials.
REPURPOSING DRUGS FOR THE TREATMENT OF ALZHEIMER’S DISEASE
Ronald van der Geest, PhD, Treeway B.V.
Phase 2a Clinical Trial to Evaluate the Safety, Pharmacodynamics and Pharmacokinetics of TW001 in Alzheimer Patients
There is ample evidence suggesting that oxidative stress plays a major role in Alzheimer’s disease. Edaravone is an antioxidant drug that is currently used in Asia for the treatment of stroke. It is FDA-approved for the treatment of amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. In preclinical models of Alzheimer’s, edaravone treatment reduces amyloid plaques, oxidative stress, and inflammation, while preserving brain cells and cognitive functions.
Edaravone is currently only available as an intravenous formulation given daily as one-hour infusions. Treeway, a biotech company, recently developed an oral formulation of edaravone called TW001. A phase I study in healthy volunteers suggested that TW001 is safe and well-tolerated.
In the first part of the proposed study, Treeway will test and validate their new oxidative stress assays developed in-house, using blood and spinal fluid samples from Alzheimer’s patients. The second part of the study consists of a phase 2a clinical trial in mild Alzheimer’s patients to determine whether TW001 reduces biological markers of oxidative stress and Alzheimer’s. They will also assess longer-term safety of TW001 and whether the treatment improves cognitive function.
Krista Lanctôt, Sunnybrook Research Institute, University of Toronto
Nabilone for Agitation Blinded Intervention Trial (NAB-IT)
Approximately 50 percent of patients with Alzheimer's disease will experience agitation, a complication that is particularly burdensome for caregivers. It is also one of the leading causes for placing patients into long-term care facilities. There are currently no approved drugs for agitation in Alzheimer's patients. Although certain antipsychotic drugs are currently prescribed off-label, they have significant side effects. As a result, there is an urgent need for safer medication options.
The ADDF has supported Dr. Lanctôt’s study of nabilone, a synthetic derivative of the active ingredient in cannabis (THC), as a potential treatment for Alzheimer’s disease. Nabilone is FDA-approved for the management of nausea and vomiting associated with chemotherapy.
Recent study results show nabilone had a positive effect on agitation in moderate to severe Alzheimer’s patients. In addition to its effects on agitation, nabilone may also be able to reduce neuroinflammation through its interactions with cannabinoid receptors. With additional ADDF funding, Dr. Lanctôt now will assess changes in agitation and biomarkers, like pro-inflammation biomarker TNF-α, in 108 patients treated with nabilone or placebo. This study will determine its effectiveness in treating severe behavioral symptoms like agitation and its potential as a disease-modifying drug for neuroinflammation in Alzheimer’s disease.
Luana Fioriti, PhD, Plico Biotech
SUMO2 mimetics as innovative inhibitors of tau toxicity in pre-clinical models of frontotemporal dementia
A major contributor to abnormal pathology in frontotemporal dementia (FTD) occurs when tau forms toxic clumps, disrupting normal brain signaling. One way neurons can protect themselves against this toxicity is through a process called SUMOylation. Plico Biotech is working on a strategy to pharmacologically increase SUMO to achieve greater cellular resiliency to tau protein toxicity in the brain. This project will test their compound in a model of FTD.
Sharon Rosenzweig-Lipson, PhD, AgeneBio Inc
In Vivo Characterization of a GABA-A alpha-5 Positive Allosteric Modulator
People with mild cognitive impairment have more memory problems than expected for their age and are also at increased risk for developing dementia. One of the reasons may be because their brain cells become more hyperactive than normal. AgeneBio is developing therapies to tackle hyperactivity in the brains of these patients. The current funding will support further characterization of a novel drug that enhances the activity of the GABA-A α5 receptor, a receptor that normally dampens the excitability of neurons. By boosting its GABA-A α5 activity, their drug can reduce hyperactivity, improve symptoms, and delay the progression to dementia in preclinical models.
Edward Spack, PhD, Therini Bio, Inc. (formerly MedRed Inc.)
Development of an Antibody Therapeutic and an Imaging Agent Targeting Fibrin-Mediated Neuroinflammation
A blood-clotting factor called fibrin has been implicated in the toxic inflammation that damages neurons in Alzheimer’s disease. Fibrin is essential for normal blood clotting after an injury but can abnormally seep into the brain because of blood vessel changes that occur in Alzheimer’s.
Therini is developing a drug to block fibrin from causing inflammation without affecting its blood clotting function. In parallel, the company is also developing an imaging agent that can detect fibrin deposits in the brain and indicate blood vessel abnormalities, which will aid in clinical development.
Hiroaki Sato, MD, PhD, McGill University Health Centre
Does intranasal insulin administration preserve cognitive function after cardiac surgery?
Each year there are 3-10 million patients suffering from postoperative delirium or postoperative cognitive dysfunction, which are associated with a 6-fold higher risk of developing dementia. Brain function may decline after surgery and older patients undergoing open heart surgery are especially at risk. Unfortunately, there are currently no medications available that prevent or treat postoperative delirium or postoperative cognitive dysfunction.
Surgeries can trigger inflammation, which in turn can contribute to impaired insulin signaling in the brain leading to cognitive dysfunction. Dr. Sato and colleagues will carry out a double-blind randomized placebo-controlled trial enrolling 494 cardiac surgery patients to test whether intranasal insulin administration preserves cognitive function and decreases risk of postoperative delirium and postoperative cognitive dysfunction. Intranasal delivery of insulin has the benefit of delivering insulin directly into the brain without affecting insulin levels in the blood, and therefore does not cause hypoglycemia (very low level of blood sugar). A positive outcome of this trial could result in a cost-effective implementation of delirium prevention using intranasal insulin in high risk surgery patients.
John Gerdes, PhD, RIO Pharmaceuticals, Inc.
Human PET Imaging Evaluations of the Astroglial L-Glutamate EAAT2 Tracer for Alzheimer’s Disease and Related Dementias
Brain imaging with techniques like positron emission tomography (PET) has proven valuable at measuring aspects of Alzheimer’s in living patients. There is great demand and potential for novel imaging agents that can index early brain dysfunction in Alzheimer’s disease. The ADDF supported the development of Amyvid™, the first approved amyloid PET scan that has revolutionized the way we conduct clinical trials, allowing researchers to ensure that patients in Alzheimer's trials have the disease. The development of additional imaging tools to track disease progression can help accelerate our efforts to select patients for clinical trials and monitor their response to emerging therapies.
Dr. Gerdes and collaborators have developed the first and only imaging agent targeting EAAT2, a protein involved in synaptic transmission in the brain. The current funding will enable the team to perform first-in-human trials in healthy participants and Alzheimer’s patients. The outcomes of this study have potential value in aiding early diagnoses.