Subscribe to eTOC

CMSC Annual Meeting

Access daily, concise peer-reviewed reports from the CMSC Annual Meeting selected by the Neurology Today editors.

Saturday, May 30, 2015



INDIANAPOLIS—The benefits of alemtuzumab appeared to hold up in high-disability, treatment-refractory patients with relapsing-remitting multiple sclerosis (RRMS) no matter which medicine the patient was switched from, according to an open-label, phase 1 study presented here on Friday at the annual meeting of the Consortium of MS Centers.


The prospective analysis of data was designed to see how well longer-term results compared with shorter-term results, and whether any difference in outcomes could be seen based on the medicine the patient was taking before being switched to alemtuzumab.


Sixty patients were stratified into either short-term (a median of 10 months after treatment initiation, with a range of six to 25 months) or long-term follow-up (a median of 82 months, with a range of 27 to 104 months), with 30 patients in each group. The study also analyzed outcomes based on whether the patients received interferon beta, glatiramer acetate, fingolimod, or natalizumab immediately before and within the prior two-year epoch preceding treatment with alemtuzumab.


The long-term cohort had a median baseline Extended Disability Status Scale (EDSS) score of 5.5 (2.0–7.5) and Multiple Sclerosis Severity Score (MSSS) of 6.7 (1.7–9.6). The short-term cohort had a median baseline EDSS of 5.0 (2.5–7.0) and MSSS of 6.3 (1.3–9.9).


Following treatment with alemtuzumab, the scores on the disability scales went down, indicating improvement.  For example, the mean EDSS change in the long-term group was −1.0 (−4.0 to +2.0) compared with −0.4 (−4.5 to +1.5) in the short-term group. The mean MSSS change in the long-term group was −2.34 (−6.84 to +0.89), compared to −0.54 (−2.82 to +1.16) in the short-term group.  [For more data on scores based on prior medication, see “Disability Outcomes Based on Prior Medication.”]


The study concluded that in this cohort of 60 patients, short-term improvements likely become more prominent with long-term follow-up, and that the improvement favors treatment of high-disability, treatment-resistant MS. “Evidence supports ongoing long-term sustained disability improvement after more than five to eight years, regardless of prior immunotherapy,” the study authors wrote in the abstract.


While acknowledging that the study was not randomized and included no control group, the results should reassure clinicians that the benefits previously seen when switching from interferon beta are still substantial when switching from glatiramer acetate, fingolimod, or natalizumab, the presenting author said.


“The data mainly serves as a benchmark,” said Samuel F. Hunter, MD, a neurologist and president of Advanced Neurosciences Institute in Franklin, TN. “Doctors are very comfortable with the effects of alemtuzumab after failure of fingolimod or interferon. What’s less well known has been what happens when you switch from glatiramer acetate or natalizumab.”


Commenting on the study, John R. Corboy, MD, FAAN, a professor of neurology at the University of Colorado School of Medicine and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus in Denver, said the current study should be seen as proof of principle that patients who have failed multiple other drugs can potentially still take alemtuzumab and still see improvements.


“These were patients with relatively high disability scores, with active, ongoing, relapsing disease,” said Dr. Corboy, who was not involved with the study. “Based on this data, alemtuzumab appears to benefit them as a rescue drug, if you will.” Dr. Corboy also serves on the Neurology Today editorial advisory board.


The most important take-away from the study, he said, was that the mean EDSS scores of patients receiving alemtuzumab actually improved.


“If verified in larger studies, that would potentially be important,” Dr. Corboy said. “We typically measure percentage of patients worsening, although a few studies, including the pivotal phase 3 alemtuzumab trials, have shown modest improvements in disability. We’d also like to know if the patients actually feel they’re functioning better.


“It is important to note, however, that this was an unblended, uncontrolled study with no MRI or patient-reported outcome measures,” he added. “Thus, the findings should be viewed as preliminary in nature.”


As an investigator-initiated study funded by Genzyme Sanofi, Dr. Hunter said that he did most of the EDSS scoring himself, and that he did not expect that MRI data would have been informative. “People with high disability usually don’t have remarkable MRIs,” he said.


Dr. Hunter disclosed that he has received support from Bayer, Biogen Idec, Genzyme-Sanofi, and Novartis, including consulting fees, fees for non-CME services from commercial interests or their agents, and grant/research support.


