June 26, 2014

Results of More Than 1,250 Studies Shared at Global MS Research Meeting

Nearly 7,000 investigators convened in Lyon, France in mid-October to present findings at ECTRIMS (European Committee for Treatment and Research in MS), the world’s largest meeting dedicated to MS research. More than 1250 scientific presentations and display posters covered virtually every aspect of research to stop MS, restore function, and end MS forever. Among these were the latest results from trials of emerging therapies, possible risk factors, disease mechanisms, rehabilitation, CCSVI and much more.


STOPPING MS: Trials of potential therapies
There is an extensive pipeline of therapies in development for MS. Results from clinical trials in progressive MS were among the highlights of the conference. Among studies reported were first results from clinical trials of experimental treatments, and also follow-up safety and benefits of approved therapies, generally supporting and expanding on original findings of their benefit for treating MS. Of note:

  • Statin for secondary-progressive MS: Dr. Jeremy Chataway (University College London) presented first results from a phase II, two-year study of high-dose simvastatin (a therapy for high cholesterol) involving 140 people with secondary-progressive MS, based on the possibility that this drug may protect against nervous system damage. Statins had previously been tried in relapsing MS with mixed results. Those who took 80mg of simvastatin, versus those who took placebo, showed nearly 40% less brain volume reduction (atrophy), and also had slower clinical progression. It was generally well tolerated, with some reporting muscle cramps and some showing an increase in liver enzymes. The investigators suggest that a phase III trial of simvastatin is warranted. (Abstract 38a)
  • Teriflunomide: Results of the TOWER study, the second phase III study to be completed in relapsing-remitting MS, were presented by Dr. Ludwig Kappos (University of Basel) on behalf of the international group that conducted the trial for Genzyme, a Sanofi company. Compared to placebo, the 14mg dose of teriflunomide (recently approved in the US as Aubagio®) reduced relapse rate by 36.3% and reduced the risk of disability progression by 31.5%. The most common adverse events included headache, liver enzyme elevations, hair thinning, diarrhea, nausea and reduction of white blood cells (neutropenia). (Abstract 153)
  • New treatment approach: AIN457 (secukinumab) is a monoclonal antibody given by monthly IV infusion which is being developed by Novartis. Dr. Eva Havrdova (Charles University, Prague) presented results of a small proof-of-concept trial in 73 people with relapsing-remitting MS, asking whether the molecule could reduce disease activity as seen on MRI compared to placebo over 20 weeks. AIN457 neutralizes an immune messenger called interleukin-17A, which has been implicated in MS disease activity. She reported that the infusions decreased active lesions MRI scans significantly over placebo. Those on the therapy had higher infection rates, but none were classified as severe. A followup clinical trial is planned. (Abstract 168)
  • Combined phase III results of BG-12: Combined results of two phase III, 2-year studies of oral BG-12 (Biogen-Idec), which had been published separately suggest this potential therapy for relapsing-remitting MS provides substantial benefits, including a 49% reduction of relapses and 30 to 32% reduction of the risk of progression, compared to inactive placebo. The trials were designed to be analyzed together. The most common adverse events were flushing and gastrointestinal events such as diarrhea, nausea, and upper abdominal pain. BG-12 reduced white blood cell counts but no infections were reported. Liver enzyme tests were elevated in the DEFINE study, but there were no reports of significant liver injury or liver failure. (Abstract 151)
  • Tysabri in progressive MS: Dr. J. Romme Christensen (University of Copenhagen) presented results from a small, unblinded clinical trial of Tysabri® (natalizumab, Biogen Idec and Elan) infusions in 24 people with primary-progressive MS or secondary-progressive MS over 60 weeks. The investigators sought evidence of effectiveness not just with MRI scans and clinical measures, but also by looking at key components in spinal fluid that are possible indicators of inflammation and nervous system tissue damage. This may be a new way to shorten clinical trials in progressive MS. In 17 who completed the study, they found signs in spinal fluid of possible benefit, and also found slowing in the rate of brain tissue loss (atrophy). There are known potential adverse events related to the use of Tysabri but the investigators did not identify any new safety issues. (A large, phase III trial in people with secondary-progressive MS is underway.) (Abstract 170)
  • Reduced frequency Copaxone: Dr. Omar Khan (Wayne State University, Detroit) presented findings from a one-year, phase III trial testing glatiramer acetate (Copaxone,® Teva Pharmaceuticals) or placebo injected under the skin 3 times per week at double the approved dose in relapsing-remitting MS. This long-approved MS disease-modifying therapy is normally taken every day. The results suggest that at this dosing regimen, the therapy reduced relapses by 34.4% and reduced the occurrence of MRI-detected MS lesions, an impact generally comparable to the approved, every-day dosing schedule. The dose was well tolerated, but produced injection-site reactions often seen with the approved dose. The team is continuing to follow participants to gather further data. (Abstract 166)
  • “Biosimilars”: In some parts of the world, people with MS are not given access to approved MS therapies or may be given substitutes, called biosimilars, which have not been tested to determine whether they truly do have similar biological effects as the therapy for which they are substituted. In a study supported by Biogen Idec, distributor of Avonex® (interferon beta-1a, given by intramuscular injection once per week), a biosimilar called Jumtab® (Probiomed) was tested for indirect indicators of biological activity. In this small study over about two years, 80.6% of those on Avonex versus 31% on Jumtab experienced flu-like symptoms which are associated with interferon activity, and also showed greater activation of another indicator of interferon activity (neopterin). These results, which require a larger study to confirm, suggest that biosimilars should be tested for their impact against MS. (Abstract P1006)

