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.
This proposal focuses on the clinical development of a small molecule therapeutic, allopregnanolone, for Alzheimer’s disease (AD). Preclinical data indicate that allopregnanolone increases the number and survival of newly born neurons, reduces AD-related pathology and improves cognitive deficits in a rodent model of AD. The applicant proposes to conduct two clinical trials of allopregnanolone, which has already undergone initial safety testing in humans. The first trial would further test its safety, establish dosing and look for preliminary efficacy in AD patients. The second, larger and longer clinical trial would aim to establish proof-of-concept for the therapy by testing allopregnanolone versus a placebo control.
Significance and Impact
- The responsiveness of this proposal to the RFA is marginal. While the applicant presents preclinical data demonstrating that allopregnanolone has effects on neural progenitor cells (NPCs), it is not clear that these effects are responsible for the cognitive improvement observed in rodent models of AD. The pharmacological target of allopregnanolone is widely expressed in the nervous system and thus the drug may produce its effects through mechanisms unrelated to NPC proliferation and differentiation.
- AD represents an enormous unmet medical need as there are currently no effective treatments for this devastating and prevalent disease.
- The Target Product Profile (TPP) does not define the degree of benefit that would be clinically meaningful in mild to moderate AD patients. This would be an important criterion in setting a go/no-go decision point for the program.
- The applicant does not discuss several clinical trials evaluating molecules that share targets with allopregnanolone, including a completed trial of lorazepam in AD and several ongoing trials of pregnanolone. While these trials may not be directly competitive, their study designs or results could inform this development program.
- The side effects of sedation and memory impairment observed in a previous clinical trial of allopregnanolone add significant risk to the project. These side effects may make it difficult to observe cognitive improvement in AD patients. It is not clear from the clinical protocol that the investigators have carefully considered this possibility and additional preclinical studies may be required to support a trial design where benefit can be observed even if sedation occurs.
- The preclinical data are robust and demonstrate efficacy of allopregnanolone in a rodent model of AD.
Therapeutic Development Readiness
- The applicant has already conducted a pre-IND meeting with FDA and has received positive and constructive feedback. The applicant has designed further preclinical safety studies to address specific FDA concerns.
- Allopregnanolone has been tested in healthy human subjects and initial data supporting its safety have been obtained.
Feasibility of the Project Plan
- The project plan is feasible although the timeline is tight. Inadequate time is built in between database lock for the first trial and protocol submission for the second.
Principal Investigator (PI) and Development Team
- The PI is well qualified to lead this development program. S/he has published extensively on neurosteroids and has an excellent track record to support the proposed studies.
- The Co-PI is highly experienced in the design and execution of clinical studies for AD.
- The applicant has assembled a skilled team that encompasses the many disciplines required for a program of this scope.
Collaborations, Resources and Environment
- The impact of this therapeutic approach could be severely affected by the limited intellectual property (IP) protection for allopregnanolone, which is in the public domain. Reviewers noted that two large and expensive Phase III trials would ultimately be required for FDA approval and funding for these trials would be unlikely without adequate IP protection. They recommended that the applicant develop another compound that could be protected by a composition of matter patent or alternatively, pursue an oral formulation of allopregnanolone which could be protected by a formulation patent.
- The applicant has assembled a strong scientific advisory board with excellent experience in AD drug development.
- The contract research organization that will run the clinical studies is qualified and has extensive experience in neurological indications.
Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. )
- Reviewers noted that clinical trial and manufacturing costs are high and don’t track enrollment.
- The budget for preclinical studies is appropriate.
Condition Applied by the Planning Award Grants Working Group (GWG)
- The Planning Award GWG set a condition that “to be eligible for the Disease Team Therapy Development Research Award competition, the applicant must at the time of Full Application address how a non-toxic and efficacious dose has been or will be distinguished from a dose that acutely impairs memory.”
- The applicant addressed this condition in several ways: by changing their proposed route of administration, choosing doses for their first clinical trial lower than that which has been shown to impair memory, and conducting a pharmacokinetic/pharmacodynamic simulation study.
- Reviewers cautioned that the sedative effect of allopregnanolone may not be solely responsible for the memory impairment observed in a previous human trial. They also noted that the applicant does not discuss published studies linking allopregnanolone levels to memory impairment in animal models. However, reviewers ultimately agreed that the condition had been met.