Disability Outcomes Based on Prior Medication


For outcomes based on prior medication, the short- and long-term cohorts were combined:


  • After switching directly from interferon beta or glatiramer acetate, the mean EDSS change was −0.9 (n = 26, with a median follow-up of 82 months).
  • After switching directly from fingolimod, the mean EDSS change was −0.4 (n = 14, median follow-up of 12 months).
  • After switching directly from natalizumab, the mean EDSS change was −0.5 (n = 11, median follow-up of 49 months).



·         CMSC Annual Meeting Abstract: Alemtuzumab improves disability after switch from other disease-modifying therapies in a high-disability treatment-refractory relapsing multiple sclerosis cohort.

Saturday, May 30, 2015



INDIANAPOLIS—Peripheral blood samples of multiple sclerosis (MS) patients who develop lymphopenia while stably treated with dimethyl fumarate (DMF) show a marked and disproportionate drop in their CD8+ lymphocytes, according to a study that was presented here on Friday at the annual meeting of the Consortium of MS Centers.


Although lymphopenia was previously observed in about 5 percent of patients in the phase 3 trials on which Food and Drug Administration approval was based, subsequent data has suggested that the disorder may be even more common in clinical practice.


Earlier this year, one case of progressive multifocal leukoencephalopathy (PML) was reported. Investigators from Washington University in St. Louis set out to characterize the cellular populations most affected by the drug, about which little had previously been known.


They conducted a cross-sectional analysis of patient samples. Patients who had been stably treated with DMF for more than six months were classified as lymphopenic based on absolute lymphocyte counts of less than 800 (grade 2 lymphopenia or worse). Samples were collected from lymphopenic and non-lymphopenic patients treated with the drug, treatment-naive MS patients, and healthy controls. All samples were then phenotypically characterized using flow cytometry.


The researchers reported that multiple lymphocyte populations were reduced in lymphopenic patients, including CD4+ T cells and T-regulatory cells. However, the strongest effect was on CD8+ lymphocytes, which were almost entirely lost. In non-lymphopenic patients treated with dimethyl fumarate, CD4+ cells were not noticeably affected.


Because CD8+ cells are important for cell-mediated immunity and viral clearance, the researchers concluded that more studies are needed to determine whether the function of CD8+ lymphocytes is also impaired in patients treated with DMF.


Erin Longbrake, MD, a fellow in multiple sclerosis and neuroimmunology at Washington University, who presented the study, said that one reason that lymphopenia is being seen more often in practice than it was in the phase 3 trials is that it’s now being used in older patients who were not included in those trials. At Washington University, the older patients appear to be at increased risk of developing the disorder.


“Almost all doctors who treat MS now have a handful of patients who became lymphopenic and are struggling to understand what the best recommendations are for managing these people,” she said.


While the drug’s profile of risks and benefits was favorable in the published clinical trials, Dr. Longbrake said, “We don’t know what will happen when patients take these drugs for five to ten years. One has to be vigilant to be sure you’re not taken by surprise by any untoward complications of the medication. DMF is a valuable tool, but I don’t think we can take lightly that we’re modulating the immune system in ways we don’t fully understand yet. Ongoing monitoring of these patients is necessary.”


Aaron Miller, MD, FAAN, a professor of neurology at the Icahn School of Medicine at Mount Sinai and medical director of the Corinne Goldsmith Dickinson Center for MS at Mount Sinai Health System in New York, said the study raises a serious question for neurologists.


“What is the potential implication of carrying very low CD8 counts for a prolonged period of time?” he said. “I don’t think we know the answer. This kind of paper, plus the observation of the one PML case, gives us a general overall warning that when new drugs come on the market, we never know all we need to know about them. There are reasons to be cautious and to continue to explore mechanisms of action and biological properties that may contribute to adverse events.”


Dr. Miller, who was not involved with the study, added, “We have to be cautious and watch carefully for future developments. Hopefully the one case of PML reported so far will be one of very few.”




·         CMSC Annual Meeting Abstract: Dimethyl fumarate effects on lymphocyte phenotype.


·         Nieuwkamp DJ, Murk JL, van Oosten BW, et al. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med 2015; 372 (15): 1474-1476.