STOPPING MS: Understanding the disease
Understanding underlying processes involved in MS and how it impacts people is an important aspect of efforts to stop MS in its tracks:

  • Gut biome: Dr. Lloyd Kasper (Dartmouth University) and colleagues presented new data on ways that bacteria in the intestines may influence immune activity. The team, funded by the National MS Society, investigated the power of molecule called polysaccharide A (PSA) that is released by specific species of bacteria in the intestines. The team showed that PSA given orally can reduce the effects of the MS-like disease EAE in mice, by stimulating regulatory cells shown to be impaired in people with MS. In immune cells cultivated in lab dishes, PSA can increase the conversion of immune responses to anti-inflammatory by stimulating these regulatory cells. (Abstract P339) View a video of Dr. Kasper and others describing MS risk factors
  • Does MS always Progress?: Drs. Melih Tutuncu, Orhun Kantarci (Mayo Clinic, Rochester) and others asked whether everyone with relapsing MS eventually develops secondary-progressive MS. Studying a large population of people with different types of MS, they found that whether a person has primary-progressive MS or secondary-progressive MS, the average age of progression is about 45 years of age. They also found that the risk of developing progression in a person with relapsing MS drops after age 45, and predicted that some 38% of people with relapsing MS will never go on to develop progression. The team noted that understanding the underlying biology of why some people don’t progress may lead to interventions to prevent progression in others. (Abstract 128)
  • Gender differences: An international collaboration called the MS Base is a worldwide online registry that tracks people with MS. A presentation focused on differences between males and females who have MS. The team reported, based on an evaluation of 16,633 patients in the registry, that males with relapsing-remitting MS begin at the same level of symptoms as females, but develop more severe disease and move more quickly to the secondary-progressive phase. In those with primary-progressive MS, males and females tend to progress at equal rates. (Abstract P230)
  • Possible immune target in MS: Rajneesh Srivastava, Dr. Bernhard Hemmer (Technische Universität, Munich) and colleagues discovered signs of an immune response to a protein called “KIR4.1,” which is found on several types of brain cells, in the serum of 47% of people with MS who were tested. Further research is needed to confirm these findings, and to understand what the role of this protein may play in MS and its potential for developing new treatments. (Abstract 74) Read more

RESTORING FUNCTION: Nervous System Repair
Several platform and poster display presentations focused on efforts to stimulate nervous system repair, and finding ways to better track MS disease activity and progression to speed clinical trials of repair strategies:

  • Repairing myelin: Dr. Catherine Lubetzki (INSERM, Paris) reviewed the state of efforts to repair myelin in MS, noting that studies suggest that prompt myelin repair can protect nerve fibers from degeneration. There are generally two approaches to repair myelin: efforts to transplant replacement cells, and efforts to improve that brain’s natural repair mechanisms. Dr. Lubetzki noted that the second approach has seen the most progress recently, as we learn more and more about signals that either inhibit or promote myelin regrowth. Both are potential targets for myelin repair, and at least one is entering clinical trials (anti-LINGO). (Abstract 90)
  • Factors in MS damage and recovery: In an invited talk, John Dystel MS Research Prize winner Dr. Richard Ransohoff (Cleveland Clinic) described cells called macrophages that are key players in both causing nervous system damage and also clearing it up to permit tissue repair. Some are derived from cells within the brain and some enter from the bloodstream, and each has different roles. This work is shedding important new light on new strategies to treat MS. (Abstract 73)
  • “On” switch for myelin-making cells?: National MS Society grantee Dr. Gareth John (Mt. Sinai School of Medicine) and collaborators described a series of studies that led to the discovery of a molecular switch, called KLF6, that controls whether myelin-making cells either mature or die, suggesting it could be a potential target to promote myelin formation and repair. (Abstract 93) Watch a video interview about this and other work related to nervous system protection and repair

Some exciting information is emerging related to the ability of rehabilitation to not only help restore function to people with MS, but also in relation to how it may help “re-wire” the brain to compensate for areas impacted by the disease. Several presentations highlighted progress being made in efforts to enhance rehabilitation in MS:

  • Brain stimulation: Dr. L. Leocani and colleagues (University of Milan) tested whether deep brain magnetic stimulation could enhance the benefit of rehabilitation on walking in people with spasticity due to progressive MS. Eleven people undergoing rehabilitation received the real stimulation, while 10 received sham stimulation, for 3 weeks following their rehabilitation sessions. Both groups showed improvement, but only those who had received real magnetic stimulation experienced improved walking speed and endurance. The investigators suggest this technique is feasible but needs a larger trial. (Abstract 162)
  • Computerized training for attention: Dr. M.P. Amato (University of Florence) conducted a controlled trial of computer-assisted rehabilitation of attention, one feature of cognitive impairment, in people with MS. They recruited 103 people with signs of attention problems. A portion received the specific computerized program for attention training and some received a non- specific computerized program as treatment. After participating at home twice a week for three months, they underwent evaluation, which showed that the intervention improved complex attention in those who used the specific program for attention training. (Abstract 117) Watch a video about research on cognition in MS
  • Electrical stimulation in rehabilitation: Drs. S. Newcome, Kathleen Zackowski and colleagues (Johns Hopkins University) described the use of electrical stimulation of muscles during cycling exercise as a rehabilitation strategy to improve walking. As a preliminary step, they reviewed cases of 14 people with secondary-progressive MS who had electrical stimulation, and found signs that this enhanced their walking improvement. The team is now conducting a clinical trial of this technique. (Abstract P1043) Watch a video with Dr. Zackowski discussing this work
  • Rehab increases brain connections: In a small study by Dr. N. Petsas and other researchers in Italy and the UK, rehabilitation training of a person’s dominant hand was shown to increase brain reorganization and connections in 20 people with MS. The team evaluated brain networks with functional MRI, which allows tracking of brain activity while a person is undertaking a task and also during a resting state. They found that training increased indicators of brain connectivity at rest, suggesting that areas of the brain reorganize to contribute to recovery in MS. (Abstract P856)

There were 21 studies reported that focused on CCSVI. Research into this phenomenon continues, including the launch of a clinical trial in Canada.

