Preclinical Efficacy and Phase I Clinical Testing of ATX-MS1467, an Antigen-Specific Immunotherapy for Multiple Sclerosis (P1.189)

Abstract

OBJECTIVE: Analyze properties of peptide combinations designed to induce specific suppression of the immune response against central nervous system (CNS) antigens. BACKGROUND: Current treatments for multiple sclerosis (MS) do not specifically target cells mediating immune pathology in the CNS. Current work has revealed the potential for immune deviation using peptide therapy as a novel approach for MS treatment. Peptides are chosen based on disease-associated T-cell epitopes that are able to induce specific immune deviation. METHODS: ATX-MS-1467 was tested in mice expressing HLA-DR15 and human T-cell receptors specific for myelin basic protein (MBP). Mice treated by subcutaneous injection were tested for suppression of T-cell responses and modulation of experimental autoimmune encephalomyelitis (EAE). Clinical trial ATX-MS-1467-002 evaluated safety and effect on gadolinium-enhancing magnetic resonance imaging (MRI) in 43 HLA DRB1*15-positive patients with relapsing MS (RMS). Each patient received fortnightly injections intradermaly (n=21) or subcutaneously (n=22) escalating from 25 to 800µg with four further 800µg doses. RESULTS: Treatment of double transgenic mice with ATX-MS-1467 resulted in >90% prevention of EAE and suppression of inflammatory cytokine secretion. ATX-MS-1467 was more effective than glatiramer acetate when given at a 70x lower cumulative dose. Treatment of 21 patients with RMS, by intradermal administration, led to a 78% reduction of MRI activity which was sustained for one month post last dose. Patients treated subcutaneously had low MRI activity at week 0 that remained low throughout the trial precluding measuring an effect. There were no unexpected safety signals in any patients treated with ATX-MS-1467. CONCLUSIONS: Treatment of MS patients with ATX-MS-1467 appears to be safe and well tolerated. There is preliminary evidence of disease improvement in patients with RMS, which is supported by efficacy data from pre-clinical models. These results favor further investigation of ATX-MS-1467 as a first-in-class, antigen-specific agent designed to improve standard of care in MS. Study supported by: Apitope Ltd, Bristol UK, and Merck Serono SA Geneva, Switzerland, a subsidiary of Merck KGaA, Darmstadt, Germany.

Disclosure: Dr. Wraith has received personal compensation for activities with Apitope International NV as found and CSO. Dr. Wraith holds stock and/or stock options in Apitope International NV, which sponsored research in which Dr. Wraith was involved as an investigator. Dr. Wraith has received research support from Apitope International NV.