STUDIES: Conflicting Biotin efficacy in progressive MS, could it promote progression?

[ActiveMSers]

I have had a decline (slight, but noticeable) since starting on my Biotin clinical trial a few months ago. Could it be the supplement? Natural progression? I could be on the placebo. I dunno, but this is at least notable. And highlights the reason we do trials instead of taking supplements willy nilly over the counter. Chat with your MS doc if you are worried. - D

Breakthrough disease under high-dose biotin treatment in progressive multiple sclerosis

ECTRIMS Online Library. Granella F. Oct 26, 2017; 200405

Abstract: P750
Type: Poster
Abstract Category: Therapy - disease modifying - 29 Risk management for disease modifying treatments

Background: Progressive multiple sclerosis (PMS) can be considered an orphan disease, because of lack of effective therapy currently available. Recently, oral high-dose biotin has been investigated as PMS treatment in a randomized clinical trial with promising results and without serious adverse events. Then, even though without indication by drug regulatory agencies, biotin has been prescribed by many clinicians in MS centres.

Aim: To report an unexpected increase of inflammatory activity in PMS patients treated with oral high-dose biotin.

Methods: We included all consecutive PMS patients who started biotin (300mg/die) in our centre, collecting clinical (relapses, EDSS score), brain and spinal MRI, tolerability and safety data.

Results: We included a total of 41 PMS patients (F 53.7%, mean age 54.3±9.82 years, mean EDSS 5.3±1.62, mean disease duration 15.8±9.28 years), with a primary progressive (PP) phenotype in 39.0% and secondary in 61.0% of cases. Mean treatment duration was 13.7±5.85 months. Annualized relapse rate increased from 0.10 in the previous year to 0.27 on treatment. Nine patients (22%), including 2 PP patients with no history of MS attacks, showed 12 relapses, 9 of them requiring steroid administration and 4 leaving residual disability. Seven patients (17%) showed MRI activity (new and/or enlarged T2 and/or Gd+ lesions), 3 of them with relapses. In 28 patients with treatment duration ≥ 12 months, EDSS score improved in 1, remained stable in 17 (60.7%), and worsened in 10 (35.7%) patients.

Conclusions: In our cohort of PMS patients treated with high-dose biotin we recorded an unexpected high rate, both clinical and radiological, of inflammatory activity. Clinicians should be very cautious when prescribing this drug until its efficacy and safety are definitely proven.

[ActiveMSers]

And a positive study. - D

Effect of MD1003 (High-Dose Biotin) for the Treatment of Progressive MS: 36-Month Follow-Up Data

Abstract: P786
Type: Poster
Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Objectives: MS-SPI was a 12-month (M) double-blind study where patients (pts; n=154) with non-active progressive multiple sclerosis (PMS) were randomised to MD1003 (n=103) or placebo (n=51). In the open-label extension phases, all pts received MD1003. Here, we present the 36M results (shown as MD1003>MD1003 [MM] vs placebo>MD1003 [PM]).

Methods: The extension phase included 133 pts (MM: 91; PM: 42). At M12, M24 and M36 we analysed: confirmed Expanded Disability Status Scale (EDSS) or timed 25-foot walk (TW25) improvement; mean EDSS change from baseline (mEDSS); TW25 evolution; and Clinician and Subject Global Impression of Change scale (CGI and SGI).

Results: EDSS or TW25 improvement was significantly higher for MM vs PM pts at M9 (13% vs 0%,
P< 0.05; confirmed at 3M); the trend was similar at M18 (13% vs 7%) and M30 (10% vs 2%; both confirmed after 6M).
mEDSS slightly decreased in MM and worsened in PM pts at M12 (−0.03 vs 0.13, P=0.01). When all patients were treated with MD1003 after M12, mEDSS remained stable and there was no significant difference between groups (M24: 0.04 vs 0.15, P=0.13; M36: 0.09 vs 0.18, P=0.35). However, the 2 mEDSS evolution curves remained parallel suggesting that earlier treatment leads to a lower disability at M36.
The proportion of pts unable to complete TW25 (or with time >180 sec) increased in both groups before M12, with a trend for less increase in MD1003 treated pts (baseline: 1% vs 2%; M12: 6% vs 19%). This proportion remained quite stable in all pts in year 2 (M24: 13% vs 20%) and in MM patients in year 3, but increased again in PM pts in year 3 (M36: 13% vs 30%).

CGI and SGI results were significantly better in favour of the MD1003 group at M12 (CGI: 4.05 vs 4.62, P< 0.0001; SGI: 4.27 vs 4.76, P=0.009). After M12, scores remained stable for MM pts and improved for PM pts, and the difference was no longer significant at M24 (CGI: 4.17 vs 4.21, P=0.93; SGI: 4.47 vs 4.41, P=0.75) or M36 (CGI: 4.11 vs 4.09, P=0.88; SGI: 4.11 vs 4.03, P=0.86). At M36, adverse events were experienced by 67% vs 79% of pts in MM and PM groups.

