Differentiating Plovamer Acetate and Glatiramer Acetate: Efficacy and Mechanism of Action in a Preclinical Model of Multiple Sclerosis (P1.187)

Abstract

OBJECTIVE: To compare the response to plovamer acetate (PA) and glatiramer acetate (GA) and investigate the mechanism of action (MOA) in a preclinical model of relapsing-remitting multiple sclerosis (RRMS). BACKGROUND: PA is a copolymer mixture of four amino acids of defined ratio, rationally designed to have improved efficacy over GA. PA competitively binds to MHC II with higher affinity than GA and drives a T-helper cell (Th)2-like response. PA is undergoing Phase II testing for RRMS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in SJL/J mice. PA, GA or vehicle were administered subcutaneously either daily or three times/week, or were co-administered with PLP at EAE induction. Disease severity was measured using a standard 0-5 clinical score (CS) scale. Blood and plasma were collected weekly for hematology and cytokine production measurements, respectively. Mouse splenocytes were cultured and re-stimulated to assess proliferation and cytokine production. RESULTS: Disease onset was delayed significantly vs. vehicle with daily PA (5 days; p<0.001), daily GA (2 days; p<0.01), PA 3x/week (6 days; p<0.001), but not GA 3x/week. In addition, PA dose-dependently decreased EAE severity when co-administered at disease induction: 10 or 30 mg/kg completely abolished disease and 3 mg/kg resulted in a 60% decrease in EAE severity. In contrast, co-administration of 3 or 10 mg/kg of GA was not efficacious; 30 mg/kg resulted in a similar decrease in CS as seen with 3 mg/kg PA, suggesting that PA was 10x more potent than GA in this preclinical model. Additional results supported previous findings that PA induces a Th2 shift. CONCLUSIONS: When compared with GA, PA more potently delays disease onset and reduces disease severity, as demonstrated in a preclinical model of RRMS. Continuing studies will provide further details on MOA. Study Supported by: Merck Serono SA Geneva, Switzerland, a subsidiary of Merck KGaA, Darmstadt, Germany.

Disclosure: Dr. Savinainen has received personal compensation for activities with EMD Serono. Dr. Crook has received personal compensation for activities with EMD Serono as an employee. Dr. Crandall has received personal compensation for activities with EMD Serono as an employee. Dr. Seng has received personal compensation for activities with EMD Serono as an employee. Dr. Boschert has received personal compensation for activities with EMD Serono as an employee. Dr. Dellovade has received personal compensation for activities with EMD Serono as an employee.