Switching multiple sclerosis patients with disease activity despite treatment with a first-line injectable to oral fingolimod (Gilenya) was associated with fewer relapses than switching them to another standard injectable, researchers have found.
In a study, patients on either interferons or glatiramer acetate (Copaxone) who were switched to fingolimod had a significantly lower mean annualized relapse rate than those who changed to another injectable immunomodulator, according to Tomas Kalincik, MD, PhD, of Royal Melbourne Hospital in Australia, and colleagues.
Patients in the study, reported online in JAMA Neurology, were switching medications following clinical relapse or disability progression while on the initial treatment.
In an accompanying editorial, Olaf Stuve, MD, PhD, of the University of Texas, and Diego Centonze, MD, PhD, of To Vergata University and Hospital in Rome, said the study adds to growing evidence that switching to newer agents like natalizumab (Tysabri) or fingolimod may be more effective.
Although it was an observational study, it assessed high-quality data and used appropriate propensity score matching to control for potential confounding factors, they wrote.
They noted, however, that the study's median follow-up of 13.1 months may be "too short to draw definite conclusions on the relapse rate."
Kalincik and colleagues conducted their matched retrospective analysis of data that was collected prospectively from MSBase, which collects data on MS patients in routine clinical care, from July 1996 to April 2014.
Patients with relapsing-remitting MS had been on a beta-interferon drug or glatiramer acetate for at least 6 months before making the change to another injectable (beta-interferon or glatiramer acetate) or to fingolimod because of clinical disease activity. They were then observed on the new medication for at least 3 months. Some of the patients initially taking a beta-interferon drug were switched to a different beta-interferon.
Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. Median follow-up was 13.1 months.
Kalincik and colleagues found that those switched to fingolimod not only had a lower mean annualized relapse rate but also a lower risk of first on-treatment relapse than those switched to another injectable immunomodulator.
Those changed to the oral drug also had a lower risk of disability progression and a higher rate of disability regression (HR 2.0, 95% CI 1.2-3.3, P=0.005), they reported.
They also had a lower rate of treatment discontinuation at 2 years.
The researchers noted that sensitivity analyses replicated in full the relapse and disability outcomes seen in the primary analysis. They did not, however, replicate the finding that switching to fingolimod improved treatment persistence, suggesting that this finding be interpreted with caution.
Kalincik and colleagues concluded that in the absence of randomized clinical trials, use of high-quality observational data provides an important tool for comparisons of drug effectiveness in a real-world setting.
In their editorial, Stuve and Centonze agreed that the quality of observational data in their study can provide "crucial information to support decision making relevant for MS management in real-world practice."
They said the results provide the first evidence that "switching to fingolimod is superior to switching to a second injectable immunomodulator with respect to disability outcomes, likely owing to the more efficient prevention of relapses associated with an incomplete recovery."
The results are in line with studies such as TRANSFORMS, one of the clinical trials leading up to fingolimod's approval, which found patients with active disease activity despite immunomodulatory therapy "may still have optimal disease control after switching to fingolimod."
In addition to the limitation of a short follow-up time, the study was also limited by lack of data on interferon-neutralizing antibodies, and because patients who were switched from one interferon preparation to another may not have served as true controls: "Most MS experts would not likely recommend this strategy because the agents are biochemically almost identical, and their mechanisms of action identical," they noted. The study, which was funded by fingolimod's manufacturer, also did not examine switches to natalizumab or newer oral agents.
Still, they concluded that evidence has accumulated that "escalating to the more effective medications natalizumab or fingolimod should be an early consideration for most patients with breakthrough disease. Switching to another injectable immunomodulator may still be considered in certain cases only."
The study was supported by Novartis, MSBase Foundation, Multiple Sclerosis Research Australia, National Health and Medical Research Council, and the Center for Research Excellence.
MSBase Foundation receives support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, and Sanofi.
