Is Biotin an Effective Treatment for Progressive MS?

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb