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DOI: 10.1055/s-2007-987507
Treatment of RRMS patients with the PPARgamma agonist actos: results of a phase I trial
Previous studies have shown that an agonist of the peroxisome proliferator activated receptor gamma (PPARg) that is currently used to treat type 2 diabetes, also shows anti-inflammatory effects in T-cells and glial cells; improves glial metabolism; and is neuroprotective. In mouse models of multiple sclerosis, PPARg agonists were shown to reduce disease severity, and in a case report the agonist Actos (pioglitazone) was shown to be well tolerated in a secondary progressive MS patient. In view of its good safety profile, we carried out a one-year, double-blinded, placebo-controlled trial of Actos (30mg daily, p.o.) as an add-on in RRMS patients taking Avonex. Primary outcomes were safety (liver function, hypoglycemia, Gd enhancement), and secondary outcomes included changes in brain lesion burden, grey matter atrophy, and changes in neurological exams (MSFC and EDSS). Other analyses included measurements of serum for IFNg and other cytokine levels. At the end of 1 year, 22 patients completed the trial. There were no indications of liver toxicity, edema, or increased Gd-enhancing lesions. The average EDSS did not change over 1 year, and the average MSFC score increased in both groups. MRI revealed that total brain lesion volume (assessed by FLAIR) increased approximately 7% in the placebo group; but was reduced 6% in the Actos group. Examination of high resolution images revealed a significant grey matter atrophy over one year occurring in the placebo group (6% loss), and this loss was attenuated by Actos (to only 2.5% loss). ELISA analyses of supernatants derived from isolated PBMCs showed a time-dependent decrease in PHA-dependent IFNg production in 6/11 patients in the ACTOS group versus only 2/10 in the placebo group. These results indicate that Actos is well tolerated in RRMS patients and suggest that it may reduce disease progression as assessed by FLAIR volume and gray matter atrophy, and reduce ongoing peripheral inflammatory responses. These findings suggest that further testing in MS patients to determine efficacy is warranted.
This study was supported by Takeda Pharmaceuticals North America; and results covered under US provisional patent 60/862,247, issued October 20, 2006.