High-dose Biotin Shows Promise for Arresting Progressive Multiple Sclerosis Disability
By Carrie Decker, ND
Founder and Medical Director, Blessed Thistle, Portland, OR
Dr. Decker reports no financial relationships relevant to this field of study.
SUMMARY POINTS
- Patients with primary or secondary progressive multiple sclerosis received 100 mg of pharmaceutical-grade biotin (vitamin B7) or placebo dosed three times daily for one year.
- The primary endpoint was an improvement in the Expanded Disability Status Scale or a 20% decrease in timed 25-foot walk time, as assessed at nine and 12 months.
- The authors found that 12.6% of patients randomized to receive biotin achieved the primary endpoint vs. none of those treated with placebo.
- Clinician- and patient-assessed impressions of change also were significantly better in the biotin group (P < 0.001 and P = 0.009, respectively).
SYNOPSIS: In this double-blind, placebo-controlled study, patients with primary or secondary progressive multiple sclerosis were randomized to receive 100 mg of pharmaceutical-grade biotin or placebo thrice daily for 12 months. The primary endpoint of an improvement in the Expanded Disability Status Scale or a decrease in timed 25-foot walk time was achieved in 12.6% of the biotin-treated patients compared to no one in the placebo group (P = 0.005).
SOURCE: Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler 2016;22:1719-1731.
Progressive multiple sclerosis (MS) is a diagnosis that no one wants to hear, as it progresses more rapidly than that of a relapse-remitting course. A diagnosis of primary or secondary progressive MS is made retrospectively based on patient history, and relapse-remitting MS (RRMS) transitions to secondary progressive multiple sclerosis (SPMS) in approximately 80% of patients with RRMS.1 Primary progressive multiple sclerosis (PPMS) occurs in approximately 10% of MS patients.2 Treatment options for the disease in the progressive state are limited, as therapies that are effective for RRMS have limited to no efficacy.3 Given these statistics and information, it is not surprising that patient populations also seek integrative medicine providers for additional support.
Sedel et al found success in a small pilot study (n = 23) investigating biotin as a therapy for patients with non-active progressive MS. They found that more than 90% of patients had some degree of clinical improvement with high doses of biotin ranging from 100 mg to 300 mg (as compared to typical adult daily intake of 30 mcg/day to 100 mcg/day).4 This larger, randomized, double-blind, placebo-controlled study assessed the effect of biotin dosed at 100 mg three times daily vs. placebo (randomized 2:1, intervention:placebo) in patients diagnosed with SPMS and PPMS.
The 154 patients (103 randomized to intervention and 51 to placebo) enrolled in this study ranged from 18-75 years of age (meeting the revised McDonald and Lublin criteria for PPMS or SPMS) and also had evidence of spastic paraparesis. For eligibility, patients were required to have an Expanded Disability Status Scale (EDSS) evaluation showing disease progression during the previous two years. Patients with clinical or radiological evidence of inflammatory activity within the past year were excluded. Concomitant medications, such as immune modulators and immunosuppressive drugs, were allowed if they were introduced a sufficient period before the study. If necessary, intravenous methylprednisolone without oral taper was allowed for relapse. Physical therapy (PT) was allowed during the study, with the exception of intensive inpatient PT programs.
The primary endpoint evaluated to determine efficacy of therapy was MS-related disability: either an improvement in the EDSS by ≥ 1 point (≥ 0.5 for initial scores of 6-7) or a 20% decrease in timed 25-foot walk time as evaluated at nine and 12 months. Secondary endpoints of mean change in EDSS from start to month 12, clinician and patient-assessed impression of change, and various additional markers of disease state also were assessed. An extended intervention period in which both groups received biotin at the dosage of 100 mg three times daily was included to further evaluate the treatment efficacy. Patients and investigators remained blinded to the initial intervention during the extension period.
Thirteen patients (12.6%; 95% confidence interval [CI], 6.9-20.6%) of the group treated with biotin had a reduction in their EDSS score or a 20% decrease in their 25-foot walk time at nine months, reconfirmed at month 12, compared to no one in the placebo group (95% CI, 0.06-0.19; P = 0.005). At a three-month evaluation point, 10 of these 13 patients were observed to have reduced EDSS scores while five had improved walk times, with two improving in both categories. Secondary endpoints of clinician and patient-assessed global impression of change were significantly better in the biotin group (P < 0.001 and P = 0.009, respectively). At months nine and 12, EDSS scores were observed to progress in 13.6% of the placebo group and 4.2% of the biotin group (P = 0.07).
Additional analysis showed the endpoint of reduced disability was achieved more frequently in patients not taking fampridine (a potassium channel blocker medication commonly used in patients with MS) than patients who were taking fampridine (12 vs. one patient), and in those who had a baseline EDSS of 4.5-5.5 than those with baseline EDSS of 6-7 (6 of 28 vs. 7 of 75). At month 24, in the extended evaluation when both groups were given biotin, 14 (15.4%) patients of the biotin-biotin group and five (11.9%) patients in the placebo-biotin group had reduced MS-related disability by the same parameters. Additionally, two patients in the intervention group who were not observed to have improvements at 12 months were better at month 24. With the patients who were on biotin for both 12-month periods, the mean EDSS scores were relatively stable over 24 months (0.04 ± 0.62).
