Pioglitazone as treatment for multiple sclerosis

Objective: To determine whether Pioglitazone (Pio), a peroxisome proliferator activated receptor gamma (PPARg) agonist, is safe in Relapsing Remitting Multiple Sclerosis (RRMS) patients and modifies T-cell activation or functional MRI activation patterns.

Background: MS is a chronic autoimmune disease of the central nervous system, which mostly appears in the relapsing remitting form. Available treatments are only partially effective and have significant side effects, therefore new therapies are needed. PPARg agonists, which are FDA approved drugs for treatment of Type II diabetes mellitus, were shown to significantly reduce inflammatory processes and inhibit T cell activation, which makes them potentially useful in MS treatment. In our previous studies, we showed that Pio reduces the severity of clinical symptoms in animal models of MS, and induces remissions in already ill mice. Recently, in a case report study, we observed no adverse effects and significant improvement of clinical symptoms after 3 year Pio treatment, suggesting that Pio may be safe and provide clinical benefit in RRMS patients.

Methods: 30 RRMS patients currently taking interferons (Avonex® or Rebif ®) will be enrolled. Patients will take Pio (Actos®, daily, 30mg, p.o.) or placebo for 1 year in a double-blind clinical setting in addition to their current medication. Safety will be determined by regular physical examinations and blood tests, including blood cytokine levels. Patients will be assessed bimonthly (by EDSS and MSFC) for neurological symptoms, and will undergo 3 MRIs. Imaging will include diffusion tensor imaging (DTI) to assess white matter integrity; and functional MRI using a modified PASAT test. T cells will be isolated bimonthly and Th1 and Th2 cytokine production (by ELISA) and expression (by real time PCR) evaluated. Effects on reactive nitrogen species production will be determined by measurements of nitrites, nitrates, and nitrosylated peptides in serum.

Results: As of March 2005, 16 patients have been enrolled and randomized to receive placebo or Pio. No serious side effects have been observed. Although still blinded, analysis of Th1 and Th2 cytokines shows a group of patients undergoing a reduction of cytokine expression. Initial fMRI analysis shows differences in regional activation between MS patients and healthy volunteers. Interim analysis maintaining blinding will be carried out in August 2005 and initial findings will be presented at the conference.