·         Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367 (12): 1098-1107.


·         Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367 (12): 1087-1097.

Saturday, May 30, 2015



INDIANAPOLIS—A post hoc analysis of combined data from the PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) and SPECTRIMS (Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon beta-1a in MS) phase 3 clinical trials of interferon beta-1a (IFNβ-1a) shows that its benefits continue to accrue to patients whose Extended Disability Status Scale (EDSS) scores are between 4.0 and 6.0, even when including subjects with secondary progressive MS, according to a presentation here yesterday at the annual meeting of the Consortium of MS Centers.


In an effort to inform the clinical debate as to whether treatment with the medication is appropriate for patients with more advanced disease, the study examined relapses, T2 lesions, and three-month confirmed progression (≥1 point EDSS increase) at years one and two in patients receiving IFNβ-1a 44 µg or placebo in a combined subgroup with EDSS 4.0–6.0.


The analysis found that IFNβ-1a (n = 171) reduced the annualized relapse rate versus placebo (n = 164) by 36.6 percent (RR 0.632 [95% CI 0.496-0.805]; p=0.0002) at one year and 36.2 percent (RR 0.638 [0.507-0.803]; p=0.0001) at two years in the combined EDSS 4.0–6.0 subgroup.


The presenter of the study said the results show that the medication remains useful for patients who have more disability, with an EDSS of 4 to 6. “There’s no reason to discount interferon beta, a tried and true, safe drug,” said Mark S. Freedman, MD, a professor of medicine and neurology and director of the MS Research Unit at the University of Ottawa.


He acknowledged that because the study is a post hoc analysis, the findings cannot be considered definitive. “It’s hypothesis-generating,” he said. “All we can say is that when we looked at relapses, progression, and MRI activity by combing the two studies, there was no obvious loss of signal in patients with more advanced disease. It still remains highly statistically significant, with one exception: It reduced disability progression at one year but not at two years, although it was trending.”


Timothy Vollmer, MD, FAAN, a professor and vice-chair of clinical research in the department of neurology at the University of Colorado Denver School of Medicine, commented that the study’s importance is in helping clinicians understand that the drug continues to work in patients with advanced disease.


He noted, however, that “interferons have very little to no effect on preserving brain volume. Newer drugs do. They’re not huge effects. But if they have more aggressive disease, I would use more efficacious drugs to preserve function and give them a better chance.”


Commenting on the study, John R. Corboy, MD, FAAN, a professor of neurology at the University of Colorado School of Medicine and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus in Denver, added: "It would have been important to know if there was any significant effect seen in those with progressive disease alone, as multiple studies suggest that the only progressive patients that benefit from treatment with any of the immunotherapies are younger patients with superimposed relapses and/or enhancing MRI lesions at baseline."    


The study was supported by EMD Serono, Inc., a subsidiary of Merck KGaA, and Pfizer Inc. Dr. Freedman’s disclosures included Bayer HealthCare (grant/research support); Novartis, Teva Canada Innovation, Sanofi-Aventis, Biogen Idec, EMD Serono (Canada), Genzyme, and Opexa (personal compensation).




·         CMSC Annual Meeting Abstract: Clinical and MRI efficacy of interferon beta-1a subcutaneously three times weekly in multiple sclerosis patients with more advanced disease (EDSS 4.0-6.0).


·         PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352 (9139): 1498-504.


·         Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon beta-1a in secondary progressive MS: clinical results. Neurology 2001; 56 (11): 1496-504.


·         Li DK, Zhao GJ, Paty DW, et al. Randomized controlled trial of interferon beta-1a in secondary progressive MS: MRI results. Neurology. 2001 Jun 12; 56 (11): 1505-13.

Friday, May 29, 2015



INDIANAPOLIS— Overweight and obese patients were more likely than those of normal weight to show a significant progression of their disease markers or symptoms of multiple sclerosis (MS) during five years of follow-up, according to a new study presented here as a poster today at the annual meeting of the Consortium of MS Centers.


Based on a review of case records for 150 patients at a single center, the retrospective analysis was the first study to examine the effects of body mass index (BMI) on progression of multiple sclerosis in adults. The findings echo those of recent studies showing that higher weight in youth is associated with both a greater risk of developing MS and an earlier age of onset. But because this and other studies have been observational rather than randomized trials, the results provide no insight into causality, let alone mechanism, said neurologists who reviewed the abstract for the Neurology Today Conference Reporter.


