Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis

Abstract

The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti-SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first-in-human study with anti-SAP antibodies.

Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis

“…Circulating miridesap concentrations were consistent with previous clinical miridesap studies (5,6,8). The regimen reduced baseline plasma SAP concentrations in all subjects to the target value of <2 mg/liter before dezamizumab was administered.…”

“…However, maximal removal of amyloid from all organs and tissues, which will be required for optimal clinical efficacy, was not achieved with just a single dose of antiSAP antibody. Here, we investigated the safety, tolerability, and efficacy of up to three cycles of treatment with miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (15 participated in the previous study, whereas 8 were new subjects).…”

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

“…As shown in Figure , miridesap itself, however, was detectable with maximum concentrations similar to reported concentrations following parenteral administration (Gillmore et al, ; Pepys et al, ; Sahota et al, ), which suggests a good bioavailability of GSK294, followed by a quick and complete conversion into miridesap.…”

Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component

“…19 CPHPC rapidly depleted circulating SAP to less than 0.5 mg per liter in patients with a small or moderate amyloid load and to less than 2 mg per liter in pa-* AA denotes A protein type, AApoAI apolipoprotein AI type, AFib fibrinogen A alpha chain type, AL immunoglobulin light chain type, and CPHPC (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid. 19 CPHPC rapidly depleted circulating SAP to less than 0.5 mg per liter in patients with a small or moderate amyloid load and to less than 2 mg per liter in pa-* AA denotes A protein type, AApoAI apolipoprotein AI type, AFib fibrinogen A alpha chain type, AL immunoglobulin light chain type, and CPHPC (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid.…”

“…19 In patients with a small amyloid load, the plasma anti-SAP antibody concentration declined with a half-life of approximately 16 hours. The median value in healthy persons is 5.3 kPa, and 90% have a value of less than 7.0 kPa.…”