Publications
Clinical Results of the First-in-Man Single Ascending Dose Study of PI-2301, a Second Generation Peptide Copolymer for the Treatment of Multiple Sclerosis
18th Meeting of the European Neurological Society, Nice France
Objectives: PI-2301 is a novel compound in a class of autoimmune therapeutics called peptide copolymers. Copolymers are random mixtures of peptide sequences comprised of limited numbers of amino acids. Copaxone® is a copolymer which has been approved as a primary treatment for Relapsing Remitting-Multiple Sclerosis (RR-MS). PI-2301, like Copaxone, is an immunomodulator which promiscuously binds to MHC Class II molecules and induces a skewed TH2 T-cell response characterized by the activation and expansion of T-cells and monocytes which secrete IL-4, IL-5, IL-10, IL-13 and CCL22. This regulatory response is believed to interfere with the expansion of autoreactive TH1/TH17 cells. PI-2301 has shown superior therapeutic efficacy as compared to Copaxone in murine experimental allergic encephalomyelitis (EAE), an animal model which resembles multiple sclerosis, in both daily and weekly subcutaneous (SC) dosing regimens. The purpose of the present study was to evaluate the safety, tolerability and early immunological effect(s) following SC administration of PI-2301 in a Single Ascending Dose, first-in-man study involving healthy, male adult volunteers.
Methods: The clinical study was designed in accordance with recommendations as defined in the Duff report and Committee for Human Medicinal Products (CHMP) guidelines issued in July 2007 for potentially immunmodulating therapeutics. Fifty-six subjects (eight cohorts of seven individuals; 5 active and 2 placebo) were given a single subcutaneous injection of PI-2301. The first dose was 0.01mg which is 100-fold below the Minimal Anticipated Biological Effect Level (MABEL) and 50,000-fold below the No Observed Adverse Effect Level (NOAEL) in the most sensitive animal species tested with PI-2301. The parameters evaluated were safety, monitoring, pharmacokinetics, in vitro T-cell recall responses, antibody response to PI-2301 and changes in serum cytokines and chemokines.
Results: PI-2301 was generally well tolerated through the doses tested thus far (6 of the scheduled 8 doses). Evidence of immune priming (as shown by T-cell specific proliferative and cytokine responses) was observed at the projected MABEL dose in humans, i.e., 1mg. Further data collection and analyses are currently underway and will be available in the coming months.
Conclusions: This study represents the initial step in the development of an improved peptide copolymer with immunomodulatory properties for the treatment of multiple sclerosis.
