High-dose biotin, a B vitamin used at lower doses as a food supplement, does not significantly improve disability or walking speed in patients with progressive multiple sclerosis, new research shows.
For this reason, and because of the possibility of false lab reports as a result of high biotin serum concentrations, investigators of the randomized, double-blind, placebo-controlled study conclude that high dose biotin is not recommended for treatment of progressive MS.
For investigators involved in the study, the findings are a blow.
"I'm very disappointed," lead investigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California San Francisco, told Medscape Medical News.
"I've spent years working on this study and was very excited about the opportunity to develop a product, a non-inflammatory drug that might improve disability in patients with MS."
The study was published online October 23 in Lancet Neurology.
Most studies of disease modifying therapies in MS use agents designed to modulate or suppress immune function. In contrast, the biotin approach targets myelin.
Biotin is essential for breaking down proteins, carbohydrates, and fats. It's especially important for healthy skin, hair, eyes, liver, and nervous system functioning.
At low doses, biotin, which is also known as vitamin B7 or vitamin H, is found in some foods and is used as a supplement to treat biotin deficiency, experienced by some pregnant women
MD1003 (MedDay Pharmaceuticals), the agent used in the study, is a highly concentrated oral preparation of biotin. High-dose biotin, explained Cree, potentially addresses two mechanisms — mitochondrial energy failure that seems to occur in MS, and enhancement of myelin metabolism.
Taking high doses of biotin may affect certain blood tests, such as thyroid function tests, some pregnancy blood tests, and cardiac tests.
An earlier pilot study demonstrated safety and efficacy of high-dose biotin in progressive MS, which prompted the design of a phase 2 randomized double blind placebo-controlled trial (MS-SPI).
Results of the MS-SPI study showed that compared with placebo, MD1003 improved disability outcomes over 12 months in patients with progressive MS.
"We were very excited about the results of the first clinical trial. It seemed to work and I was excited of course to see a bigger study replicate it," said Cree.
The new study, known as MS-SPI2, was designed to extend the observations of the first study in a larger, more diverse patient population.
It included 642 adult patients with primary or secondary progressive MS without relapse in the past 2 years. It was conducted at 90 centers in 13 countries. The mean age of study subjects was 52.7 years, 54% were women, and 65% were diagnosed with secondary progressive MS.
In this patient population, the mean expanded disability status scale (EDSS) score was 5.4, and the mean timed 25-foot walk (TW25) was 11.7 seconds. About 58% of subjects required a walking aid (EDSS 6.0 or 6.5), 46% were receiving concomitant disease-modifying therapies, and 5% had at least one gadolinium-enhancing lesion on MRI.
Investigators randomly assigned patients to receive placebo or MD1003 at 100 mg three times daily. This dose is some 300-fold higher than the dose in over-the-counter supplements. Participants, investigators, and assessors were blinded to treatment assignment. Participants were permitted to continue any disease-modifying therapies.
The study's primary endpoint was improvement of MS related disability at month 12, confirmed at month 15. Improvement was defined as either a decrease from baseline in EDSS of at least 0.5 points (if baseline EDSS was 6.0 – 6.5) or 1.0 point (if baseline EDSS was 3.5 – 5.5), or a decrease of at least 20% from baseline in TW25.
About 12% of patients in the MD1003 group and 9% of in the placebo group improved in either EDSS or TW25 at month 12, with confirmation at month 15 (odds ratio [OR] 1.35; 95% CI, 0.81 - 2.26; P = .31)
For the EDSS component of the primary endpoint, 7% of those in the MD1003 group and 6% in the placebo group had a response (OR, 1.07; 95% CI, 0.57 - 2.02; P = .87). For the TW25 component, 7% in the MD1003 group and 3% in the placebo group had a response (OR, 2.02; 95% CI, 0.98 - 4.39; P = .07).
"There was a trend favoring treatment that didn't reach statistical significance," said Cree, adding that the timed 25-foot walk "was close."
"I think there's something there when you look at it, but not to the extent that was seen in the first study," he added.
Cree believes the difference in the outcomes of two studies is how the placebo group performed. In the first study, which had a small placebo group of only 50 patients, there was "a rather unusual performance in the placebo-treated patients in that absolutely none of them got any better."
However, in the second study, "there was a very clear placebo effect," said Cree.
"I think we got an inaccurate assessment of the magnitude of the therapeutic effect from the first study because the placebo group did so poorly."
Abnormal Lab Findings
Although disappointed in the results of the second trial, Cree is taking the findings in stride
"This is science; this is how this goes. You take your best shot and if you do it right, you get a clearly interpretable result. We did it right and we got a clearly interpretable result — the drug didn't work in the way we hoped it would," he said.
