MedDay Updates Status Of Pioneering Pivotal Phase III Study Design In Progressive Multiple Sclerosis

MedDay, a Paris, France based biotechnology company specializing in treatment of neurological disorders, has released more information regarding the design of its (MS-SPI) clinical trial that is investigating the efficacy and safety of the investigational medicine MD1003 in treatment of primary and secondary progressive multiple sclerosis (MS).

Progressive MS is a serious and severely disabling condition with a high unmet medical need,” says Dr. Peder Walberg, CEO of Medical Need, a company that identifies and satisfies unmet medical needs of individual patients and / or situations in health care, in close collaboration with research institutions, industrial partners, health care professionals, patient organizations and other key stakeholders. Dr. Walberg observes that “MD-1003 has shown great promise for these severely affected patients which currently have a very poor prognosis and may represent a significant break-through in the treatment of progressive MS.”

MD1003 is a highly-concentrated pharmaceutical-grade biotin (vitamin H) which at a dosage of 300 mg/day corresponds to 10,000 times the official recommended daily intake (RDA) for biotin. At such doses, MD1003 is no longer considered a food supplement because of potential toxicity and its new therapeutic properties at this dosage recategorize it as an active pharmaceutical ingredient.

Biotin is a key co-factor for enzymes involved in energy production and synthesis of myelin. Biotin has potentially two targets related to progressive MS: (1) it activates the Krebs cycle in demyelinated axons to increase energy production; (2) it activates acetyl-CoA carboxylases (ACC1 and ACC2), the rate-limiting enzymes in the synthesis of long chain fatty acids required for myelin synthesis.

MD1003 — biotin at active pharmaceutical concentration administered at doses of 100 – 300 mg /day — is thought to have both pro-myelinotic effects and to enhance energy supply for nerve impulse transmission. A patent protecting the dose and use in multiple sclerosis (MS) has been allowed in both the U.S. and Europe. The medicine’s mode of action 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 long chain 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 demonstrated in a pilot open label study involving 23 subjects with primary and secondary progressive MS. Results were encouraging, with up to 90 percent of subjects exhibiting clinical improvement over time. Treatment efficacy was also assessed using electrophysiology studies and magnetic resonance spectroscopy. Results were published this year in the Journal of Multiple Sclerosis and Related Disorders.

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The Open Access paper, entitled “High doses of biotin in chronic progressive multiple sclerosis: A pilot study“ (DOI: http://dx.doi.org/10.1016/j.msard.2015.01.005), is coauthored by MedDay co-founder and Chief Executive Officer Frederic Sedel, with Caroline Papeix, Agnes Bellanger, Valerie Touitou, Christine Lebrun-Frenay, Damien Galanaud, Olivier Gout, Olivier Lyon-Caen, and Ayman Tourbah.

The aim of the uncontrolled, non-blinded, proof of concept pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. The coauthors note that biotin activates enzymes involved in energy production and myelin synthesis, and 91.3 percent of SPMS or PPMS patients improved clinically with high doses of biotin. Improvements were observed in chronic optic neuropathy, homonymous hemianopia or myelopathy, and in all cases improvement was delayed from two to eight months following the treatment’s onset.

Two multi-centric double-blind placebo-controlled trials are currently underway.

The study paper observes that no drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin, on the other hand, is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among other things, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis.

Twenty-three consecutive patients with primary and secondary progressive MS were recruited for the study from three different French MS reference centers. The participants were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures.

The coauthors report that visual acuity improved significantly in four patients with prominent visual impairment related to optic nerve injury. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatments onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases, improvement was delayed from 2 to 8 months following treatments onset. The researchers conclude that these preliminary data indicate that high doses of biotin might have an impact on disability and progression in progressive MS. The theory is being further tested in two phase 2b/3 double-blind placebo-controlled trials currently in progress, involving 250 patients and 21 MS reference centers in France and the UK (ClinicalTrials.gov Identifiers: NCT02220933 and NCT02220244).