The researchers disclosed financial relationships with Biogen Idec, Novartis, Genzyme, Merck Serono, Teva, Bayer Schering, Sanofi, Lundbeck, Bayer, Biologix, GSK, Roche, and bioCSL.
The editorialists disclosed financial relationships with Teva, Opexa, Merck Serono, Genzyme, Bayer Schering, Biogen Idec, Novartis, Almirall, GW Pharmaceuticals, Roche, and Mitsubishi.
Source: MedPage Today © 2015 MedPage Today, LLC (11/02/15)
Studies in Sweden and Germany indicate that underweight women with multiple sclerosis who take the MS drug Gilenya (fingolimod) seem to be at increased risk for lymphopenia. The drug also poses a risk for patients who have low lymphocyte levels before they start drug treatment.
Lymphopenia (also known as lymphocytopenia) is a condition in which a person has a deficiency (penia) of lymphocytes, which are a subset of white blood cells (leukocytes). Lymphocytes, which can be T cells, B cells, or natural killer cells, play a crucial role in supporting immune system function.
It’s been known that fingolimod can lower the level of circulating lymphocytes. In fact, among the serious side effects reported by the Food and Drug Administration (FDA) and the drug’s manufacturer, Novartis Pharma Stein AG, is infections.
Risk of infections is increased because the drug lowers lymphocyte levels. The two newly reported studies cast new light on some of the factors associated with this risk.
In the German study, 418 individuals with relapsing-remitting multiple sclerosis were enrolled in an open label study in which they took 0.5 mg of fingolimod daily. Blood samples were collected on four separate occasions: immediately before treatment and at months 1, 4, and 6. In the Swedish study, data from 438 patients were used to validate the findings.
Here are some of the findings:
- Women who had a body mass index (BMI) less than 18.5 kg/m2 had a 26 percent increased risk for developing lymphopenia (counts at or lower than 0.2 x 109/L associated with drug use. This effect was not seen in men with this BMI.
- Individuals whose starting lymphocyte levels were less than 1.6 x 109/L had a 46 percent increased risk of lymphopenia while using the drug.
- Use of glatiramer acetate (Copaxone) before use of Gilenya seemed to help protect against the development of lymphopenia, although the researchers were uncertain about the immunologic effect of this drug.
Prior research (phase III trials) has indicated that the decline in lymphocyte counts among MS patients who take fingolimod is not associated with meal timing or the use of other medications, such as corticosteroids.
The findings of the two new studies provide doctors with additional information to consider when Gilenya is on the treatment table, such as monitoring of female patients who are underweight and/or individuals who have low baseline lymphocyte counts. Other serious side effects that may develop with use of Gilenya include slow heart rate (bradycardia), which can occur when starting treatment; macular edema, which typically appears after three to four months of treatment; liver problems; and shortness of breath.
Food and Drug Administration
Warnke C et al. Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology 2014. DOI:10.1212/WNL.0000000000001049
Source: Emaxhealth (05/01/15)
Novartis announced today that the Phase III INFORMS study in primary progressive multiple sclerosis (PPMS) did not show a significant difference between fingolimod and placebo on a combination of disability measures. The safety results were consistent with the well-characterized safety profile of fingolimod in relapsing MS (RMS).
PPMS is a disorder of the central nervous system (CNS) which affects approximately 10% of the 2.3 million patients diagnosed with MS worldwide. PPMS is a distinct disease form, different from relapsing MS in terms of its basic disease process, near-absence of acute relapses and fewer active MRI lesions. The severe irreversible damage to the CNS in PPMS is thought to be caused by different pathways leading to loss of nerve cells and a more rapid, continuous loss of function over time which profoundly impacts patients' lives. Additionally, the disease is typically diagnosed later than other types of MS, when significant damage to the CNS has already occurred. Despite considerable research and academic focus, there are currently no approved treatments that have been shown to change the course of this debilitating disease and management focuses mainly on the treatment of symptoms.
"We understand this news is very disappointing for those affected by PPMS and involved in its management. While PPMS is a focus of the MS community, relatively little is known about the disease so finding effective treatments remains a challenge. We will actively work with the MS community to review and analyze the INFORMS results to help increase the understanding of this devastating disease," said Vasant Narasimhan, Global Head of Development at Novartis Pharmaceuticals. "Gilenya (fingolimod) revolutionized the treatment of relapsing MS as the first oral disease-modifying therapy. We remain strongly committed to continuing to research new treatment options for patients with MS and other neurological conditions."
The INFORMS study was based on the knowledge that fingolimod enters the central nervous system (CNS) and can interact with damage-causing cells residing in the CNS. It was hypothesized that this central effect, which is well understood in relapsing forms of MS, would also be relevant in PPMS. As opposed to the consistently strong efficacy seen in relapsing MS, the results of the INFORMS study seem to suggest that PPMS and relapsing forms of MS have different underlying mechanisms.
Fingolimod, marketed as Gilenya®, is approved in the US for first-line treatment of relapsing forms of MS in adults. In the EU, Gilenya is indicated for adult patients with highly active relapsing-remitting MS (RRMS) defined as either high disease activity despite treatment with at least one disease-modifying therapy (DMT), or rapidly evolving severe RRMS. Gilenya is the only DMT to impact the course of relapsing MS with high efficacy across four key measures of disease activity: relapses, MRI lesions, brain shrinkage (brain volume loss) and disability progression. The likelihood of achieving 'no evidence of disease activity' (NEDA) across four key measures is more than four-times greater in relapsing MS patients treated with Gilenya compared to placebo. The safety profile of Gilenya in RMS is well understood and based on substantial evidence from three major clinical trials and extensive real-world experience in more than 100,000 patients, with the total patient exposure now at approximately 172,500 patient years.
The INFORMS study is a double-blind, randomized, multi-center, placebo-controlled parallel group study, comparing the efficacy and safety of fingolimod (0.5 mg) versus placebo in people with primary progressive multiple sclerosis (PPMS). The INFORMS study is the largest clinical trial ever conducted in PPMS. Nine-hundred and seventy (970) people aged 25-69 years with PPMS were enrolled in INFORMS from 148 sites, across 18 countries, including Australia, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, Turkey, UK and the US. Patients were treated for at least three years.
The primary endpoint was to evaluate the effect of fingolimod versus placebo on reducing the risk of three-month sustained disability progression based on a composite measure of Expanded Disability Status Scale (EDSS), assessment of upper limb function (9-Hole Peg Test, HPT), and walking speed (25-foot Timed Walk Test, TWT).
About Gilenya (fingolimod)
In relapsing MS, the loss of physical and cognitive function is driven by two types of damage that result in the loss of neurons and brain tissue - distinct inflammatory lesions (referred to as focal damage), and more widespread inflammatory neurodegenerative processes (referred to as diffuse damage). Focal damage results in the loss of brain tissue and can clinically present as relapses. Diffuse damage starts early in the disease, often goes unnoticed and is also associated with loss of brain tissue and accumulated loss of function.
Gilenya (fingolimod) targets both focal and diffuse central nervous system (CNS) damage that drive loss of function in relapsing MS. It prevents cells that cause focal inflammation from reaching the brain (referred to as 'peripheral' action), but also enters the CNS and reduces the diffuse damage by preventing the activation of harmful cells residing in the CNS (referred to as 'central action'). It is important to address both focal and diffuse damage in relapsing MS to effectively impact disease activity and help preserve an individual's physical (e.g. walking) and cognitive (e.g. memory) function.
Phase III studies with fingolimod are currently being conducted in two rare diseases, pediatric MS and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), where there is a high unmet need.
About Novartis in Multiple Sclerosis
Novartis is committed to the research and development of innovative and targeted treatment options for people suffering from different types of MS.