Discussion: These results indicate that: MD1003 effects seem sustainable over time; disease progression halts when pts switch from placebo to MD1003; delayed treatment in PM pts results in higher disability over time; and MD1003 is well tolerated over 36M.

These data suggest that targeting neuronal metabolism in PMS might represent a new class of long-term disease-modifying therapy.

[ActiveMSers]

Ayman Tourbah is the lead author on this and the above study. - D

Effect of MD1003 (High-Dose Biotin) in Spinal Progressive Multiple Sclerosis (MS-SPI): Subgroup Analyses

ECTRIMS Online Library. Tourbah A. Oct 26, 2017; 200442Abstract: P787
Type: Poster
Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Objectives: MS-SPI was a 12-month (M) double-blind, randomised, placebo-controlled study evaluating the effect of MD1003 on non-active progressive multiple sclerosis (PMS) patients (n=154), followed by an open-label extension phase where all patients received MD1003. The results indicated at 9 months a statistically significant 3 month confirmed improvement of patients in the MD1003 as compared to placebo, using the Expanded Disability Status Scale (EDSS) score. Here we present the results of subgroup analyses in the main phase of the study.

Methods: The global population (n=154) was split into the following subgroups of interest: EDSS low (4.5-5.5; n=35) or high (6-7; n=119); concomitant use of fampridine (n=72) or not (n=82); primary progressive MS (PPMS; n=55) or secondary progressive MS (SPMS; n=99); concomitant use of disease-modifying therapy (DMT; n=61) or not (n=93); and undergoing new intensive physical therapy during the study (n=29) or not (n=125). Analyses of both observed and imputed data were performed on these covariates using van Elteren tests and mixed models. A forest plot analysis of the treatment's effect in different subgroups using a mixed model has been performed.

Results: When adjusting for different baseline covariates, MD1003 effect is statistically significant for the whole population. The P-values for the change in EDSS from baseline to M12 in the intention-to-treat population (observed data, imputed data) were: EDSS score: 0.0181, 0.0604; fampridine use: 0.0083, 0.0304; PMS type: 0.0056, 0.0407; DMT use: 0.0098, 0.0407; undergoing physical therapy: 0.0092, 0.0390; mixed model analysis of EDSS score/fampridine use/PMS type/DMT use: 0.0866, 0.0733; and mixed model analysis of MS type/DMT/physical therapy: 0.0438, 0.0345.
The forest plot analysis showed that whatever the subgroup studied the results systematically favoured the MD1003 over the placebo group. Although the relatively small numbers of patients in some of the subgroups precluded statistical significance, the same trends were observed among all different subgroups.

Discussion: There is no evidence that a specific subgroup did not benefit from MD1003 treatment in patients included in the MS-SPI trial.

[ActiveMSers]

Lead author: David Brassat

MD1003 (High-Dose Biotin) for the Treatment of Progressive Multiple Sclerosis: Baseline Data and Results from a Cohort of Patients included in a Early Access Program

ECTRIMS Online Library. Brassat D. Oct 25, 2017; 199796

Abstract: EP1776
Type: ePoster
Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Objectives: MD1003 (biotin 100 mg three times per day) was granted an early access program called Qizenday® cohort Temporary Authorisation for Use (ATUc) in July 2016, following a named patient use called nominative ATU (ATUn) granted in 2015, by the French National Agency for Medicines and Health Products Safety, for treatment of adult primary (P) and secondary (S) progressive multiple sclerosis (PMS) patients 1 year relapse free. ATUc baseline characteristics at inclusion, and efficacy and safety results from both the ATUn and ATUc, are presented.

Methods: The ATUc included 5483 patients (61% female) between 13 July 2016 and 12 January 2017 (SPMS: 3080 [56%]; PPMS: 1524 [28%]; PMS type not reported: 880 [16%]); 2781 patients (51%) already received MD1003 as an ATUn. Further patients are currently included in the ATUc. To date, mean baseline values were: age: 57 years; time from diagnosis: 18 years (SPMS: 21 years; PPMS: 13 years); Expanded Disability Status Scale (EDSS) score: 6.1 (SPMS: 6.2; PPMS: 5.9) and walking distance (WD): 218.1m.
Here we report follow-up changes in EDSS, WD and clinical global impression (CGI) over a period of 1 year.
Further results covering the period until July 13 2017, with additional patients and a longer observation period, will be presented.

Results: To date, mean change in EDSS remained stable over 1 year while an increase in WD related to duration of MD1003 exposure was observed. An increased proportion of patients had improved CGI related to MD1003 exposure duration.
Safety data were consistent with the MD1003 summary of product characteristics.

Discussion: In this large cohort of patients, the efficacy and safety of MD1003 are consistent with the MS-SPI trial results.

[ActiveMSers]

Biotin in Multiple Sclerosis in clinical practice: a cohort of 154 patients

ECTRIMS Online Library. Fromont A. Oct 25, 2017; 199804

Abstract: EP1784
Type: ePoster
Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: Biotin is vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis and could promote remyelination. One double blind placebo controlled trial showed improvement in a significant proportion of patients with progressive multiple sclerosis (MS). Biotin is available in France in temporary use since July 2015.