One of these, MS-SPI, is a randomized double-blind multicenter placebo-controlled (2:1) trial of MD1003 300 mg/day in patients with progressive MS who have demonstrated progression in the two years prior to enrollment. A total of 154 patients with a baseline EDSS (Expanded Disability Status Scale) score of between 4.5 and 7 were enrolled from 16 MS reference centers across France. Treatment duration was one year.

The study’s primary endpoint was defined as the proportion of patients who improved at nine months (M9) with confirmation at 12 months (M12) — improvement defined as either a decrease in the Kurtzke Expanded Disability Status Scale (EDSS — a method of quantifying disability in multiple sclerosis) by at least 1 point for baseline EDSS =5.5 and 0.5 points for EDSS =6; or an improvement in TW25 (a timed 25-foot walk) of at least 20 percent. Comparison reference for each outcome was the best EDSS and TW25 scores obtained at the screening and randomization visits.

The main secondary endpoints for the study were to evaluate the effect of MD1003 in stabilizing or slowing the rate of MS symptoms progression. These endpoints include the change in EDSS between M0 and M12 the proportion of patients with progression at M9 confirmed at M12 and the change in TW25.

Data from the MS-SPI study will be presented at the Clinical Trials Plenary Session at The American Academy of Neurology (AAN) Annual Meeting in Washington DC on Friday April 24th at 1200 EST.

In addition, a phase 2b/3 clinical study has started in the adult form of X-linked adrenoleukodystrophy, funded by the European Leukodystrophy Association (ELA) and involves four reference centers in France, Germany and Spain.

Neurologist, neuroscientist, and MedDay CEO Frederic Sedel MD, PhD observes in a release: “This trial was particularly ambitious. This is the first time that a study in progressive MS has evaluated the proportion of patients improved at M9 and confirmed at M12. This challenging clinical endpoint was designed during discussions with European and US regulators. We look forward to presenting the results of the trial at AAN later this month.”

Another important objective of the trial is to evaluate the safety of long-term treatment with MD1003 300 mg/day. Serious and non-serious adverse events recorded during the trial will also be presented at the AAN meeting.

Full session details and data presentation listings for the 2015 Annual Meeting can be found through the AAN website:
http://www.aan.com/conferences/2015-annual-meeting

The most common disabling neurological disease among young adults, onset of MS first symptoms typically manifest between 20 and 40 years of age. A strong majority (85 percent) of patients will experience an initial phase of relapsing-remitting neurological dysfunction (RRMS) which typically evolves into a secondary progressive disease at a later point in the disorder’s clinical course (SPMS). Once in the progressive phase, persons with MS typically experience gradual worsening of neurological disability leading to problems with vision, walking, incontinence, cognitive changes, fatigue, and pain. Primary progressive MS (PPMS), which is characterized by symptomatic progression from onset is less common affecting 10 to 15percent of patients.

Despite the different initial clinical phenotypes, the time to reach certain disability milestones and the ages at which the milestones are reached are similar for patients with both PPMS and SPMS. Recent guidelines have consequently proposed grouping PPMS and SPMS as a single entity called progressive disease. The overall prevalence of patients with progressive disease is estimated to be at least 40 percent of all MS patients.

MedDay was founded in 2011 by Frederic Sedel and Dr Guillaume Brion, MD, who trained at the Paris Medical School and in pharmaceutical marketing, and who has founded and developed service companies in the field of clinical development for the pharmaceutical industry. Dr. Brion gained broad experience in setting up and managing more than 200 clinical trials from first human administration to large multi-center, multi-national pivotal clinical trials at Groupe de Recherche et d’Etudes Scientifiques (GRES), TARS, Versus Clinical Research Services and Farma Research, all CROs dedicated to early clinical development

Sources:
MedDay Pharmaceuticals
the Journal of Multiple Sclerosis and Related Disorders
Medical Need
The American Academy of Neurology

Image Credits:
MedDay Pharmaceuticals
Medical Need