Preclinical Efficacy and Phase I Clinical Testing of ATX-MS1467, an Antigen-Specific Immunotherapy for Multiple Sclerosis (P1.189)
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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.
Monday, April 28 2014, 3:00 pm-6:30 pm
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