Whether the results would have been different with an even larger patient population, or an even longer follow-up period, is unclear and "would take a fair amount of funding "to find out, said Cree.
No significant therapeutic benefits were observed in any prespecified subgroups. Interestingly, those with lower body mass index [BMI] seemed to benefit from the intervention whereas those with higher BMI appeared to benefit from placebo, leading to a neutral effect in the overall population.
"Although there were some trends in the right direction favoring a therapeutic effect in various subgroups, none of those really reached a level of statistical significance," said Cree.
Results of exploratory analyses using biomarkers of neuronal injury (serum neurofilament light) and MRI markers of axonal integrity magnetic resonance spectroscopy appear to exclude a neural protective role of biotin.
"We were hoping to see a neuroprotective effect, but we didn't," said Cree.
Taken together, the results "suggest no beneficial effect of MD1003 in patients with multiple sclerosis" the investigators write.
The number of treatment-emergent adverse events (AEs) was similar in both study groups — 84% for MD1003 vs 85% for placebo. About 26% of both groups had at least one serious AE. The most frequently reported were nervous system disorders (13% in the MD1003 group, 16% placebo group) followed by MS relapse (9% and 10%, respectively).
"We didn't really see much in the way of problematic AEs, and the ones that were truly treatment-emergent were quite uncommon," Cree noted.
The main AE associated with therapeutic intervention was abnormal lab findings. Cree explained that biotin concentrations in the blood can interfere with biotin-dependent assays, such as those used to test for troponin, a protein released when the heart muscle is damaged.
This can lead to serious consequences if, for example, a patient with a heart attack is misdiagnosed and isn't sent to the angio-catheter lab.
"We knew about the possibility of abnormal lab findings and had a risk mitigation strategy, but nonetheless it still wound up occurring," said Cree.
Important Information for Clinicians
It is important for clinicians to know that "taking high dose biotin can have serious health consequences and that patients can potentially be misdiagnosed based on a misleading lab result," said Cree, adding that serious consequences did not occur during the study.
At month 15, there were no differences between the two groups in the number of participants with new or enlarging T2 lesions or the number with gadolinium-enhancing lesions.
Because high-dose biotin has been used off-label for both relapsing and progressive MS patients, "getting the message out that it didn't work is important," said Cree.
He noted that patients with nonactive progressive MS "have not been investigated extensively." Lessons learned from this study "will be informative for other studies down the road," he said.
He believes the negative results of this trial signal the end of investigating high-dose biotin in MS. "MedDay [Pharmaceuticals] has shuttered their doors as a consequence of this study, so I think there is very little enthusiasm to pursue further development of high-dose biotin."
Although the results on the 25 ft walk came close to suggesting a significant improvement, "whether that's enough to go ahead and do another study is going to have to be a decision for others down the road."
Cree said it is important to investigate MS treatments beyond immune suppression.
"We should not just look at MS treatment from the point of view of what the immune system has to do with MS, but also what other mechanisms underlie progression of MS, which is critical to our understanding," he said.
Not Completely Surprising
In an accompanying editorial, Jeremias Motte, MD, and Ralf Gold, MD, Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Germany, said SPI2 was "planned and performed well, paving the way for how future studies in patients with progressive multiple sclerosis should be conducted."
They note that because study participants "were carefully recruited," atypical clinical parameters "do not explain the negative results of the study."
The results "are not completely surprising," they write, noting that the previous MS-SPI study was criticized for its methodological limitations, including a short follow-up of the placebo-controlled phase and the very small placebo effect, which "might have produced some biased results."
That placebo-treated participants can have variable outcomes in MS trials is "well recognized" and a strong placebo effect in patients with progressive MS "is a real phenomenon," Motte and Gold note.
Although the current study revealed no safety concerns with high-dose biotin, the drug should not be considered completely harmless, they add.
"A transient myopathy resembling a multiple acyl-coenzyme A dehydrogenase deficiency has been described as an adverse event in another study," the editorialists write. In addition, they caution, some studies suggested an association of new disease activity with biotin supplementation.
The study was sponsored and supported by MedDay Pharmaceuticals. Cree reports he has received consultancy fees from Akili, Alexion, Atara, Biogen, EMD Serono, Novartis, Sanofi, and TG Therapeutics. Gold reports receiving grants and personal fees from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience, outside the submitted work; and compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Motte has disclosed no relevant financial relationships.
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Cite this: End of the Road for High-Dose Biotin in MS? - Medscape - Oct 27, 2020.