The study author agreed that the study has its limitations and needs to be followed up with a randomized prospective trial, but said that in the meantime, it provides useful clinical information for neurologists and patients alike.


“It’s 150 patients from a single center, and it’s retrospective,” said study author Aliza Ben-Zacharia, DrNP, ANP, MSCN, a nurse practitioner and neurology teaching assistant at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai Health System in New York. “But regardless of the limitations, it’s good, valid  information. Patients always want to be proactive and to be able to change the course of their disease and have some control. We can point to the data and suggest that patients with MS may consider participating in weight management programs and may schedule an appointment with a nutritionist for proper counseling.


“We don’t know yet if you lose weight, your risk goes down,” she added. “All we know for now is there is a remarkable association between weight, MRI, and [scores on] the Extended Disability Status Scale [EDSS]. I think that this is sufficient data to share with patients. Some patients will want to take ownership of the disease and enroll in weight management programs and lose the weight.”


Dr. Zacharia conducted a logistic regression analysis to determine the association between baseline BMI of 150 patients at her center and their MS progression over five years retrospectively as measured by EDSS, new lesions on MRI, relapse rate, and the Timed 25-Foot Walk (T25FW).


The mean age was 45.5 years; 79 percent were female; 68 percent were never smokers, and 77 percent had relapsing-remitting MS. The mean BMI was 27, with 27 percent of patients classified as overweight and 30 percent as obese.


After controlling for age, gender, race/ethnicity, disease duration, brain changes, number of relapses, and MS type, the patients’ odds of having an increased EDSS by at least one point was eight times greater in obese patients with mild disability compared to those with normal BMI (p=0.017).


The odds of having new brain MRI lesions was 6.2 times greater in overweight subjects (p<0.0001) than in subjects with normal BMI after controlling for potential confounders. But in a violation of any expected dose-response rate between weight and MS, the odds were only 2.6 times greater in obese subjects (p=0.048).


The odds of having at least one relapse in five years was 3.8 times greater (p=0.47) in obese patients than in their non-obese counterparts after controlling for gender and smoking history. The odds of having a 20 percent change on the T25FW were 1.1 times (p=0.040) greater for each increase of one unit of the baseline BMI after controlling for age, gender, and disease duration.


Commenting on the study, Aaron Miller, MD, FAAN, a professor of neurology at the Icahn School of Medicine at Mount Sinai and medical director of the Corinne Goldsmith Dickinson Center for MS at Mount Sinai Health System, said: “It’s a provocative finding that should lead to additional studies to better understand the nature of the relationship between body weight and MS. But it doesn’t tell us whether the body mass index is actually causing the worsening.


“It could be a marker of a genetic predilection that causes both increased weight and risk of MS,” said Dr. Miller, who was not involved with the study. “The big question is whether improving body mass would have any salutary effect on the course of MS.”


The relationship between weight and MS could be a case of reverse causality and needs to be explored further, said Dalia Rotstein, MD, MPH, an assistant professor of neurology at the University of Toronto.


“Advanced MS can lead to decreased activity which can cause obesity,” Dr. Rotstein said. “There is some evidence that leptin levels may be increased in MS, but again the causal direction of that relationship is unclear.


“I don’t think you can go wrong by recommending a healthy diet to patients," she said. "Without question, comorbidities like diabetes and cardiovascular disease can adversely affect MS progression. But I certainly wouldn’t recommend weight-loss drugs. We really need a stronger evidence base.”









Friday, May 29, 2015



INDIANAPOLIS—Physical and cognitive symptoms of key interest to multiple sclerosis (MS) patients improved significantly more over 96 weeks for those randomized to daclizumab high-yield process (DAC HYP) than for those who received intramuscular interferon beta-1a (IFNβ-1a), marketed under the trade name Avonex, according to new data from the DECIDE trial presented here today at the annual meeting of the Consortium of MS Centers.


The DECIDE study randomized 919 patients with relapsing-remitting MS to receive 150 mg of subcutaneous DAC HYP once every four weeks and 922 to 30 mcg of IFNβ-1a intramuscularly once a week. DAC HYP is a humanized monoclonal antibody that binds to CD25, a subunit of the IL-2 receptor of T cells.


