Highlights from the 65th American Academy of Neurology Annual Meeting

Several scientists and physicians from the Tisch MS Research Center of New York and affiliated International Multiple Sclerosis Management Practice attended the 65^th American Academy of Neurology (AAN) Annual Meeting in San Diego, CA from March 16-23, 2013.  Drs. Armistead Williams, Violaine Harris, and James Stark presented a series of research highlights from the conference during the April 1, 2013 lab meeting.  Notable conference presentations included:

ENIGM: A French Observational Study about Switching from Natalizumab to Fingolimod in Multiple Sclerosis

Session Presenter: Mikael Cohen, Nice, France

• When MS patients switch from natalizumab to another therapy, physicians have two interrelated goals: reducing PML risk without increasing relapse risk.
• This session discussed safety and efficacy results from a prospective study of 177 patients switching from natalizumab (Tysabri) to fingolimod (Gilenya) therapies.  Study subjects received an average of 36 natalizumab treatments prior to fingolimod initiation.
• The overall risk of at least one relapse for patients switching treatments in the study was 50%.  During the washout period, the risk was 25%, and during the first 6 months of fingolimod treatment, the risk was 35%.
• The duration of the washout period and the presence of natalizumab neutralizing antibodies were considered risk factors for a relapse.  In addition, a relapse during the washout period was associated with a relapse after fingolimod initiation.
• EDSS scores worsened during the washout period.

Early Initiation of Fingolimod Treatment Reduces the Recurrence of Disease Activity after Natalizumab Discontinuation in Multiple Sclerosis

Abstract Presenter: Joachim Havla, Munchen, Germany

• This poster outlined results from a retrospective study of patients switching from natalizumab to fingolimod treatments.  Differences in annualized relapse rate and gadolinium enhancing lesions were compared in patients who began fingolimod treatment less than or equal to 24 weeks after natalizumab discontinuation (fingolimod group, n=32) and patients who began fingolimod treatment more than 24 weeks after natalizumab discontinuation (therapy free group, n=11).
• 47% and 73% of patients in the fingolimod and therapy free groups had one or more relapses, respectively (annualized relapse rate 0.8 vs. 1.8, p=0.03). 
• In the fingolimod group, patients who started fingolimod treatment within 12 weeks of natalizumab discontinuation (n=10) had a lower annualized relapse rate than patients who began fingolimod therapy more than 12 weeks after natalizumab discontinuation (n=22) (annualized relapse rate 0.4 vs. 0.9).  However, this difference did not achieve significance.
• Significantly more patients in the therapy free group developed gadolinium enhancing lesions after natalizumab discontinuation.

Durable Efficacy of Alemtuzumab in Relapsing-Remitting Multiple Sclerosis Patients Who Participated in the CARE-MS Studies: Three Year Follow-Up

Session Presenter: Edward Fox, Round Rock, TX

• This session included follow up data from the year 3 extension of the CARE-MS I and CARE-MS II clinical trials (each 2 year studies comparing alemtuzumab and subcutaneous interferon beta-1a in RRMS patients).
• Efficacy Results: The annualized relapse rate was 0.13 for year 3, and the mean EDSS remained unchanged.  Only 20% of study participants required alemtuzumab re-dosing as a result of a relapse or new MRI lesions.
• Safety Profile: The 1% risk of immune thrombocytopenia (previously reported) persisted in the extension study.   The risk of thyroid disease (also previously reported) was found to be highest in year 3 (30%).  One case of neutropenic sepsis was observed.

Fingolimod-Effect on Brain Atrophy and Clinical/MRI Correlations in Three Phase 3 Studies–TRANSFORMS, FREEDOMS and FREEDOMS II

Session Presenter: Jeffrey Cohen, Solon, OH

• Based on previous studies, fingolimod appears to reduce the rate of brain atrophy by 32% as compared to placebo treatment.
• This effect on atrophy was seen within 6 months and occurred regardless of the presence of gadolinium enhancing or non-enhancing lesions at baseline.

