A global Phase 3 clinical trial assessing MD1003 — also known as high-dose biotin — for progressive multiple sclerosis (MS) might lead to the approval of one of the first treatments helping select progressive patients to improve.
The trial aims to prove that high-dose biotin can reverse disability in non-active progressive MS. While this has been seen in an earlier Phase 3 trial, the new trial is much larger — ensuring a much greater volume of data will be collected — and, equally important, it may bring the U.S. Food and Drug Administration (FDA) to initiate a review of the treatment’s effectiveness as a first step toward possible approval.
Multiple Sclerosis News Today spoke to Dr. Frédéric Sedel — co-founder and CEO of MedDay Pharmaceuticals, which is developing the treatment — and the man who, by chance, led the team that discovered that biotin in high doses benefits progressive MS patients.
The story of how biotin ended up in a Phase 3 MS trial is, in many ways, a story about Sedel. It is a story of a French researcher who followed the path laid out before him and his colleagues by research findings. It is also, indeed, a story of lucky circumstances — a rarely mentioned but often influential contributor to medical research.
The trial, called SPI2 (NCT02936037), is in its early stages of enrollment — and recruiting across the U.S., Canada and several European countries — but Sedel expresses a clear hope, even a guarded expectation, that outcomes will be good. His optimism is partly based on data from earlier clinical trials, showing that high-dose biotin could reverse disability progression in some patients.
And it is partly based on the fact that thousands of MS patients are already under biotin treatment in France — where the drug was granted early access rights under a special program — in advance of potential European and U.S. regulatory approvals.
The SPI2 trial — made possible by funding of mainly French investors — aims to recruit 600 patients at 70 sites worldwide. Recruitment is ongoing, and MedDay hopes to be done by the end of the year. (Enrollment information is available here.)
Patients will be randomized to receive either 100 mg of biotin three times a day, or placebo.
The trial will be double-blind, and data will not be available until the patients have been treated for 15 months — which researchers expect to be by mid-2019.
Sedel pointed out that there will be no interim analysis. “An interesting point with biotin is that it doesn’t seem to work in the short term,” he said. “When we start the drug, we start to see an effect after at least nine months of treatment.”
Participants who complete the trial will then be enrolled into a 12-month, open-label extension study, meaning all will be given biotin.
A study for the usually excluded
Unlike the vast majority of MS clinical trials, the Phase 3 SPI2 trial is enrolling only primary and secondary progressive patients without relapses.
The reason for this is that researchers believe that neurodegeneration — and not inflammation — causes disability to accumulate in progressive patients. Progressive patients are, therefore, frequently excluded from clinical trials of drugs aiming to stem disease activity by harnessing inflammation.
In contrast, the pharmaceutical formulation of high-dose biotin — which is a type of vitamin B — has no impact on inflammation, the driving force behind relapses and “active disease.”
“The biotin that we use has no anti-inflammatory effect – so there is no impact on the relapses,” Sedel said.
Including patients with relapses might also make data difficult to interpret, Sedel — who was a practicing neurologist at a leading Paris hospital before starting MedDay — pointed out.
“We don’t want to be polluted by relapses, which may cause unwanted noise in the evaluation. Because if you have relapses then the patient will worsen, not because of the drug but because of their ongoing inflammation,” he said.
To meet these criteria of a “pure neurodegenerative MS population” — as Sedel put it — the trial is recruiting patients who are moderately to severely disabled, scoring 3.5 to 6.5 on the Expanded Disability Status Scale (EDSS).
Disability is, of course, also needed to prove the main point of the trial: that the drug can actually reverse neurodegenerative disease processes, and hence, disability.
The trial will have a narrow focus within the defined patient group. To make it easier to measure improvements, the study will home in on patients with walking difficulties. Measuring improvements in the timed 25-foot walk test is, along with changes in EDSS, its primary outcome measure.
But MS disability comes in many shapes and forms. Will high-dose biotin help patients with other types of disability?
Sedel clearly believes so.
“We are focusing on the population which has gait impairment, to be able to get enough of a homogenous population — and we see an effect on gait impairment, but it doesn’t mean there is no effect on the other functions,” he said. “We don’t think this is only a drug for gait improvement. We have other scales in the trial … [and previous trials] showed that not only gait was improved.”
A twist of fate
How did Sedel discover the potential of biotin in MS? The vitamin is sold over-the-counter as a supplement, but in doses a hundred-fold lower than those used in MS.
To explain, Sedel took us on a brief tour of his earlier career.
“I was a neurologist, and I was – that’s weird – but I was the inventor of this drug. That’s how life goes; it can be strange like that,” Sedel said of his time at Pitié-Salpêtrière Hospital in Paris, France.
There, he studied rare genetic conditions causing inherited metabolic diseases. Many of these conditions involve enzymes needed for normal brain function.
Although these diseases can be caused by abnormalities in a host of different enzymes, they can be treated in similar ways, Sedel explained.
