RADIKAL THERAPEUTICS, INC. — Department of Health and Human Services SBIR Phase II: NIAMS

Description

Radikal Therapeutics is developing the first therapeutic Resolvin molecule intended for the management of rheumatoid arthritis RA Resolvins are endogenous picomolar potent small molecules that activate a complex intracellular mechanism by which tissue inflammation is modulated and ultimately resolved Our technical approach is supported by research demonstrating the utility of our candidate therapeutic Resolvin R in reducing injury in clinically relevant rodent models of RA R is potentially superior to its competitors by virtue of a novel mechanism of action distinct from existing therapies and those in development and its ability to increase host immune defense as opposed to the more typical immunosuppression that is associated with methotrexate calcineurin inhibitors and anti TNF inhibitors Safety studies in rats dogs and humans do not reveal toxicity at doses logs in excess of the intended therapeutic exposure Aim Establish the PK properties of enteral R including joint tissue distribution following gavage delivery to mice with arthritis We will undertake a full analysis of the PK profile of R Plasma and joint tissue concentrations of C labeled R will be measured following administration to male SD rats with collagen induced arthritis A full PK profile of R will be constructed Aim Scale up the synthetic route of R and generate batches sufficient for primary reference standard and pharmacology studies To lower cost and allow for large scale manufacturing RTX has invented a novel proprietary step synthetic route performed as a proof of concept at a mg scale Even at this early stage the overall yield is and represents an improvement in efficiency of over times that of any prior synthesis and a fold cost saving We now wish to utilize this new synthesis as a platform for the production of gram amounts of research grade material in the first instance and to develop this into a viable manufacturing process for g and ultimately kg amounts of R We now propose to optimize our new process with the intent of achieving a further fold increase in yield and elimination of half of the chromatographic isolation steps The campaign will include i identification and improvement of those synthetic steps that are rate and or yield limiting ii identification of those telescoping steps that do not require discrete purification of each intermediate iii consideration of protection deprotection strategies and protecting groups iv assessment of the shelf life use of unstable intermediates within an appropriate window v analysis of by products to understand and reduce competing side reactions vi choice of reagents for scale up replace where possible with safe routine cheaper reagents vii examination of alternatives to chromatographic separations viii development of analytical methods for analysis of intermediates and relevant impurities ix generation of multi g batches and x development of analytical methods for batch analysis and release of the API Existing therapies of rheumatoid arthritis provide many with only marginal relief and are often ineffective We are developing a revolutionary approach to the medical management of refractory rheumatoid arthritis based on the use of R that leverages the endogenous mechanism by which inflammation is naturally resolved We now propose to carry out studies to define the concentration of R in blood and joint tissue and to improve its manufacturing process so as to reduce the cost of goods and thereby increase its commercial appeal