Deborah Brauser

September 23, 2016

LONDON — The oral antioxidant lipoic acid can decrease brain atrophy in patients with secondary progressive multiple sclerosis (SPMS) while sustaining safety and tolerability, new imaging research suggests.

The small, 51-patient pilot trial showed that those randomly assigned to 1200 mg of lipoic acid daily had a significantly lower annualized rate of whole-brain atrophy at 96 weeks, as measured by MRI, than the participants who were assigned to matching placebo.

In fact, the atrophy reduction rate was 66% in the active treatment group — and they had a trend toward a greater improvement in walking speed.

In addition, reports of adverse events (AEs) were mostly similar between the two treatment groups. Although those receiving lipoic acid had more cases of gastrointestinal upset than those receiving placebo (17% vs 3%, respectively), they had half as many falls (15% vs 38%).

Rebecca Spain, MD, from the VA Portland Health Care System and the Department of Neurology at Oregon Health and Science University, told Medscape Medical News that "it's still early days" but the findings are exciting.

"In my patients with progressive MS who are motivated to take an over-the-counter supplement, I am now providing them with this data. Of course I'm also making it clear that we don't yet know if it will change the long-term course of MS," she added.

Dr Spain presented the results here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016.

Michael Hutchinson, MD, St Vincent's University Hospital, Dublin, Ireland, marked the trial as a "clinical highlight" during a presentation he gave at the meeting's end.

"This was such an interesting study," said Dr Hutchinson, who was not involved with the research. "Lipoic acid looks like a potential molecule that we might be using more of."

Inexpensive, Readily Available

The agent "is an inexpensive antioxidant with multiple biological functions," explained Dr Spain during her presentation. "The r-enantiomer is produced endogenously in mitochondria, where it plays a key role in oxidative respiration."

Animal models have shown that the antioxidant can reduce inflammation, as well as macular and spinal cord atrophy.

"There is a great unmet need to find a disease-modifying therapy for progressive MS. We wanted to look at lipoic acid as possibly filling this role since it's a small-molecule agent that, because of its low cost, could be readily available to anybody who needed it," said Dr Spain.

The current study included 51 patients with SPMS (61% women; 96% white; mean age, 58.5 years). Of these, 27 received lipoic acid and 24 received placebo.

The mean disease duration for the entire group at baseline was 29.6 years and the mean Expanded Disability Status Scale (EDSS) score was 5.5. All of the participants underwent yearly MRI.

The primary outcome measure was annualized percentage change in brain volume, with structural image evaluation using normalization of atrophy (SIENA).

At 96 weeks, the group receiving placebo had a whole-brain atrophy rate of 0.65% per year, "which is comparable to rates in other progressive MS natural history cohorts," said Dr Spain.

On the other hand, use of lipoic acid resulted in a significantly lower annualized atrophy rate of 0.22%, which represented a 66% reduction vs placebo (P = .004).

Clinical Benefits Need Clarification

Those taking lipoic acid group also had greater improvement on the timed 25-foot walk test than the placebo group, although this result just missed significance (P = .057).

There were no between-group differences in the other secondary outcomes, including total deep grey-matter volume, change in cortical thickness, or number who had stable or improved EDSS scores.

On the basis of pill counts, treatment adherence was greater than 80%. And there were five study dropouts, all in the lipoic acid group. Two notable AEs in that cohort included one case of new-onset proteinuria and one of worsening renal function.

"But a consulting nephrologist did not think either of those events were related to the lipoic acid," said Dr Spain. "And renal events have not been noted in other trials of this agent for other conditions."

She added that the positive primary findings now need "further exploration with a larger population to clarify the effect size, to determine the clinical benefits associated with reductions in brain atrophy, and to explore the underlying mechanisms of action of lipoic acid in progressive MS."

Dr Spain noted that "SIENA is not a perfect measure" and that brain volume can be influenced by such things as a patient's dehydration status, which is not controlled for. "The only way to control for all these variables is to have a large trial, which will blunt the effect of the individual variations."

She reported that such a trial is now in the planning stages, with an estimated patient population of around 115.

"Encouraging Results"

"This was a small study but it had a very marked outcome," Dr Hutchinson told Medscape Medical News.

"Basically, lipoic acid significantly reduced the rate of atrophy," he said, noting that healthy brains atrophy at a rate of about 0.2%.

For people with MS, particularly SPMS, "it's usually two to three times that. But in this case, people who were on lipoic acid had a rate of loss at 0.22%, whereas for those taking placebo it was 0.66%. So there was a three-fold difference."

"It looks very encouraging," reiterated Dr Hutchinson. "And it's lovely to see all of these studies coming to address what was up until now a relatively intractable problem — progressive MS."

However, he said that the argument that will likely come out of this study and/or agent is: "Will you need to continue to use some sort of active anti-inflammatory drug, like siponimod, which was talked about earlier at this meeting, plus a neuroprotective?"

The study was supported by the Department of Veterans Affairs and the National Institutes of Health. Pure Encapsulations, which is located in Sudbury, Massachusetts, provided the lipoic acid and placebo. Dr Spain and Dr Hutchinson have disclosed no relevant financial relationships.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Parallel Session 12, oral presentation 222. Presented September 16, 2016. Plenary Session 2, oral presentation 258. Presented September 17, 2016.

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