A CIRM Disease Team to Develop Allopregnanolone for Prevention and Treatment of Alzheimer's Disease

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Alzheimer’s disease (AD) is now a nation-wide epidemic and California is at the epicenter of the epidemic. One-tenth of all people in the United States diagnosed with AD live in California. In the US, 5.4 million people have AD and another American develops AD every 69 seconds. No therapeutic strategies exist to prevent or treat AD. Further, current therapies neither treat the disease nor sustain therapeutic benefit. Our goal is to develop a small molecule therapeutic, allopregnanolone (APα), that will prevent and treat AD. APα promotes the ability of brain to regenerate itself by increasing the number and survival of newly generated neurons. The APα-induced increase in newly generated neurons was associated with a reversal of cognitive deficits and restored learning and memory function to normal in a mouse model of AD. Remarkably, APα also reduced the amount of AD pathology in the brain. The unique mechanism of APα action reduces the risk that APα would cause proliferation of other cells in the body. Preclinical findings indicate that APα has the potential to be effective for both the prevention of and early stage treatment of Alzheimer’s disease. Further, APα was effective in aged normal mice and induced neurogenesis and restored cognitive function suggesting that APα could be beneficial for sustaining cognitive function and prevent development of AD in a normal aged population. APα has been proven safe in male and female animals and humans. Together, these findings provide a strong foundation on which to conduct a clinical trial of APα in persons with mild cognitive impairment, persons at risk for AD and in those diagnosed AD. We propose a regenerative therapeutic development project that includes late-stage FDA mandated IND-enabling chronic APα exposure, manufacturing and CMC of APα, IND FDA submissions followed by two clinical trials. The first clinical trial is to assess the safety and tolerance of once per week exposure to multiple doses of APα for 12 weeks and to evaluate whether APα is cleared from the blood. We will also evaluate the effect of APα on cognition and effects in brain that could be indicative of regeneration by measuring, by MRI, hippocampal volume, white matter integrity and a marker of functional connectivity. MRI will also be included for safety purposes, as required by FDA, to rule out occurrence of amyloid related imaging abnormalities (ARIA). In the second, proof of concept trial, 144 participants will be randomized to a single APα dose (selected based on the prior dosing and safety study) or placebo, given weekly over 48 weeks. The primary objectives of this clinical trial are to further assess safety and tolerability and to determine the impact of APα on cognition and MRI biomarker outcomes to support subsequent phase 3 development. Joining us in this endeavor are internationally recognized experts who share our commitment to developing a therapeutic to halt the epidemic of AD.

Statement of Benefit to California: 

California is at the epicenter of the epidemic of Alzheimer’s disease (AD). Nationwide there are 5.4 million persons living with AD. Ten percent or over half a million Californians have AD. Among California’s baby boomers aged 55 and over, one in eight will develop AD. It is estimated that one in six Californians will develop a form of dementia. By 2030 the number of Californians living with AD will double to over 1.1 million. While all races and ethnic groups and regions of the state will be affected, not all regions within California will be equally affected. Los Angeles County has the greatest population in the state and thus will be the true epicenter of the Alzheimer’s epidemic in California. Alzheimer’s is a disease that affects an entire family, community and health care system. Nation-wide there are nearly 15 million Alzheimer and dementia caregivers providing 17 billion hours of unpaid care per year. Total costs for caring for people with AD, totals $183 billion per year. California shouldered $18.3 billion of those costs and most of those costs were born by persons and health care services in Los Angeles County. Because of the psychological and physical toll of caring for people with Alzheimer’s, caregivers had $7.9 billion in additional health care costs. Proportionally that translates into $790 million of health care costs for Californians. In total, California spent over $19 billion per year for costs associated with Alzheimer’s disease. Multiple analyses indicate that a delay of just 5 years can reduce the number of persons diagnosed with Alzheimer’s by 50% and dramatically reduce the associated costs. We seek to develop a regenerative therapeutic, allopregnanolone (APα) to prevent and treat AD. APα promotes the innate regenerative capacity of the brain to increase the pool of neural progenitor cells. The APα-induced increase in neurogenesis was associated with a reversal of cognitive deficits and restored learning and memory function to normal in a mouse model of AD. Further, APα reduced the development of AD pathology. APα crosses the blood brain barrier and acts through a mechanism unique to neural progenitor cells and thus is unlikely to exert proliferative effects in other organs. Because APα was efficacious in both pre pathology and post-pathology stages of AD progression, APα has the potential to be effective for both prevention of and early stage treatment of AD. A regenerative therapeutic for Alzheimer’s that both halts the disease while regenerating the brain will restore both the person afflicted with the disease and those that give care.