Comparison of the Location of Cortical Grey Matter Lesions, Using DIR and PSIR

Session Presenter: Varun Sethi, London, United Kingdom

• Grey matter demyelination accounts for 59% of all brain demyelination by volume.  Of total grey matter demyelination, 15% is grey matter/white matter demyelination.
• Double inversion recovery (DIR) fluid attenuated inversion recovery (FLAIR) is inaccurate when classifying cortical lesions.  In this study, it was found to incorrectly represent juxtacortical lesions as cortical lesions.
• Overall, 3T MRI sequences cannot adequately identify cortical demyelination.  The dominant grey matter demyelination is subpial and, therefore, remains invisible.

Controversies in Neuroscience Plenary Session: Is the Evidence Sufficient to Give Vitamin D to Everybody in the General Population to Prevent Multiple Sclerosis?

Session Presenters: Pro: Alberto Ascherio, Boston, MA; Con: George C. Ebers, Oxford, United Kingdom

• Dr. Ebers supported vitamin D supplementation (daily dose 4,000 IU) in the general population.  He argued that vitamin D supplementation is safe (studies have shown that daily doses as high as 120,000 IU do not cause hypercalcemia), and similar regimens (i.e. smallpox vaccine and folate supplementation) were also resisted for years but are now commonplace.  Furthermore, a study in Norway found an interesting correlation between Vitamin D Receptor Resistant Rickets (VDRR) and MS.  VDRR occurs in an estimated 1 in 200,000 people.  In Norway, 3 people were diagnosed with VDRR, and in every case, each person also had MS.  The probability of independently developing both diseases is 1 in 32 x 10¹⁹.  Ebers argued that this association between vitamin D and MS is comparable to the association between folate and neural tube defects, and supplementing the general population with vitamin D from birth could eradicate MS.
• Dr. Ascherio argued against vitamin D supplementation in the general population until long term safety studies are conducted.  Vitamin D is a pleiotropic hormone and could have unexpected effects.  He cited studies of vitamin A supplementation as an example because vitamin A was shown to increase cancer risk in smokers, an unanticipated effect.

IL33 – A Biomarker for Clinically Isolated Syndrome



Session Presenter: Subramaniam Sriram, Nashville, TN

• This study identified the cytokine IL33 as a biomarker correlating with the initial demyelinating event in MS.
• Levels of IL33 RNA transcript in blood were 3000% greater in patients with clinically isolated syndrome (CIS) compared to controls.
• Progression to established RRMS was associated with a decrease in IL33 levels when compared to the CIS group.
• This study suggested that IL33 may be an initial response of the innate immune system in MS. 

Differential Loss of KIR4.1 on Oligodendrocytes and Astrocytes in Multiple Sclerosis Lesions

Session Presenter: Lucas Schirmer, Munich, Germany

• Antibodies against the inward rectifying potassium channel KIR4.1 are found in a subpopulation of MS patients suggesting a role of KIR4.1 as a target of the autoimmune response in MS.
• This study found that KIR4.1 was widely expressed in oligodendrocytes and astrocytes in the normal brain, but was lost in active lesions. 
• KIR4.1 immunoreactivity was restored in chronic lesions exhibiting scar formation, as well as in lesions undergoing remyelination.
• These findings are consistent with the idea of a primary immune response against KIR4.1 in at least a subset of MS patients.

ASIC1 Blockade in Primary Progressive Multiple Sclerosis: Evidence of Neuroprotection with Amiloride

Session Presenter: Tarunya Arun, Oxford, United Kingdom

• Converging evidence from basic science suggests that blockade of acid sensing ion channel1 (ASIC1) through amiloride, a potassium sparing diuretic, has neuro- and myelo-protective effects in experimental models of MS.
• This study tested the neuroprotective effect of amiloride in a cohort of 14 PPMS patients over a period of 3 years.
• Tissue loss as measured by MRI was decreased during the treatment phase, compared to the pre-treatment phase (p=0.018 corrected). Tissue damage measured by DTI was also reduced during the treatment phase (p=0.02 corrected).
• This pilot study is the first translational study on neuroprotection targeting ASIC1 in patients and supports further investigation of amiloride as a novel neuroprotective drug in MS.