The median improvement from baseline on the Multiple Sclerosis Functional Composite (MSFC) score was 0.091 (−0.096, 0.287) for DAC HYP versus 0.055 (−0.136, 0.240) for IFNβ-1a (p=0.0007). Significant differences in components of the MSFC score were seen on the Timed 25-Foot Walk (T25FW), the nine-hole peg test, and the paced auditory serial addition test.


On another measure of cognitive ability, the Symbol Digit Modalities Test (SDMT), the mean change from baseline over 96 weeks of DAC HYP was 4.08 (±12.40), compared with 2.89 (±12.71; p=0.0274) for IFNβ-1a.


“These are tertiary outcome measures, but in some ways they’re more reliable and reproducible than standard examinations,” said the presenting author of the paper, Michael D. Kaufman, MD, FAAN, a neurologist at the Cole Neurological Institute of the University of Tennessee in Knoxville.


“There’s a good deal of imprecision in measuring outcomes in MS, because the disease is so variable,” Dr. Kaufman told the Neurology Today Conference Reporter. The more outcomes for which you can show a benefit, the more confidence you have in the primary outcome measures. These results are very consistent with findings on the primary and secondary endpoints. If there’s one message here, it would be that in tests which are patient-driven yet still relatively objective, daclizumab outperformed Avonex across all subtests over 96 weeks.”


A neurologist who specializes in the treatment and study of MS said that while physicians tend to focus on MRI scans, relapses, and changes on exam, patients are much more interested in symptomatic improvement they can discern for themselves.


“For many years, we have been focusing mostly on outcomes as measured by the physicians,” said John R. Corboy, MD, FAAN, a professor of neurology at the University of Colorado School of Medicine and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus in Denver. “This study represents additional movement toward outcomes reported by and important to patients. Physical and cognitive function are clearly relevant to what patients care about.”


While improvement was greater for patients on DAC HYP, Dr. Corboy pointed out that they also improved overall on IFNβ-1a. “It’s been a struggle to identify functions that actually improve with medications, going all the way back to the beta interferons,” he said. “It’s nice to see improvements in both groups.” (Dr. Corboy also serves on the editorial advisory board of Neurology Today.)


Results on primary and some secondary endpoints of the DECIDE trial were first reported in April at the AAN Annual Meeting in Washington, DC. There, Ludwig Kappos, MD, chair of neurology at the University of Basel in Switzerland, reported that patients randomized to DAC HYP showed a 45 percent reduction in the annualized relapse rate over 96 to 144 weeks of treatment compared with those who received IFNβ-1a (p<0.0001). The proportion of patients who remained relapse-free at 96 weeks was 73  percent in the DAC HYP group compared with 59 percent on IFNβ-1a, a reduction of 41 percent (p<0.0001). Significant differences in favor of DAC HYP were also seen on MRI-defined lesions.


In the new results presented by Dr. Kaufman, significant differences were seen between the DAC HYP vs. IFNβ-1a groups for several tests:


  • The T25FW— 0.000 (−0.099, 0.083) compared with −0.017 (−0.124, 0.075; p = .0060);
  • the Nine-Hole Peg Test — 0.063 (−0.195, 0.356) versus 0.017 (−0.273, 0.291; p= .0016);
  •  the Paced Auditory Serial Addition Test-3 — 0.177 (−0.088, 0.530) versus 0.177 (−0.088, 0.442; p = .0411).

Raising a note of caution, Dr. Kaufman said: “It seems at this point that as you incur the efficacy, you also increase the risk. The art of medicine is going to be to determine, until we have a more rational basis, which patients merit the more efficacious drugs. I think it’s far from settled at this point. The moderately effective drugs have only been introduced in the past few years. We don’t yet know what their 10-year efficacy will be in large numbers of people.”


For now, Dr. Kaufman said, his clinical approach is patient-driven. “I try to present the risks and benefits of all the drugs, and have the patient involved in the decision,” he said. “There are people who start on interferon and continue to be stable on it. I wouldn’t switch people who have been stable. But I am using fewer traditional injectable therapies overall because I generally recommend the strongest treatment that has a reasonable risk of toxicities for the unique patient I’m caring for.”