During the placebo-controlled study, 12 (11.7%) patients from the intervention group and nine (17.6%) patients from the placebo group withdrew from the study. Of these, six in the treatment group withdrew because of adverse events (suicide, mucocutaneous rash, asthenia, muscle spasms, abdominal pain, and libido disorder), while seven from the placebo group withdrew because of adverse events (overdose, dry mouth, intracranial hemorrhage, mental disorder, extrasystoles, muscle spasticity, and pregnancy). Five patients (4.9%) in the biotin group and four patients (7.8%) in the placebo group experienced MS relapse during the placebo-controlled study.
COMMENTARY
Given that progressive MS patients typically do not experience a reduction in EDSS scores, the current findings are noteworthy for this population.5 Since potentially effective medication options are minimal and the information from this study has rapidly populated patient support networks for individuals with MS, providers should be aware of the study. Overall safety was considered comparable to the placebo population. Although adverse events such as a mucocutaneous rash often suggest a reaction to intake of a new substance, subsequent patch testing was negative for biotin.
One issue of clinical importance that was observed with the biotin intervention was laboratory findings suggesting hyperthyroidism in six patients during the placebo-controlled phase and five patients during the extension phase. This apparent hyperthyroidism (low thyroid-stimulating hormone and high triiodothyronine or thyroxine) was determined to be due to biotin interference with standard thyroid laboratory tests, as a biotinylated antibody is used for this testing.6 Only one patient of the six with apparent hyperthyroidism was found to have Graves’ disease (iodine-induced hyperthyroidism) as confirmed by histology.
The proposed mechanism by which these observed effects of biotin may affect progressive MS are not via alteration of the inflammatory aspect of this disease. Rather, it has been suggested that the biotin-dependent carboxylases, which are involved in production of key intermediaries of the Krebs cycle, are supported by increased biotin, meeting increased energy demands of unmyelinated axons, which may be up to 5,000 times higher than those that are myelinated.7,8 Mitochondrial injury associated with inflammation also may reduce energy availability.9 Three of these biotin-dependent carboxylases are expressed in astrocytes and neurons and play a central role in neuronal energy production. The combination of a potential energy deficit and increased need is proposed to lead to a virtual hypoxia. Biotin, which is completely orally absorbed and transported across the blood-brain barrier in a saturable system,10 can be provided to the central nervous system with oral supplementation.
The effects of both lower and higher dosages of biotin were assessed in the pilot study (dosages ranging from 100 mg to 600 mg). Although symptom improvements were seen with dosages of 300 mg daily compared to 100 mg, no further benefit was appreciable at the higher dosage of 600 mg.4 In this study, mild transient diarrhea was noted with biotin supplementation. Although the high-dose biotin formulation used in this study, known as MD1003 or Cerenday, currently is in Phase III trials that are scheduled to complete in September 2019, higher-dose biotin supplements are available from numerous nutraceutical companies at doses of 8 mg to 10 mg per capsule, and from some as a powder or 100 mg capsule.
The lack of an intention-to-treat analysis, which makes a thorough assessment of these findings incomplete, is noteworthy about the Tourbah et al study. The considerable number of dropouts from both groups (11.7% from the intervention group and 17.6% from the placebo group) may affect the significance of the current findings. However, since a high percentage also dropped out of the placebo group, the results may not change dramatically; however, it should have been included for completeness.
A reasonable strategy given the possible benefit and minimal negative implications other than cost would be to initiate biotin at the dosage of 100 mg three times daily for individuals with MS of either a primary or secondary progressive course. An initial evaluation at three months would be prudent, as many of the individuals in the current reported study did experience reduced EDSS scores or improved walk times by this point in the study. However, if improvement has not yet been seen, there still is potential for such, as some individuals did not have measurable disease-course improvements until 24 months. Thus, if the cost of therapy was not prohibitive, patients could choose to continue if desired. Additionally, medications and disease EDSS score at the time of intervention also should be considered, as those on the medication fampridine and with an EDSS score of 6-7 were less likely to experience improvements.
REFERENCES
- Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003;9:260-274.
- Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of primary progressive multiple sclerosis. Neurology 2009;73:1996-2002.
- Feinstein A, Freeman J, Lo AC. Treatment of progressive multiple sclerosis: What works, what does not, and what is needed. Lancet Neurol 2015;14:194-207.
- Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: A pilot study. Mult Scler Relat Disord 2015;4:159-169.
- Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.
- Kwok JS, Chan IH, Chan MH. Biotin interference on TSH and free thyroid hormone measurement. Pathology 2012;44:278-280.
- Hassel B. Carboxylation and anaplerosis in neurons and glia. Mol Neurobiol 2000;22:21-40.
- Quarles RH, Macklin WB, Morell P. Myelin formation, structure and biochemistry. In: Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Brady S, Siegel G, Albers RW, Price D, eds. New York: Elsevier, Inc.; 2006: 51-71.
- Witte ME, Mahad DJ, Lassmann H, van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med 2014;20:179-187.
- Spector R, Mock D. Biotin transport through the blood-brain barrier. J Neurochem 1987;48:400-404.
In this double-blind, placebo-controlled study, patients with primary or secondary progressive multiple sclerosis were randomized to receive 100 mg of pharmaceutical-grade biotin or placebo thrice daily for 12 months. The primary endpoint of an improvement in the Expanded Disability Status Scale or a decrease in timed 25-foot walk time was achieved in 12.6% of the biotin-treated patients compared to no one in the placebo group (P = 0.005).
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.