“The nice thing is that you can treat these patients with inborn errors of metabolism by different co-enzymes,” Sedel said. Co-enzymes are factors needed to facilitate the work of enzymes. One of the co-enzymes used was high-dose biotin.
At the time, Sedel discovered a group of patients who shared the common feature of brain damage caused by defective myelin. Sedel believed that their brain abnormality was caused by a common genetic defect. Since the patients became better with biotin treatment, he named the disease biotin-responsive leukodystrophy.
But work to identify the presumed genetic cause proved difficult, Sedel and his team also discovered that one of the patients was, in fact, misdiagnosed. This man most likely had a type of progressive MS that resembled leukodystrophy. And he responded very well to high-dose biotin.
While an observation of one patient becoming better after a treatment can be intriguing, it’s a drop in the ocean. So Sedel launched a small pilot trial to see if other progressive MS patients reacted to biotin in a similar way.
Although small, the study’s findings spoke for themselves. Of the 23 enrolled patients, 91.3 percent experienced a lessening in disability.
The development spurred Sedel, together with Dr. Guillaume Brion, to start MedDay in 2011. But it took until 2013 for the two to fully commit to the development of MD1003. “2013 was when myself and Guillaume decided to leave our privileged jobs and go full time in the company.”
The recruitment of sponsors allowed MedDay to launch two additional clinical trials — the MS-SPI (NCT02220933) and MS-NO (NCT02220244) studies. Just as the currently running study, the MS-SPI trial included only progressive patients without relapses.
The MS-NO study, in contrast, also enrolled relapsing patients. The study was intended to examine if biotin could help speed recovery after a relapse in patients with optic neuritis. But unlike the clear effects found in people with progressive disease, researchers did not see treatment impact in this group.
Data from the French MS-SPI trial — published in the Multiple Sclerosis Journal in 2016 — showed another picture. In the pilot study, researchers recorded all types of improvement. This time, the criteria were more strict: patient needed to improve their EDSS score or their performance in the timed 25-foot walk test. Of those receiving MD1003, 12.6 percent did. In the placebo group, that number was 0.
“That’s how we became completely convinced that there was something completely new here, something working on the neurodegeneration. We knew that biotin had no effect on T-cells, B-cells; it had nothing related to inflammation,” Sedel said.
“What we observed in patients was progressive improvement, which was very unusual, as you know — patients with progressive MS, as with other neurodegenerative diseases, are not supposed to really improve.”
The results, he said, seem to be durable throughout the currently running extension trial, which will continue to monitor its patients until biotin becomes approved. “We do not end the trial until we get market approval, because it is very important to get long-term data.”
But as the extension continues, people are dropping out, making analyses of durability difficult. “The data on the population that is still being followed in this trial, which may not be representative of the whole population … it seems that there is a sustained efficacy,” Sedel said, underscoring the need to be cautious in interpretations.
Although Sedel did not mention reasons for people quitting the study, they may be linked to the fact that French patients can now access the drug outside of the trial.
French authorities granted MD1003 a temporary license, known as an ATU, allowing access before the European Medicines Agency (EMA) have its say on marketing authorization. Since MedDay is obliged to keep track of these patients, the program can provide important data supporting the effectivity of the treatment.
“Physicians have treated about 5,000 patients, which is huge. I think it’s very rare to have a drug … [in an investigative stage with] results in some 5,000 patients,” Sedel said.
MedDay has presented data from the extension phase at earlier scientific conferences, and plans an update for the ECTRIMS meeting in Paris in October. There, the company will also showcase observations in the early access patients.
In Europe, data from the French MS-SPI trial and the early access program has been accepted by the EMA as sufficient to apply for regulatory approval.
“This data are competent enough to get [considered for] European approval and this is what we are discussing today with the EMA,” Sedel said. A decision, he said, is possible by year’s end.
The FDA, in initial discussions, asked for a study in a U.S. population, which prompted the launch of the SPI2 trial. The global Phase 3 study largely intends to confirm previously acquired findings. But it will also include more measures of MD1003’s safety and efficacy. Researchers will use scans to measure brain changes, follow ambulation remotely, measure ambulation remotely, and, again, evaluate participants’ quality of life.
MedDay has no plans to compare MD1003’s effects to other MS drugs, because such a comparison cannot be done.
“In this non-active progressive population, this is no real comparator — there is no other drug, to my knowledge, today available to treat the patients who are still progressing despite the control of their inflammation. That’s why we cannot use a comparator, we can only use a placebo against our drug,” Sedel said, and took Ocrevus (ocrelizumab) — newly approved for primary progressive MS — as an example.
“It would not make sense to compare biotin with Ocrevus … because Ocrevus is acting on one thing and biotin is working on something else. You are comparing apples with bananas, or whatever you say in English,” he said.
Although authorities have yet to approve MD1003, Sedel clearly believes in the potential of biotin, and, by extension, in the future of his company. He started the company with just one partner. “Today we are 75, and we will continue to grow,” he said.
If the SPI2 trial is successful, he is sure to be right.