Date: 2016-09-02
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in the Multiple Sclerosis Journal
Company: Medday (France)
Product: MD1003 (high doses of pharmaceutical-grade biotin)
Action
mechanism: vitamin. MD1003 is an active pharmaceutical ingredient administered at a dose of 300 mg /day has patent protection in EU and US for dose and use in multiple sclerosis. MD1003 has a mode of action which potentially influences two targets related to progressive MS: (1) it activates acetyl-CoA carboxylases (ACC1 and ACC2), the rate-limiting enzymes in the synthesis of fatty acids required for myelin synthesis, and (2) it activates the Krebs cycle in demyelinated axons to increase energy production.
MD1003’s proof of concept has been obtained in a pilot open label study involving 23 subjects with primary and secondary progressive MS. Results were positive with up to 90% of subjects exhibiting clinical improvement over time. Treatment efficacy was also assessed using electrophysiology studies and magnetic resonance spectroscopy.
Disease: multiple sclerosis
Therapeutic area: Autoimmune diseases - Neurodegenerative diseases
Country: France
Trial
details: The MS-SPI study was designed to assess the potential of MD1003 to reverse disease progression in patients with not-active progressive MS. Patients included in the study had to demonstrate disease progression of disability in the previous two years with no evidence of inflammatory activity. Patients were randomized to receive either MD1003 (n=103) or placebo (n=51) for 12 months, followed by a 12-month extension phase during which all patients received MD1003 but remained blinded as to whether they had received the active drug during the first phase. The primary endpoint was particularly challenging, and defined as the proportion of patients with either improvement of EDSS or TW25 (timed 25-foot walk) after nine months (M9) confirmed at 12 months (M12), which equates to a confirmed reversion of progression. Patient enrolment commenced in October 2013 and was completed in January 2014 with 166 patients screened and 154 patients randomized (103 in the MD1003 arm and 51 in the placebo arm). There were no statistically significant differences in the characteristics of the patients in the two patient groups.
There were 12 treatment discontinuations in the MD1003 arm and 8 in the placebo arm. All analyses being performed according to the intent to treat (ITT) principle, all randomized patients were analysed according to the treatment arm they were assigned to. (NCT02220933)
Latest
news: * On September 2, 2016, MedDay, a biotechnology company focused on the treatment of nervous system disorders, announced the online publication of results from the previously reported Phase IIb/III, MS-SPI study of MD1003 in patients with progressive multiple sclerosis (MS) in the Multiple Sclerosis Journal. The objective of the study was to confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo controlled study. According to the key findings published in the journal, a total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced Expanded Disability Status Scale (EDSS) progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. In conclusion, MD1003 achieved sustained reversal of MS-related disability in a subset of patients with progressive MS and was well tolerated. The publication is titled “MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study” (abstract). The MS-SPI study was designed to assess the potential of MD1003 to reverse disease progression in patients with not-active progressive MS. Patients included in the study had to demonstrate disease progression of disability in the previous two years with no evidence of inflammatory activity. Patients were randomized to receive either MD1003 (n=103) or placebo (n=51) for 12 months, followed by a 12-month extension phase during which all patients received MD1003 but remained blinded as to whether they had received the active drug during the first phase. The primary endpoint was particularly challenging, and defined as the proportion of patients with either improvement of EDSS or TW25 (timed 25-foot walk) after nine months (M9) confirmed at 12 months (M12), which equates to a confirmed reversion of progression. The primary endpoint was met (p=0.0051) with 12.6% of patients in the MD1003 arm showing a confirmed reversion of progression at M9 (confirmed at M12), compared to none (0%) in the placebo arm. During the 12-month extension phase, patients initially on MD1003 exhibited sustained improvement compared to baseline, with 13.2% of patients showing improvement at M18 (confirmed at M24) and 15.4% of patients showing improvement at M24. When patients in the placebo group were switched to MD1003 for the extension phase, the proportion of responders reached 7.1% at M18 (confirmed at M24) and 11.9% at M24, demonstrating that treatment with MD1003 reversed progression in some patients switched to MD1003. The primary judgement criterion was supported by the mean change of EDSS from baseline in the overall population. The mean EDSS decreased between M0 and M12 in the MD1003 group (-0.03) compared to progression in the placebo group (+0.13, p=0.014). During the extension phase, the values remained relatively constant compared to baseline in patients maintained on MD1003 (from -0.03 to 0.04 at M24), indicating sustained efficacy, whereas patients initially on placebo stopped progressing on EDSS once switched to MD1003 (from +0.13 at M12 to +0.15 at M24, compared to baseline). The efficacy demonstrated on EDSS was also supported by the mean clinical global impression of change scale (CGI) which was worse at M12 in the placebo group compared to the MD1003 group (p<0.0001). It remained constant in the extension phase for patients initially on MD1003 and improved after patients were switched from placebo to MD1003. As a result no difference was observed between the two groups at the end of the extension phase (p=0.92). * On April 21 2016, MedDay announced full study results from the MS-SPI and MS-ON trials, including the MS-SPI extension data, which will be presented at the 2016 American Academy of Neurology Annual (AAN )Meeting. MS-SPI and MS-ON studies tested the efficacy of MD1003, a patented pharmaceutical-grade biotin administered at a dose of 300 mg per day in the treatment of multiple sclerosis. Overall these data show the best effect size ever observed to date and confirm the good safety profile of MD1003. * On October 7, 2015, MedDay announced that, during the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Barcelona, Spain, Prof A. Tourbah, the Principal Investigator of the Phase 3 MS-SPI study, will present a subgroup analysis. The MS-SPI double-blinded placebo-controlled trial with MD1003 was conducted by MedDay in 154 patients in France suffering from primary progressive multiple sclerosis or secondary progressive multiple sclerosis. * On June 19, 2015, MedDay reported additional positive data from its pivotal Phase III clinical trial, MS-SPI, with MD1003, a highly-concentrated pharmaceutical grade biotin, in patients with Progressive Multiple Sclerosis. The data, to be announced at The 1st Congress of the European Academy of Neurology (EAN), shows an improvement of the Clinical Global Impression of change observed after 12 months of treatment with MD1003 and confirms the positive results presented at the American Academy of Neurology in April 2015.
