This administrative supplement application to R01 AG061898 requests costs to perform activities that are within the scope of the R01 project, but were unforeseen at the time of award of the grant. The R01 project is to conduct phase 1 clinical studies of MW01-2-151SRM (=MW151), a novel, brain-penetrant, orally bioavailable, small molecule therapeutic candidate for Alzheimer?s disease (AD). MW151 targets a particular form of dysregulated inflammation, injurious proinflammatory cytokine overproduction in the brain, that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. Thus, this project is advancing clinical development of a promising drug candidate that could have disease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism. Because of the urgent need to develop disease-modifying therapeutic strategies for AD, it is critical to complete the phase 1 safety trials and continue to move MW151 forward in development. This administrative supplement is requested because of two major unforeseen circumstances. First, the conduct of the phase 1a clinical trial was substantially delayed because of COVID-19 restrictions on human studies imposed in March 2020 at the Duke clinical site. This delay has resulted in the necessity for additional drug storage time and longer-term stability testing that were not planned for. Second, the FDA has recently issued a new guidance document in September 2020 related to control of nitrosamine impurities in drugs that we need to address in the MW151 development program. Therefore, we will pursue two specific aims in the supplement.
Aim 1 : Management of MW151 drug substance and drug product. We will maintain MW151 drug substance and reference standard storage, perform additional re-tests, and do QC and stability tests on the drug substance and the drug product over a longer time frame than originally planned. The plasma samples for MW151 PK measurements will also be stored for longer than anticipated before analysis, so we will need to add two additional stability time points to the validated bioanalytical method.
Aim 2 : Nitrosamine assessment. Because of the increasing number of approved drugs that have been recalled or put on clinical hold by the FDA because of nitrosamine contamination, the FDA recently issued a guidance document for immediate implementation. Therefore, MW151 API will be subjected to a nitrosamine risk assessment. Depending on the level of risk determined, the presence or absence of nitrosamine(s) will be measured with a validated high resolution, high sensitivity LC-mass spectrometry method. If a nitrosamine contaminant is present at levels above the FDA-recommended Acceptable Intake Limits, then future studies will develop strategies for changes in the manufacturing process to reduce or prevent nitrosamine impurities before MW151 is brought into phase 2 clinical trials.
Success in the proposed supplement activities will allow us to complete the first-in-human phase 1 clinical trial in healthy adult volunteers and provide safety and dosing information required to progress to the next stage of development for MW151. MW151 is a promising brain-penetrant, small molecule drug candidate that targets dysregulated inflammation in the brain and has the potential to be a first-in-class disease modifying therapy for Alzheimer's disease.
