Two neuroprotection studies in MS: Ibudilast promising, inosine not so much
Two studies appearing back-to-back in PubMed today evaluated agents with potential neuroprotective activities for efficacy in MS. One of the studies came out with a positive finding, the other produced no evidence for efficacy.
The first study evaluated an oral drug called ibudilast which belongs to a class called phosphodiesterase inhibitors. This drug is used in Japan and Korea to treat asthma and cerebrovascular disorders. Based on pilot MS trial results and hints of possible neuroprotective effects in animal studies, a group of investigators decided to conduct a multi-center, placebo-controlled trial to see whether it would affect MS disease activity and progression. 297 people with MS participated and were randomized to 60 mg or 30 mg ibudilast daily, or placebo. At the end of 12 months, a 12-month extension followed, with placebo subjects moved to one of the two ibudilast doses.
The results of the study showed no major effect of the drug on indicators of disease activity such as number or volume of new lesions or relapses. However, subjects on ibudilast, particularly the higher dose, had lower brain atrophy rates. A comparison of MRIs showed that ibudilast treatment was associated with fewer lesions converting to MRI "persistent black holes," an indication of lasting damage. In addition, after 24 months, those subjects who had been on ibudilast from the beginning were less likely to have progressed on the EDSS scale than those who were initially on placebo.
No serious safety concerns were reported at the doses tested, so it seems that ibudilast is worth further study. Since the drug had little effect on inflammatory activity, the authors suggest studying it in conjunction with an immune-modulating drug to see if the combination results in both lower disease activity and improved brain tissue preservation.
The second study did assess this type of combination -- inosine plus IFN-beta -- but did not demonstrate the hypothesized effect on disability progression. Inosine is a precursor of uric acid, a protein which appears to be neuroprotective based on lab and animal studies, but is found in decreased levels in the serum of people with MS. 159 subjects were randomized to IFN-beta combined with either oral inosine supplements or placebo and followed for 24 months. Unfortunately, the primary endpoint of reduced risk of EDSS progression was not met; nor were any other endpoints having to do with disability or relapses. The authors conclude that the uric acid pathway and other neuroprotective mechanisms need to be better understood in MS. They also noted, as has been observed before, that success in treating EAE is not a great predictor of success in human trials.