  • Italian prevalence study: One study reported results from a 35-center observational study in Italy of the prevalence of CCSVI using Doppler ultrasound with blinded (without knowledge of diagnosis) technicians and assessments. Dr. Giancarlo Comi (San Raffaele Hospital, Milan) led a team of trained sonographers and neurosonography expert readers. The confirmed diagnosis of two or more CCSVI criteria were found in 3.26% of 1165 people with all types of MS; 2.13% of 376 healthy controls, and 3.1% of 226 people with other neurological diseases. (Abstract 167)
  • Combined review: The Canadian CCSVI Systematic Review Group presented an analysis that combines results of multiple published studies related to CCSVI. They looked at 14 studies that used ultrasonography to determine the frequency of CCSVI in people with MS and control populations. Results have been mixed, but their review found a significant association between CCSVI and MS versus healthy controls. The researchers note that because varying methods were used and many studies lacked blinding, no definite conclusion can be reached. (Abstract P1086)
  • Texas prevalence study: Dr. Jerry Wolinsky (University of Texas Health Science Center, Houston) and team reported results from a prevalence study of CCSVI in 206 people with MS and 70 non-MS participants, which was among studies supported through a collaboration between the National MS Society and the MS Society of Canada. Ultrasound investigations conducted under blinded conditions found alterations consistent with CCSVI in 3.88% of the MS and 7.14% of the non-MS subjects, a difference that was not statistically significant. They also used other imaging technology including magnetic resonance venography, which also did not reveal significant differences in people tested. (Abstract P628)
  • Dehydration key?: Medical student Claudio Diaconu and colleagues at Cleveland Clinic who are conducting a National MS Society-supported CCSVI study conducted a separate study in which 11 people with MS and 5 non-MS controls fasted from food and drink for 12 hours before undergoing Doppler ultrasound evaluation for CCSVI. They then drank a 1.5-liter sports drink to replenish their fluids and then re-tested. Before hydration, 7 out of 16 met two or more criteria that define CCSVI. After hydration, only 2 out of 7 still met criteria for CCSVI. These results suggest that studies of CCSVI should standardize the state of hydration among participants, and also offers one possible explanation for the mixed results of reported CCSVI studies. (Abstract P627) View a video interview with this team
  • Registry: The British Columbia Ministry of Health in Canada funded the establishment of a registry to capture experiences of people with MS who have undergone venoplasty procedures to treat CCSVI. Preliminary results of the registry, which began in December 2011, were reported by the team, based on interviews of 80 people:
    • Most had venoplasty alone, and a few had venoplasty and stent placement
    • 49 reported that their limbs felt warmer after treatment
    • Compared to before the procedure, 52.6 % felt their health was somewhat or much better, and 47.5% felt their health was the same, worse or much worse
    • 66.3% reported their fatigue was somewhat to much better, 32.6% reported it to be the same or worse
    • 11.3% reported complications related to the procedure, the most common being pain; 14% reported complications within the first month of the procedure. (Abstract P626)

Progress was reported in efforts to understand how genes help make people susceptible to developing MS, as well as other factors that contribute, including exposure to Epstein-Barre virus, exposure to sunlight/levels of vitamin D, and cigarette smoking. Finding out what triggers MS will lead to possible ways of preventing it. Highlights included:

  • Lifestyle Risk/Protective Factors: Confirming a previous study in women, Swedish investigators Dr. L. Alfredsson (Karolinska Institute, Stockholm) and colleagues reported that being overweight before age 20 is associated with increased risk for developing MS in both men and women. The investigators speculate that controlling obesity in adolescents may reduce the incidence of MS. (P 714) In a separate presentation, the team reported that eating fatty fish, with relatively high vitamin D content, one to seven times per week slightly lowers the risk of developing MS, especially for those who receive low sunlight exposure. (Abstract P371)
  • Benefits of Vitamin D: Dr. Alberto Ascherio (Harvard University, Boston) and international colleagues analyzed data on vitamin D levels in participants of the BENEFIT study, which had tested Betaseron® (interferon beta-1b, Bayer Healthcare) in people with a first neurological episode (CIS) not yet diagnosed as definite MS. The original study had shown that Betaseron over 2 years could delay the time to conversion to clinically definite MS compared with placebo. In this vitamin D study, the team found that those with higher serum vitamin D levels were less likely to convert to MS, and also showed benefits in MRI scans and progression, on top of benefits provided by the active therapy. (Abstract P831)

These and many other presentations reflect the rapid pace of progress in understanding and treating multiple sclerosis.

Source: National MS Society (USA)