The Novartis MS portfolio includes Gilenya (fingolimod, oral DMT) and Extavia® (interferon beta-1b for subcutaneous injection) for the treatment of relapsing MS. In addition to the current clinical development program with Gilenya, Novartis is investigating BAF312 (siponimod), a second generation, selective S1P1 and 5 receptor modulator, in the largest Phase III trial in secondary progressive MS (SPMS). The IL-17 pathway is also being explored as a novel therapeutic target in MS.
Source: Novaratis 01/12/14
SMC first to introduce oral Gilenya® as a first line treatment option for people with a severe form of MS(14/10/14)
SMC first to introduce oral Gilenya® as a first line treatment option for people with a severe form of MS
• Scottish people with a severe form of relapsing remitting multiple sclerosis are first in UK to get access to once daily pill fingolimod as a first line treatment option1
• Once daily pill fingolimod reduces the risk of relapses by 67% compared to placebo2
Today, the Scottish Medicines Consortium (SMC) has accepted once daily pill fingolimod (Gilenya®) as a first line option for people with a severe form of relapsing remitting MS, which has been shown to reduce the risk of relapses by 67% compared to placebo.1,2 This is the first time that an oral treatment has been made available as a first line treatment option for people with this severe form of MS - known as rapidly evolving severe relapsing remitting MS (RES RRMS).1
The SMC heard from patient groups that MS is an incurable progressive disease with devastating effects on those with the condition and their families.1 Symptoms can include intense pain, mobility problems, severe depression, fatigue, incontinence and loss of vision.1 MS affects over 100,000 people in the UK, with rates highest in Scotland.3,4
85% of people with MS are diagnosed with the relapsing remitting form - when symptoms flare up aggressively - known as relapses.5 There are different types of RRMS, including highly active and RES RRMS.6 In September 2012, the SMC agreed to reimburse fingolimod for people with highly active RRMS who are failing on first line interferon injections.7 Today’s decision means that fingolimod is now also reimbursed for RES RRMS – when a person has two or more disabling relapses in one year with associated MRI changes.1 The SMC’s decision to broaden access to fingolimod means this is the first time that people with this more severe form of RRMS will have the choice of a once daily pill as a first line treatment option.1
Prior to today’s decision, only one SMC approved treatment was available for people with RES RRMS – a hospital-based infusion called natalizumab required every 28 days.1 Fingolimod is a once daily pill that can be taken at home after the first dose, avoiding the need to travel to hospital every month. It has been shown to reduce relapses by 67% compared to placebo in those with RES RRMS (ARR 0.24 for fingolimod and 0.74 for placebo).2 The analysis was conducted in a subgroup of patients from the original phase III FREEDOMS trial.
Scottish patients with RES RRMS will have access to once daily pill fingolimod as a first line treatment option before those in the rest of the country. This is because the SMC process allows manufacturers to submit new data at any time. NICE is set to review fingolimod alongside a range of other MS treatments in 2015. This means that people with this severe form of RRMS north of the border will have an increased choice of first line treatments before their southern counterparts.
Today’s announcement follows a series of recent decisions by the European Commission and NHS England to extend the use of fingolimod to a wider group of people, just three years after its original licence was granted in March 2011.
To date, more than 100,000 people worldwide have been treated with fingolimod in clinical trials and in the post-marketing setting.8 Fingolimod has been approved in 80 countries.8
References 1. SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya®). October 2014
2. Devonshire V, Havrdová E, Radue EW et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012; 11:420-28
3. The Scottish Parliament. Briefing for the Public Petitions Committee. http://www.scottish.parliament.uk/ResearchBriefingsAndFactsheets/Petitions%20briefings%20S3/PB10-1353.pdf Last accessed 10 October 2014.
4. MS Society. What is MS? http://www.mssociety.org.uk/about_ms/what_is_ms/index.html Last accessed 10 Oct 2014
5. MS Society. http://www.mssociety.org.uk/what-is-ms/types-of-ms/relapsing-remitting-rrms Last accessed 10 October 2014
6. MS Trust. http://www.mstrust.org.uk/atoz/types.jsp Last accessed 10 October 2014
7. SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya®). SMC No. (763/12). 12 March 2012
8. Gilenya World Watch. http://www.gilenya-world-watch.com/English.html Last accessed 10 October 2014
9. European Commission. Community register of medicinal products for human use. Gilenya. http://ec.europa.eu/health/documents/community-register/html/h677.html Last accessed 10 October 2014.
