Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Background and Purpose: Miridesap depletes serum amyloid P component (SAP) and forms a component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates parenteral administration. We sought to identify a pro-drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability. The pharmacology of palindromic miridesap is unique; previous pro-drug efforts did not progress to the clinic. Experimental Approach: Using a screening cascade focused on physicochemical properties, physical and gut stability and conversion to miridesap in liver microsomes and blood, we identified GSK3039294 (GSK294). Based on a favourable preclinical profile, we tested it in healthy participants. Key Results: GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in MDCK-II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro-drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial depletion of plasma SAP. The study was terminated due to arrhythmia, the relation of which to GSK294 remains unclear. Conclusion and Implications: Our preclinical screening cascade, identified a novel palindromic orally dosed pro-drug that preserved the unique pharmacology of parenteral miridesap. The pro-drug depleted circulating SAP with a time course and extent similar to that of parenterally-administered miridesap. This is the first drug reported to lower SAP in the clinic following oral dosing.


Journal article


British journal of pharmacology



Publication Date



Duncan Richards, University of Oxford, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences Windmill Road, Headington, Oxford, OX37LD, United Kingdom, Mark Bamford, Glaxo, SmithKline, Stevenage, Hertfordshire, United Kingdom, Lia Liefaard, Glaxo SmithKline, Stevenage, Hertfordshire, United Kingdom, Nazneen Haque, Glaxo SmithKline, Stevenage, Hertfordshire, United Kingdom, Gareth Lewis, Glaxo SmithKline, Ware, Hertfordshire, United Kingdom, Jim Storey, Glaxo SmithKline, Stevenage, Hertfordshire, United Kingdom, Disala Fernando, Glaxo SmithKline, Clinical Unit, Cambridge, Cambridgeshire, United Kingdom, Subramanya Kumar, Glaxo SmithKline, Clinical Unit, Cambridge, Cambridgeshire, United Kingdom, Douglas Thompson, Glaxo Smith Kline, Stevenage, Hertfordshire, United Kingdom, Duncan S Holmes, Glaxo SmithKline, Stevenage, Hertfordshire, United Kingdom


Pro-drug, serum amyloid P component, pharmacokinetic/pharmacodynamic profile