As a result of the planning grant award, the Allopregnanolone (APα) team accomplished the following that enabled submission of the CIRM Disease Team Therapy Development Research Awards Proposal:
1) Created a team of experts in regeneration, neurology and Alzheimer’s disease drug development to generate strategy and overall development plan. Through the team’s efforts we developed preclinical and clinical studies, determined correct dosing parameters for clinical studies, identified an optimal route of administration, developed chemistry, manufacturing and controls, and submitted our Pre-IND documents to the FDA.
2) Filed a Pre-IND document with the FDA and held a Pre-IND meeting with the FDA and obtained feedback from the FDA on our program. FDA provided guidance on requirements for the preclinical plan along with input on the design of our two Phase 2 clinical studies. We also obtained agreement that we may cross-reference the existing IND of our academic partner, Michael Rogawski at UC Davis and utilize product manufactured at UC Davis.
3) We developed an integrated CMC plan to manufacture allopregnanolone (clinical API) and established compliant processes to ensure material requirements are met for the preclinical and clinical studies. Manufacture of clinical API will be conducted at the UC Davis CIRM GMP facility.
4) FDA required preclinical IND-enabling research strategy was developed. Teams at USC and a California-based CRO, were identified to conduct three studies: 1) Bridging Study: subcutaneous to IV dosing and administration to bridge from previous subcutaneous preclinical analyses to clinical studies using IV APα administration to determine a) optimal IV dose to promote neurogenesis and b) optimal infusion rate to achieve required peak of APα and area under the curve. 2) Cerebral Microhemorrhage: The FDA advised a safety test for the occurrence of cerebral microhemorrhages localized to the cerebral vasculature in areas of cerebral amyloid angiopathy with various anti-Aβ immunotherapies. 3) Chronic GLP Toxicity Analyses: Based on FDA guidance, safety studies will be required for chronic exposure of Alzheimer’s patients to APα. To initiate the chronic exposure Phase 2a Proof of Concept trial, chronic preclinical toxicology is required. We have designed 6-month and 9-month IV dose GLP toxicity studies in rat and dog, respectively. The studies include systemic toxicology and toxicokinetic evaluation.
5) In support of developing ideal dosing parameters for the Phase 2 clinical studies, the California CRO, Simulations Plus was utilized. ADMET Predictor™ was used to estimate the biopharmaceutical properties of APα. Predictive modeling of optimal dosing regimen and expected human exposure in Alzheimer’s patients was performed.
6) Designed two Phase 2 clinical trials, a Multiple Ascending Dose (MAD) and a Proof of Concept. A California-based CRO, Worldwide Clinical Trials and Alzheimer’s clinical trials expert were identified to partner with USC to design and conduct our clinical trials. Phase 2 MAD study primary objectives are to evaluate safety, tolerability and pharmacokinetics. MAD exploratory objectives are to evaluate effect of allopregnanolone on MRI biomarker outcomes and cognition. Proposed MRI biomarkers include hippocampal volume, white matter integrity, and functional connectivity. Phase 2 Proof of Concept trial primary objectives are to evaluate safety and tolerability with long-term exposure. Therapeutic efficacy of allopregnanolone will be determined by outcomes on cognition and biomarkers of regeneration in brain.
7) A Steering Committee and Advisory Board were established. Both advisory groups are composed of internationally recognized researchers, translational scientists, regulatory experts and therapeutic development experts. The charge of the Steering Committee is to provide oversight that CIRM allopregnanolone team progress is on track to meet milestones, ensure that processes and strategies are aligned. The Advisory Board is comprised of internationally recognized experts in Alzheimer’s disease and experts in stem cell biology. Advisory Board members will provide an objective evaluation of CIRM allopregnanolone project progress. The functions of Advisory Board are: 1) Advise CIRM allopregnanolone project leadership on identifying key milestones; 2) Review progress on meeting milestones and hitting development targets; 3) Provide strategic and tactical counsel to the Leadership team and Steering Committee.
8) Generated viable commercial potential through partnership with SAGE Therapeutics. Ensured patent progression and prosecution through USC. Engaged key opinion leaders in the field and educated these experts regarding therapeutic potential of allopregnanolone as a first in class drug for neuroregeneration in Alzheimer’s disease.