Funded Programs Clinical

Evaluation of MSDC-0160 in subjects with mild Alzheimer's disease

Summary:
MSDC-0160, is the first of a generation of "PPAR-sparing" insulin sensitizer. This compound has completed proof of concept phase 2a studies in type 2 diabetes patients that showed that this compound can exert similar pharmacology as pioglitazone but without causing volume expansion and weight gain, side effects that limit the use of pioglitazone. MSDC-0160 is currently being developed for type 2 diabetes, but given the mechanism of action of the compound and recent results in animals, it is important to see if this agent could have important effects in the treatment of Alzheimer's disease. MSDC and collaborators have shown that MSDC-0160 binds to mitochondria and improves metabolism. Numerous workers in the Alzheimer's field have found that loss of mitochondrial function in the brain predates the loss of cognitive function. Preclinical studies show that the MSDC-0160 gets into the brain of mice and can reduce the size and number of plaques in a mouse model of Alzheimer's disease. The compound also improves learning in mice. Given these findings and new research understandings, we will propose to directly test MSDC-0160 in patients with mild to moderate Alzheimer's disease. We predict that treatment with MSDC-0160 will improve metabolism in the brain, which can be directly measured with FDG-PET scan images. We suspect that this improvement in brain metabolism will correlate with positive effects on measures of cognition (episodic memory and executive function). If these hypotheses are confirmed in this clinical trial, a change in development strategy will be indicated for MSDC-0160. We would seek immediate support for rapidly making this compound available for Alzheimer's patients while we pursue an alternate development strategy for the treatment of Alzheimer's disease.

A Randomized, Double-Blind, Placebo-Controlled Phase 2 study to evaluate the effect of PBT2 (once daily for 52 weeks) on Abeta deposition in the brain of patients with Alzheimer\'s Disease

Summary:
The accumulation of amyloid (Abeta) in the brains of patients suffering from Alzheimer\'s disease is widely accepted to be related to both the pathogenesis and the devastating symptoms of the disease and is a key target for many of the efforts to develop a treatment. Prana scientists discovered that abnormal, aging-related interactions between key biologically important metals and Abeta can explain many of the neuropathological and cognitive symptoms characteristic of AD. Prana scientists are developing a novel drug for the treatment of AD, PBT2, that can attenuate the interaction between bioavailable metal ions and Abeta to reduce many of the downstream toxic events resulting from this interaction and also the ongoing aggregation and accumulation of Abeta. In a clinical trial of 78 patients with mild AD, after a 12 week treatment period PBT2 has been shown to reduce Abeta in the cerebrospinal fluid of patients who received the drug as well as to improve cognitive outcomes. The proposed study will employ Pittsburgh Compound-B (PiB), 2-(4\'methylaminophenyl benzothiazole for positron emission tomography (PET) imaging of the brain in patients with amnestic MCI and mild AD to assess the effect of PBT2 on Abeta deposition.

Safety/Tolerability and Effects on Cognitive Impairment, Impaired Cerebral Cortical Metabolism and Oxidative Stress of R(+)Pramipexole Administered to Subjects with Early Alzheimer's Disease

Summary:
Increasing damage to nerve cells and brain tissue from oxygen free radicals has been found in Alzheimer's brain tissues and animal models of relatively rare familial Alzhiemer's disease (AD). There is substantial evidence that this "oxidative stress" occurs very early in AD and is responsible for progression of AD. In this application, subjects with early AD will take increasing doses of a novel neuroprotective drug (R(+)PPX) that has already been tested in ALS patients and accumulates in brain tissue. The AD subjects taking R(+)PPX will have special brain scans to measure metabolism and assays of markers for oxidative stress. The goal of this study is to determine if early AD patients tolerate high doses of R(+)PPX.

Pilot trial of Metformin in the prevention of Alzheimer's disease Investigator(s): Jose Luchsinger, MD MPH Institution(s): Columbia University, New York, NY

Summary:
Diabetes and "hyperinsulinemia" (high insulin levels) have surfaced as important risk factors for Alzheimer's disease (AD). There are ongoing clinical trials of anti-diabetic agents (e.g. rosiglitazone) in the prevention and treatment of AD based on the hypothesis that reduction of insulin levels will decrease AD progression. However, recent reports of safety concerns with rosiglitazone widely covered by the scientific and lay press have put the use of this medication in the prevention and treatment of AD into question. Dr. Luchsinger proposes to continue a phase II pilot clinical trial of metformin, a safe and effective medication in the prevention and treatment of diabetes and the reduction of insulin levels, in the prevention of cognitive decline among persons with amnestic mild cognitive impairment (AMCI), a transitional stage between normal cognition and AD. Luchsinger will complete recruitment of 40 subjects with grant 270901 from ISOA. With the additional funding raised through the "fund-a-scientist" program, he will continue to follow-up these 40 subjects and will recruit 10 new participants.

Efficacy and Safety of Filgastrim (Neupogen®) as a Pro-cognitive Agent for Alzheimer's Disease Investigator(s): Juan Sanches-Ramos, MD, PhD Institution(s): University of South Florida

Summary:
The use of blood stem cell-mobilizing agents for treatment of neurologic diseases is being applied to patients with Alzheimer's disease (AD). Administration of filgastrim to mouse models of AD resulted in a dramatic improvement in cogntive function and a marked decrease in amyloid plaque deposition. Filgastrim is already clinically approved for other indications (to increase blood stem cell production in leukemia) and in normal donors of blood stem cells. This clinical study will be the first to determine whether filgastrim administration will be effective and safe as a pro-cognitive and disease-modifying agent in patients with AD.