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.