The MS-SPI study was designed to assess the potential of MD1003 to reverse disease progression in patients with not-active progressive MS. The primary endpoint was defined as the proportion of patients with either improvement of EDSS or TW25 (timed 25-foot walk) after nine months (M9) confirmed at 12 months (M12), which equates to a confirmed reversion of progression. The primary endpoint was met (p=0.0051) with 12.6% of patients in the MD1003 arm showing a confirmed reversion of progression at M9 (confirmed at M12), compared to none (0%) in the placebo arm. During the 12-month extension phase, patients initially on MD1003 exhibited sustained improvement compared to baseline, with 13.2% of patients showing improvement at M18 (confirmed at M24) and 15.4% of patients showing improvement at M24. When patients in the placebo group were switched to MD1003 for the extension phase, the proportion of responders reached 7.1% at M18 (confirmed at M24) and 11.9% at M24, demonstrating that treatment with MD1003 reversed progression in some patients switched to MD1003.
The primary judgement criterion was supported by the mean change of EDSS from baseline in the overall population. The mean EDSS decreased between M0 and M12 in the MD1003 group (-0.03) compared to progression in the placebo group (+0.13, p=0.014). During the extension phase, the values remained relatively constant compared to baseline in patients maintained on MD1003 (from -0.03 to 0.04 at M24), indicating sustained efficacy, whereas patients initially on placebo stopped progressing on EDSS once switched to MD1003 (from +0.13 at M12 to +0.15 at M24, compared to baseline).
The efficacy demonstrated on EDSS was also supported by the mean clinical global impression of change scale (CGI) which was worse at M12 in the placebo group compared to the MD1003 group (p<0.0001). It remained constant in the extension phase for patients initially on MD1003 and improved after patients were switched from placebo to MD1003. As a result no difference was observed between the two groups at the end of the extension phase (p=0.92).
Findings from both MS-SPI trial show that, overall, MD1003 is well tolerated. The incidence of adverse events was similar across the two groups in both studies. In some patients, abnormal laboratory data indicated that MD1003 could affect the results of immunoassays which use biotinylated antibodies and substrates.
The Clinical Global Impression of change is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. During the MS-SPI trial, the Clinical Global Impression of change has been assessed by the clinician (clinician global impression, CGI) as well as by the patient (subject global impression, SGI) after 12 months of treatment. Mean CGI and SGI scores assessed at month 12 were statistically significantly better in the intervention group compared with the placebo group (p* On April 24, 2015, MedDay announced results from the pivotal Phase III clinical trial, MS-SPI. The study demonstrated evidence of the efficacy and safety of MD1003, a highly-concentrated pharmaceutical-grade biotin administered at a dose of 300 mg per day in the treatment of primary and secondary progressive multiple sclerosis, a major area of unmet medical need.
The primary endpoint was met (p=0.0051, Fisher’s exact test) in the intent to treat population with 12.6% of patients in the MD1003 arm showing an improvement of EDSS (Expanded Disability Status Scale) or TW25 (a timed 25-foot walk) at Month 9, confirmed at Month 12, compared to none of the patients (0%) in the placebo arm.
The primary endpoint was supported by secondary analyses showing evidence for a decrease in the risk of disease progression. The mean change of EDSS between M0 and M12 decreased in the MD1003 group (-0.03) compared to progression in the placebo group (+0.13, p=0.015). In the MD1003 arm, only 4% of patients treated with MD1003 exhibited EDSS progression at M9 confirmed at M12 vs 13% in the placebo group (p=0.07), which equates to a 67% decreased risk of progression in the active arm within the studied period. The study was not prospectively powered to reach significance for this secondary endpoint.
MD1003 was well tolerated. The overall incidence of adverse events was similar across the two groups. One patient died from suicide in the active arm, however this event was not considered as related to the drug. In 5 patients, abnormal laboratory data indicated that MD1003 may affect the results of immunoassays which use biotinylated antibodies and substrates.
* On April 17 2015, MedDay announced that the primary endpoint was met in its pivotal clinical trial MS-SPI. MS-SPI investigated the efficacy and safety of MD1003, a highly-concentrated pharmaceutical-grade biotin administered at a dose of 300 mg /day, in the treatment of progressive multiple sclerosis. Detailed data will be presented for the first time at the Clinical Trials Plenary Session at The American Academy of Neurology (AAN) Annual Meeting.
