The SPI2 study did not replicate the improvements observed in prior study, instead suggesting that biotin (MD1003; MedDay Pharmaceuticals) is ineffective in patients with progressive MS.
New results from the SPI2 study (NCT02936037) suggest that high-dose, pharmaceutical-grade biotin (MD1003; MedDay Pharmaceuticals) does not improve disability or walking speed significantly in patients with progressive multiple sclerosis (MS), and cannot be recommended for the treatment of the disease.1
The data show that for the primary outcome—a composite of the proportion of participants with confirmed improvement in Expanded Disability Status Scale (EDSS) or timed 25-foot walk (TW25) at month 12 (confirmed at month 15)—only 12% of those treated with biotin (n = 19) improved compared to 9% of those in the placebo group (n = 29), for an odds ratio (OR) of 1.35 (95% CI, 0.81–2.26; P = .31). In total, the study included 642 participants randomized to either 100-mg oral biotin 3 times daily (n = 326) or placebo (n = 316).
In the prior MS-SPI study, high-dose biotin appeared to improve disability outcomes over 12 months in patients with progressive MS. Study author Bruce Cree, MD, PhD, MAS, clinical research director, UCSF Multiple Sclerosis Center, and colleagues noted that they did not anticipate to see a replication of the results from the smaller MS-SPI study.
“Given that SPI2 was a substantially larger trial done in a more diverse patient population, it seems more likely that the favorable observations from MS-SPI were due to a type 1 error rather than a type 2 error in SPI2,” they wrote. “Therefore, we conclude that biotin is ineffective in patients with progressive multiple sclerosis.”
Additionally, Cree et al. identified the previously known potential for high-dose biotin to have deleterious health consequences caused by interference on laboratory tests based on a biotin-streptavidin interaction. In this assessment, 25 inaccurate laboratory results were recorded, with the most common error being the mischaracterization of hyperthyroid in euthyroid participants.
For the EDSS component of the SPI2 primary end point 22 patients (7%) in the biotin group and 20 (6%) in the placebo group reported a response (OR, 1.07; 95% CI, 0.57–2.02), and for theTW25 component, 22 (7%) and 11 (3%) in each group, respectively, had a response (OR, 2.02; 95% CI, 0.98–4.39). In total, 5 participants in the biotin group and 2 in the placebo group improved on both components. The percentage change in mean TW25 between month 0 and month 15 was 20.7% (standard deviation [SD], 52.1) in the biotin group and 22.5% (SD, 53.4) in the placebo group, but the between-group difference (0.30) was not significantly different.
With regard to the secondary outcomes, 60 (18%) patients in the biotin group and 62 (20%) of the placebo group reported 12-week confirmed EDSS progression. The time-to-confirmed progression analysis revealed no significant differences between groups (hazard ratio [HR], 0.97; 95% CI 0.68–1.39), though a pre-specified subgroup analysis revealed a possibly positive effect of biotin in low-BMI patients (≤25.6 mg/kg2) for an OR of 1.76 (95% CI, 1.05–2.95) that had a corresponding negative effect in those with high-BMI (OR, 0.60; 95% CI, 0.36–1.00), though it was not significant.
Treatment-emergent adverse events (AEs) were reported in 277 (84%) of 331 participants in the biotin group and in 264 (85%) of 311 in the placebo group. At least 1 serious AE was reported by 87 (26%) and 82 (26%) participants, respectively, with 1 (<1%) death recorded in the biotin group.
In addition to not meeting the primary or secondary end points, Cree and colleagues concluded that “exploratory analyses using biomarkers of neuronal injury, MRI markers of axonal integrity magnetic resonance spectroscopy, and a sensitive measure of ambulation found no differences between the treatment groups and exclude a neural protective role of biotin. Taken together, these results suggest no beneficial effect of MD1003 in patients with multiple sclerosis.”
The topline data were originally announced in March 2020. At the 2017 joint meetings of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (MS Paris), positive data from a phase 2/3 study of MD1003 showed improvements on EDSS and TW25 compared with placebo.2 Then, in December 2019, the company reported positive results from the phase 3 MS-PSI study (NCT02220933), which demonstrated the drug’s ability to meet the primary end point as well as demonstrate a potential to reverse disease progression in progressive MS over a 12-month period.2,3