Natalizumab Related PML: An Evolving Risk Stratification Paradigm

Session Presenter: John Foley, Salt Lake City, UT

• This researcher discussed correlations between demographic data and PML risk in MS patients on natalizumab (Tysabri).
• Natalizumab serum concentrations and receptor saturation are moderately correlated with PML cases.  Interestingly, factoring in patient body mass dramatically increases this correlation.
• In patients, natalizumab serum concentrations and receptor saturation appear to increase with treatment frequency and duration, suggesting that lengthening intervals between treatments may lower concentrations and mitigate PML risk.

Safety and Tolerability of BG-12 (Dimethyl Fumarate) in Patients with Relapsing–Remitting Multiple Sclerosis: An Integrated Analysis of Phase 2 and 3 Placebo-Controlled Studies

Session Presenter: J. Theodore Phillips, Dallas, TX

• This session outlined the safety profile of BG-12.  Results from phase 2 and phase 3 placebo-controlled studies were pooled.
• Discontinuation rate for BG-12 treated patients was 14% (similar to the placebo group).
• 30% of BG-12 treated patients experienced flushing during the first month of treatment.
• 20% of BG-12 treated patients experienced gastrointestinal events during the first two months.
• Renal protein levels were slightly elevated in BG-12 patients.
• Leukopenia occurred at a higher in rate in the BG-12 group.
• BG-12 treatment did not appear to increase risk of malignancies or opportunistic infections.
• 3 patients receiving BG-12 died during the study time periods, but none of these deaths were considered related to the study drug.

Gastrointestinal Tolerability Events in Relapsing–Remitting Multiple Sclerosis (RRMS) Patients Treated with Oral BG-12 (Dimethyl Fumarate) in DEFINE and CONFIRM

Abstract Presenter: Krzysztof Selmaj, Lodz, Poland

• This poster summarized gastrointestinal (GI) adverse events (AEs) in patients receiving BG-12 or placebo in the DEFINE and CONFIRM clinical trials.
• 769 patients were treated with BG-12 twice a day for two years; 771 patients received the matching placebo treatment.
• 40% of patients in the treatment group reported GI AEs, compared to 31% of patients in the placebo group.  The most common GI AEs included: nausea (9%), diarrhea (9%), upper abdominal pain (7%), lower abdominal pain (7%), and vomiting (5%).
• Most GI events were mild or moderate in severity and resolved within 3 months of treatment initiation.  Study discontinuation associated with GI AEs occurred infrequently (<1%, 1%, and 1% for abdominal/upper abdominal pain, nausea/vomiting, and diarrhea, respectively).

Week 144 Results of a Phase II, Randomized, Multicenter Trial Assessing the Safety and Efficacy of Ocrelizumab in Patients with Relapsing–Remitting Multiple Sclerosis (RRMS)

Session Presenter: Stephen Hauser, San Francisco, CA

• The speaker presented results from a phase II clinical trial of ocrelizumab in RRMS patients.  Results encompassed a total of 144 weeks (96 weeks of treatment, followed by 48 weeks of follow up).
• 220 patients initially enrolled in the study, and 168 patients remained in the study through week 144.  The initial 220 patients were randomized to one of the following treatment groups: IV ocrelizumab 600 mg, IV ocrelizumab 2000 mg, placebo, or open-label IM IFN beta-1a 30 μg.
• Ocrelizumab CD20 binding differed from that of rituximab.
• Safety results: Rates of adverse and serious adverse events in the ocrelizumab groups were similar to the placebo group.  4 patients in the study died, but only one death was considered possibly related to ocrelizumab treatment.
• Efficacy results: Patients receiving ocrelizumab displayed 89% and 91% reductions in new or enlarging T2 lesions compared to the placebo group and the IFN beta-1a group, respectively.  Further, patients receiving 2000 mg ocrelizumab had no gadolinium enhancing lesions at 96 weeks.  From weeks 96 to 144, 3 patients developed gadolinium enhancing lesions.