In collaboration with F Hoffmann-la Roche & Co Ltd we have developed a new chemical entity, carboxy pyrrolidone hexanoyl pyrrolidone carboxylic acid (CPHPC), that inhibits binding of SAP to amyloid fibrils in vitro with approximately micromolar IC50. Administration of a sufficient dose to amyloidotic mice in vivo completely removes mouse SAP from the deposits (1). Human SAP binds CPHPC much more avidly than does mouse SAP and the stable complex that forms in vivo between 2 human SAP molecules and 5 CPHPC molecules is immediately cleared by the liver, leading to swift depletion of all circulating SAP for as long as the drug is administered (2). This is the first example of a novel pharmacological mechanism in which a pathological human protein is depleted by a low molecular weight drug. However ex vivo dissociation of human SAP that has already bound to amyloid deposits in vivo, requires millimolar CPHPC concentrations. Nevertheless, since circulating SAP is made exclusively in the liver, is the sole source of SAP in the amyloid deposits, and is in dynamic equilibrium with the amyloid SAP pool, sustained plasma depletion should eventually clear all the SAP from the deposits. CPHPC for treatment of amyloidosis is licensed exclusively to a UCL spinout company and we now have about 30 patient years of experience of CPHPC administration to patients with various forms of systemic amyloidosis. There have been no drug related adverse effects, nor any toxicity or abnormal investigational findings. CPHPC is not metabolised and is very rapidly cleared, mostly by the kidney, with a plasma half life of about 1.5 h. Thus although the modest CPHPC doses deployed so far maintain complete depletion of plasma SAP and cause measurable depletion of SAP from the amyloid deposits (2), significant amounts of SAP remain in the deposits even after months of treatment. Consequently we have not yet effectively tested the hypothesis that complete removal of SAP from amyloid deposits would reduce new amyloid deposition and/or promote amyloid regression with clinical benefit. We are therefore currently exploring alternative dose regimes and routes of CPHPC administration in order to achieve the high blood and tissue concentrations of the drug required for clearance of all SAP from the tissue amyloid deposits. We are also conducting a preliminary study in Alzheimer’s disease, in which the amyloid deposits are many orders of magnitude smaller than in systemic amyloidosis, and where depletion of circulating SAP should be sufficient to deplete SAP from the cerebrospinal fluid and the deposits.