Aim: To study baseline characteristics and follow up of patients treated with Biotin in Dijon (Burgundy).

Methods: We studied all progressive MS treated with biotin for more than 3 months included in EDMUS database. EDMUS is used in Dijon since 2000 and includes patients from burgundy MS center. We calculated number of primary progressive (PP) or secondary progressive (SP) form of MS, mean age and EDSS at biotin initiation, proportion of patients for which biotin was used as add on therapy or with fampyra, number of adverse events, Clinical Global Impression (CGI) Scale assessed by patient.

Results: 154 patients were treated with biotin, 114 had SPMS and 40 PP. The mean age at MS onset was 32.0 and 45.6 years respectively. Mean age at biotin initiation was 57.6 years with mean EDSS at 6.9 for SPMS; 61.6 years and 6.7 for PPMS. The mean duration of treatment was 8.8 months. 35 patients had biotin as add on therapy among SPMS and 12 for PPMS. 19 (16.7%) patients with SPMS reported adverse events (skin rash, hyperpilosity, diarrhea, anxiety asthenia, oedema) and 3 (7.5%) patients with PPMS (abdominal pain, diarrhea, constipation). 42% of patients reported CGI= 4, 39.5% CGI< 4, 18.4% CGI>4. 48 (31.8%) patients were under fampyra and 103 (68.2%) without, those under fampyra reported CGI improvement more frequently (56% versus 32%)

Conclusion: Despite short treatment duration, biotin is well tolerated, and seems more effective among patients under fampyra.

[Suebee]

Dave, thank you so much for assembling all these studies on biotin.
The best way to describe my response is with
I'm sorry you have not had the result you wanted. I wanted to be in that study because biotin seems so promising...

Thinking in large picture, and completely guessing with no science, I wonder if the reason there are different results is related to how all the B vitamins require balance to be absorbed and most effective by the body? Since everyone in the studies would have different levels of other vitamins in their systems, each person's body would absorb the biotin in different amounts. IDK. (Just thinking out-loud with my keyboard... )
Any way, thanks again for keeping us informed about Biotin. I hope scientists can clear up the equivocal results.

[Grumpy]

Hi guys. I was turned down for the study, but went on high dose biotin anyway. I'm diagnosed SP, on Aubagio, statins, lipoic acid.

6 weeks in on the biotin I see also to be getting worsening symptoms accompanied by acute pain.

I'm in the process of trying to get hold of my neurologist to see if this counts as an exacerbation, and if I should drop the biotin and/or do a course of steroids.

The only other exacerbation I've had in recent years was also medication related, when I came off gilenya and got double vision (also an effect noted in a small study but not picked up more generally).

It seems odd that none of the other biotin studies have picked this up if its a widespread issue, though

[Gcwildlands]

Thanks Dave, I think it’s important to go the next step and find a research neurologist specializing in MS to help you/all understand the significance and relative merit/scientific credibility of these published articles. In fact it would be a great service to find one or more to invite as probono educational advisors to activemsers.org, who could evaluate study design and statistical strength of results.

Having been on hd biotin for more than a year now, per a leading research doctor’s recommendation, I can contribute that benefits from biotin generally take some months to be noticeable above the ongoing fluctuations in symptoms due to progression or warm temperatures, low blood sugar, exercise recovery, lack of sleep, relapse, fatigue, holding your mouth wrong, and so on. It makes sense that it would take significant time to repair. That plus the experience that benefits are subtle—I’m still running only in dreams—makes me question big noticeable increase in symptoms being related to the biotin, but it is a pharmaceutical dose...

True one shouldn’t just try whatever supplement is showing promise, but with an expert to guide you and update you on a cohort of patients in their care, in the context of an academic based clinic, you may find something helpful, if only at keeping hopeful.

My main concern would be that speculation and anecdotal discussion plus trying to make sense of the science on our own here may lead to being critical of what is another equally important route to new treatments, if the risk is logically lower and the supplement doesn’t interact with other pharmaceutical treatments—in this case because biotin is water soluble and side effects seem limited to faster growing stronger nails and slightly thicker hair. Conversely there are clinical trials that are highly risky and one should have good advisement on these as well before participating.

I hope you are actually on the biotin and in time find that it’s given you just a little boost, enough to let you excercise just a bit more/harder/longer, because activity is still the uncontested champion of treatments. #KeepMoving #neverstopneverstopping

[ActiveMSers]

Good post GC and good points. My neuro is the lead MS researcher in New Mexico and I had an appointment with him a few days ago. He said the same things. Let's give it some time, don't put too much weight into every study you see (abstracts presented at ECTRIMS often don't get accepted/published in a journal), and let's see what the 6-month MRI tells us. I'm cool with that.

Turns out my walking test was similar to the results three months ago, so if I am slowing, it's nothing crazy. No changes in my fine-tuned EDSS, even small ones.

Thanks again for the reminder to be patient! And the reminder not overreact to one small study.