Disease Team Therapy Planning I
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. And the situation is worse than expected. Results of a recent two year clinical study show that the currently available medications for managing AD symptoms are ineffective in patients with mild cognitive impairment or mild AD. We seek to develop a small molecule therapeutic, allopregnanolone (APα) to 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 preclinical mouse model of AD. Further, APα reduced the amount of AD pathology in the brain. Importantly, when given peripherally either by injection under the skin or applied topically to the skin, APα was able to enter the brain to increase the generation of new neurons. The unique mechanism of APα action reduces the risk that APα would cause proliferation of other cells in the body. Because APα was efficacious in both pre-pathology and post-pathology stages of AD progression, APα has the potential to be effective for both the prevention of and early stage treatment of Alzheimer’s disease. Further, APα induced neurogenesis and restoration of cognitive function in normal aged mice suggesting that APα could be efficacious to sustain cognitive function and prevent development of AD in a normal aged population. In other clinical studies, APα has been proven safe in animals and humans and in both men and women. Together, these findings provide a strong foundation on which to plan a clinical trial of APα in persons with prodromal and diagnosed Alzheimer’s disease. To plan for a Phase I-IIa clinical trial to determine safety, dosing and clinical efficacy, we have assembled an interdisciplinary team of clinicians, scientists, therapeutic development, regulatory, data management and statistical analysis experts. The objectives of this proposal are to: a) develop allopregnanolone as a therapeutic for Alzheimer’s disease; to plan an early clinical development program for its use as a neurogenesis agent; b) file a complete and well-supported IND with the Food and Drug Administration (FDA); c) complete phase I/IIa clinical studies to evaluate safety, biological activity, and early efficacy in humans; and (d) complete a phase II clinical trial that will evaluate efficacy and lead to larger multisite clinical studies of efficacy.
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 care givers 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 small molecule 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 preclinical 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 the prevention of and early stage treatment .
EXECUTIVE SUMMARY Project Synopsis The goal of the applicant is to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and complete a Phase I/IIa and Phase IIb clinical trial for the use of allopregnanolone (APa) in the treatment of Alzheimer’s disease (AD). AD is a form of dementia that affects brain function, including memory, cognition, and behavior, which is characterized by defined pathologies in brain tissue. There are currently no effective treatments for this highly prevalent disease, and the personal and financial costs to the family, community, and health care system are immense. The applicant seeks to develop APa as a small molecule therapeutic to treat AD and proposes that administration of APa will increase neurogenesis in the brain and lead to improvements in cognition, memory, and learning as well as decrease the development of AD-associated pathology. Significance and Impact - The patient population is appropriate and represents a gigantic unmet medical need given the number of people who have, or who will have, AD. - The proposed studies may lead to an effective therapeutic, and, if successful, could have an impact on AD, for which there is currently no effective treatment. - The therapeutic proposed by the applicant is one of many AD therapeutics currently in development. The impact and competiveness of this therapy will be established gradually over many years by large clinical trials, and it is currently equally competitive with other therapeutics in development. - The proposal is responsive as the proposed single small molecule targets endogenous stem cells, the applicants have demonstrated disease-modifying activity, and proposed activities are within scope. However, the responsiveness of this proposal does hinge upon the accuracy of the proposed mechanism of action - APa targeting neural stem cells. - The target product profile (TPP) is typical and well developed. Project Rationale and Feasibility - The preclinical data is strong and suggests that in animal models of AD, APa promotes neurogenesis and neuronal survival, reverses cognitive defects, and reduces the pathology burden in AD. - APa has been reported in the literature to induce sedation, decrease eye movements, and inhibit episodic memory in healthy volunteers. However, the proposed therapeutic, at the appropriate dose, may indeed be efficacious as the negative effects on memory could be due to dosing or only observed in healthy individuals. This issue was the central concern regarding this application. Reviewers felt that the applicant must address the dose specific effects of APa and provide preclinical evidence that a non-toxic and efficacious dose range can be clearly distinguished from a dose range where a memory limiting affect occurs. - The scientific rationale is based on strong preclinical efficacy data and a reasonable hypothesis – that APa improves AD by promoting neurogenesis and behavioral function – is provided. However, the applicant has not definitively demonstrated a causative link between neurogenic and behavioral effects and reviewers suggested further studies are necessary to establish this link. - APa has been tested clinically in healthy humans and nontoxic doses were demonstrated. - Moving forward to test clinical benefit presents a significant dilemma when a negative effect has already been demonstrated clinically. The applicant should be aware of this when developing the IND package and full application. - Preclinical POC studies and the IND-enabling studies have been well considered and articulated and, though some detail remains to be worked out, there are no major concerns with the described studies. - No clinical trial plan was presented. Should the applicant submit a full application, this must be included. The clinical plan should include methods to detect and monitor adverse affects on memory and allow investigators to distinguish acute memory impairment from a longer-term memory benefit. - The timeline proposed in the draft project plan is reasonable, assuming that the recommended preclinical dosing/toxicity studies can be completed with a positive outcome in the near future. However, given the preclinical IND-enabling activities remaining, it might more reasonable that an IND could be filed in 2-3 years, and the clinical program could proceed thereafter. If a full application is submitted, the applicant should keep in mind that reviewer recommendations might extend that period by a year or more and should carefully consider the project scope and timeline to ensure sufficient time is available to complete all proposed activities. Principal Investigator (PI) and Planning Leader - The PI is a well-known and highly published investigator who is quite capable of leading this project. - Topical formulation for a transdermal administration is planned, and reviewers strongly recommended inclusion of experts or companies specializing in transdermal drug delivery. - The planning leader (PL) is prominent and well published with extensive experience in the design and execution of clinical AD studies. - There is some concern as to whether the PL will have sufficient time for planning and for supervising IND-enabling studies. It may be beneficial to include on the team a qualified, industry experienced project manager to work with the PL.
- Programmatic Review
- A motion was made to move this application into Tier 1, Recommended for Funding. Reviewers noted the primary concern with this proposal – that APa has been shown clinically to impair memory and that the applicants did not address this issue in the proposal. Since the adverse effect was observed in non-cognitively impaired people at a low dose of APa, a significantly different population and dose than that proposed in the application, reviewers suggested that additional experiments to those presented in the application will be needed to develop a dosing scheme that distinguishes effects that acutely impair memory from those that improve memory in the longer term. In developing a safe and efficacious dosing scheme, the team must also demonstrate how the transdermal dose translates to dosing in the brain. The motion to move this application to Tier 1 was amended to include the following condition: 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 may alternatively forfeit this Planning Award and enter the Early Translational Awards III competition at the Full Application stage to acquire more compelling preclinical data. The amended motion carried.