10. NHS England commissioning guideline for Gilenya. June 2014
Source: Novartis (14/10/14)
The immunosuppressive drug fingolimod (trade name: Gilenya) was approved for an expanded therapeutic indication in May 2014: It is now also available for adults with highly active relapsing remitting multiple sclerosis (RRMS) who had received other pretreatment than interferon beta (IFN-β). In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether the drug offers an added benefit over the appropriate comparator therapy in this patient group.
According to the findings, such an added benefit is not proven: For some of the patients, the drug manufacturer presented no data. For other patients, the available study data either showed no differences between the treatment groups, or the data were not evaluable.
G-BA specifies appropriate comparator therapy
The Federal Joint Committee (G-BA) distinguishes between two patient groups for the assessment: In patients with highly active RRMS despite full previous treatment (no interferon beta), fingolimod was to be compared with glatiramer acetate or interferon beta. In patients with incomplete previous treatment, the G-BA distinguishes between two cases for the appropriate comparator therapy: In patients who had received glatiramer acetate, this medication was to be optimized and continued. In patients who had received a different drug, treatment was to be changed to interferon beta or glatiramer acetate.
Only data of few study participants relevant for the assessment
One relevant study was available for the early benefit assessment, an approval study on fingolimod (TRANSFORMS), which compared treatment with fingolimod versus treatment with IFN-β1a in adults with RRMS. However, the disease was rated as "highly active" in only nearly half of the 866 participants. Only 263 of these 402 patients had received full previous treatment. Only 42 participants, i. e. a little less than five percent of the total study population, had not been treated with interferon beta (17 patients in the fingolimod arm, 25 in the interferon beta arm). However, only these patients correspond to the subpopulation relevant for this benefit assessment, because it is only this subpopulation that fingolimod had received expanded approval for. The informative value of the results was considerably limited because only data of few participants were evaluable.
Differences between treatment arms not statistically significant
No deaths occurred during the total study duration of 12 weeks. There were differences between the fingolimod and the interferon beta group with regard to relapses and disability progression, but these were not statistically significant.
No evaluable data were available for the patient group for which fingolimod was newly approved regarding other aspects of the outcome "morbidity", e.g. fatigue or activities of daily living, and for the outcome "health-related quality of life". One of the reasons for this is that different proportions of patients were not considered in the analysis.
There were group differences in side effects (serious adverse events and treatment discontinuation due to adverse events), which again were not statistically significant.
Dossier without relevant study on patients with incomplete treatment
In its dossier, the manufacturer presented no relevant study for patients who had not received full previous treatment.
In summary, an added benefit of fingolimod is therefore not proven for patients with highly active relapsing remitting multiple sclerosis (RRMS) who had received a different pretreatment than interferon beta.
Discrepancy between approval and study population
In 2011, fingolimod had been approved for two therapeutic indications: for rapidly progressive severe RRMS and for highly active RRMS that had been pretreated with interferon beta. For these two patient groups, IQWiG had published a dossier assessment according to AMNOG in January 2012.
In this first assessment the problem had already occurred that participants with different types of RRMS had been included in the relevant study, and that the authorities had then limited the approval to specific, relatively small patient groups. Since the first approval and assessment, the manufacturer apparently conducted no further studies for the expansion of approval.
G-BA decides on the extent of added benefit
The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.
Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (13//10/14)
The European Commission has endorsed the recent Committee for Medicinal Products for Human Use (CHMP) positive opinion recommending the expanded use of Swiss drug major Novartis’ drug Gilenya (fingolimod) for adult patients with highly active relapsing-remitting multiple sclerosis (RRMS).
