LONDON – Medday Pharmaceuticals SAS reported its phase III trial of MD1003 in progressive multiple sclerosis (MS) has met the challenging primary endpoint of improving mobility, with 12.6 percent (p = 0.051) of patients showing an improvement in either the Expanded Disability Status Score (EDSS) or a timed 25-foot walk (TW25), after nine months of treatment.

At the request of the FDA, patients were assessed again at 12 months, when the improvement was maintained.

In addition to prompting improvements in a significant proportion of patients, there was a decrease in the rate of disease progression of 67 percent in the treated group as a whole (n = 103).

Overall, the mean change in EDSS in the active arm was -0.03 at 12 months, compared to progression in the placebo group of +0.13 (p = 0.015).

"This is the first time there has been a study of a drug that not only prevents progression, but also improves a significant number of patients," said Frederic Sedel, CEO of Paris-based Medday.

All patients were assessed twice at the start of the trial, with the best score taken as the baseline. There was no statistically significant difference in the characteristics of the patients in the treated and placebo groups and patients showing an improved score at nine months and 12 months were scattered among all 16 trial centers, indicating there are no extraneous factors behind the improvements, Sedel said.

The data were presented at the American Academy of Neurology annual meeting in Washington Friday by the principal investigator Ayman Tourbah, who said it was a "pioneering and stringently designed" trial. "The fact that no patient in the placebo group met the primary endpoint indicates the study bar was designed to be very high," Tourbah said.

This was the first trial in progressive MS to use improvement in EDSS or TW25 as a primary endpoint, Sedel said. "No patient is supposed to spontaneously improve, so this was really ambitious," he told BioWorld Today.

MD1003, a concentrated, patented, formulation of biotin (vitamin H), administered orally at 300 mg per day, was well tolerated. One patient in the treatment arm committed suicide but that was not considered to be related to the drug. It also emerged that MD1003 confounded immunoassay tests that use biotinylated antibodies or substrates.

Sedel noted that MS trials typically are designed to show a decrease in the rate of progression of 20 percent or more, requiring large phase III studies of at least 600 patients. By setting a more ambitious primary endpoint it was possible to show efficacy in a much smaller phase III, involving 154 patients.

"There was a high risk in this trial. When you are a small company, you can't do large trials with 600 patients. We had to put the bar high to have a statistical effect. The fact we achieved that is very encouraging and very good news for patients, of course," said Sedel.

FURTHER ANALYSIS EXPECTED THIS YEAR

Tourbah had only a 15-minute slot to make this first presentation of the MD1003 study and was limited to top-line data. Further results on secondary endpoints are due to be reported in June.

Given that, Sedel declined to say whether patients who had an improvement in EDSS or TW25 scores also had an improved quality of life, though he did say, "Here again, we have very nice data."

Patients were scanned for brain lesions, but Sedel said that was done in order to exclude any patients with relapsing-remitting MS from the trial. Relapsing-remitting disease is characterized by lesion-promoting inflammation, whereas in both primary progressive and secondary progressive MS there is almost no inflammation.

"MD1003 is not supposed to impact on inflammation. MRI [scans] were not used as an efficacy criterion, but as a safety criterion, to exclude patients with lesions in case biotin activated the immune system," said Sedel.

In the event, no inflammatory effect was observed. However, it is hoped the MRI studies might provide additional data on the mechanism of action.

MD1003 is thought to have a twofold effect, activating acetyl-CoA carboxylases that are the rate-limiting enzymes in the production of fatty acids required for myelin synthesis, and also activating the Krebs cycle in axons that have been demyelinated, increasing their energy supply.

In addition to the further analyses of other secondary endpoints, a second phase III trial in MS patients with permanent visual loss caused by optic neuritis, is due to report later this year.

"The bar is again high; the goal is to reverse permanent disability," Sedel said, noting there are objective measures such as visual acuity and nerve conductance parameters, with which to assess effect.

Assuming positive results, there will be sufficient data to file for approval in Europe. "For the FDA we would have to discuss whether there needs to be a U.S. study or [if it will be sufficient] to show the data we have are applicable to a U.S. population," said Sedel.

Medday was founded by Sedel in 2011 to commercialize research he has carried out in rare inherited diseases. MD1003 originally was intended as a treatment for inborn errors of metabolism, but the chance finding of its effect in MS led to a change in direction.

The company has made notable progress with sparse means, raising $10.5 million in its first formal funding round in April 2013. Sedel said he is now looking for a series B to keep progressing the MD1003 program.