The indication expansion will now give clinicians the flexibility to use fingolimod in the highly active RRMS group, for patients needing to switch from interferons as well as glatiramer acetate (Teva’s Copaxone) and other DMTs.
Prior to the indication expansion, fingolimod, which generated sales of nearly $2 billion last year, was limited for use in those patients with highly active RRMS not responding to an interferon.
The European Commission approval was based on a favourable review of the long-term efficacy and safety data for fingolimod and comes three years after the initial licence was granted in March 2011. Fingolimod is now approved in 80 countries and it is estimated that more than 91,500 patients have been treated with fingolimod in clinical trials and in the post-marketing setting.
.Fingolimod is the only established oral therapy approved by the UK’s drugs watchdog the National Institute for Health and Care Excellence (NICE) for the treatment of highly active RRMS that is effective across four key measures of MS disease activity – relapses, MRI lesions, brain volume loss and disability progression, the drugmaker noted. Novartis says it will work with the relevant European funding bodies to ensure that patients who meet these new criteria are able to access fingolimod in the near future.
Novartis International AG announced new data showing that more patients with relapsing multiple sclerosis treated with Gilenya (fingolimod) achieved an average annual rate of brain volume loss within the range of those expected for healthy adults of a similar age vs. those patients taking placebo. People with multiple sclerosis experience shrinkage of the brain up to three to five times faster. This acceleration starts early in people with relapsing MS, even before symptoms are apparent.
"These data are impressive as they show that Gilenya slows brain volume loss in relapsing MS patients, an important indicator of disease activity," said David Epstein, Division Head, Novartis Pharmaceuticals.
Gilenya is an oral disease modifying therapy that works on four key measures of multiple sclerosis disease activity - relapses, MRI lesions, brain volume loss and disability progression.
Source: NASDAQ. (01/05/14)
Swiss drug giant Novartis said that the Committee for Medicinal Products for Human Use or CHMP has issued a positive opinion to expand the EU label for Gilenya (fingolimod) in relapsing remitting multiple sclerosis or RRMS.
The recommendation is to expand the label to include adult patients who have not responded to at least one disease-modifying therapy or DMT, including newly-approved oral DMTs. Gilenya is currently licensed in the EU for adult patients with RRMS who have not responded to treatment with interferons, or have rapidly evolving severe MS.
Novartis also announced new pooled analyses presented at the 66(th) American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania from the pivotal FREEDOMS and FREEDOMS II trials in multiple sclerosis or MS, confirming the consistent efficacy of Gilenya across four key measures of MS (relapse rates, MRI lesions, brain volume loss and disability progression). Addressing these four measures through effective treatment and disease management is important for improving the course of MS for patients.
The pooled analyses from the FREEDOMS and FREEDOMS II trials show that in patients with high disease activity previously treated in the past year, Gilenya demonstrated significant efficacy across the certain measures.
Gilenya reduced relapses (as measured by the annualized relapse rate) by almost half (48%) compared to placebo; new T2 lesion formation was reduced by 69% compared to placebo; Gilenya reduced the rate of brain volume loss by 46% compared to placebo; using a stringent six-month disability measure, Gilenya reduced disability progression by 45% compared to placebo.
Source: RTT News Copyright © 2014 RTTNews (29/04/14)
Differential effects of fingolimod on B-cell populations in multiple sclerosis
BACKGROUND: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells.
OBJECTIVE: To clarify the effects of fingolimod on B-cell populations in patients with MS.
METHODS: We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts.
RESULTS: The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells (CD38int-high), particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138+) among whole plasmablasts, in the patients treated with fingolimod.
CONCLUSIONS: The marked reduction of Ki-67+ memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138+ plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual patients.
Nakamura M, Matsuoka T, Chihara N, Miyake S, Sato W, Araki M, Okamoto T, Lin Y, Ogawa M, Murata M, Aranami T, Yamamura T.
Source: Mult Scler. 2014 Feb 13. & Pubmed PMID: 24526661 (18/02/14)