Highlights from the American Academy of Neurology’s 2015 Annual Meeting

Clinical Trials

Daclizumab HYP – The DECIDE Trial of RRMS

Daclizumab high-yield process (HYP) is a new therapy that has been studied in relapsing-remitting multiple sclerosis (RRMS). It is a humanized monoclonal antibody against CD25, a receptor on T cells that is thought to become activated in MS. Daclizumab is believed to work by selectively targeting these activated T cells without causing general T-cell depletion.

This therapy results in a “reversible modulation” of the immune system. This means that while the medication alters the immune-system response to slow the attack caused by MS on myelin and nerves (axons) of the brain and spinal cord, it does so without causing permanent changes to immune system function. DECIDE was a randomized, double-blind, active-controlled study (“active-controlled” denotes that the control group was given an existing treatment that has already been shown to be effective, versus a placebo, which has no active ingredients). This study compares DAC HYP 150mg injected subcutaneously once every four weeks, to intramuscular interferon once weekly. The primary endpoint was the annualized relapse rate (ARR). A total of 1,841 patients were randomized into the study.

Treatment with DAC HYP versus interferon resulted in a 45-percent reduction in the ARR and a 41-percent reduction in the proportion of patients who relapsed. MRI outcomes were also positive favoring DAC HYP as this agent brought about a 54-percent reduction in the number of new/enlarging T2 lesions (more intense lesions, which are areas of inflammation). Furthermore, DAC HYP reduced the risk of confirmed disability by 16 percent. The benefits of this drug compared to interferon were seen in many subgroups of patients – men, women, both older and younger than 35, and irrespective of prior treatment with interferon. The authors concluded that DAC HYP demonstrated superior efficacy compared with weekly interferon across key clinical, radiographic, and patient-reported MS outcome measures in relapsing MS patients.

A variety of side effects and adverse events were seen with this agent. Infections, significant skin reactions, and liver effects were observed. The side-effect profile and safety issues will warrant careful monitoring if this medication is approved.

Immediately following the AAN meeting, the United States Food and Drug Administration (FDA) accepted for review the Biologics License Application (BLA) requesting marketing approval of Daclizumab HYP for relapsing forms of MS. If approved, this will be marketed under the brand name Zinbryta™.

Gilenya® (fingolimod) – The INFORMS Trial of PPMS

Gilenya is an FDA-approved oral treatment for MS that blocks lymphocytes from exiting lymph nodes and reaching the nervous system. It is approved for RRMS, and was studied in a large, randomized, double-blind, placebo-controlled trial called INFORMS, to assess efficacy in patients with primary-progressive MS (PPMS). A novel primary composite endpoint was used, based on increase in disability as measured by the Expanded Disability Status Scale (EDSS), the 25-Foot Timed-Walk Test (T25FW), and the 9-Hole Peg Test (9-HPT). Other key endpoints were the formation of new lesions and percent brain volume change (PBVC), or brain atrophy (the shrinking or reduction of brain volume).

INFORMS was a three-year trial that randomized 970 patients, and was adequately powered (that is, enough patients were included and enough measurements were made) to assess the primary endpoint. Unfortunately, none of the endpoints were met. Gilenya did not prevent the accumulation of disability in patients with PPMS any greater than placebo. Furthermore, PBVC did not differ between the Gilenya and placebo groups.

Unsurprisingly, given this agent’s success in preventing relapses and new MRI lesions in RRMS patients, there were fewer new MRI lesions seen in the Gilenya-treated patients. The safety results were generally consistent with fingolimod in prior MS trials. It is disappointing that Gilenya did not significantly slow disease progression in PPMS. These findings have important implications for the understanding of PPMS, and will no doubt allow researchers to refine how PPMS is studied moving forward.

MD1003 – High-Dose Biotin in Progressive MS

Biotin is a vitamin involved in key steps of energy metabolism and fatty acid synthesis, though most people think of it as being “good for hair and nails.” Among other actions, biotin activates an enzyme in myelin synthesis. Using this hypothesis and building upon data from a small, open-label pilot study, MD1003, a high-dose biotin preparation of 300 mg/day, was studied in a Phase III trial of patients diagnosed with secondary-progressive MS (SPMS) or PPMS. (This dose is hundreds of times higher than what can typically be purchased as a supplement of this vitamin.) In a relatively small study, 154 patients were randomized to high-dose biotin or placebo.

The primary endpoint of the study was defined as the proportion of patients who improved at nine months, with a confirmation of the improvement at 12 months. Improvement was defined as either a decrease in EDSS (Expanded Disability Status Scale) or an improvement in T25FW (timed 25-foot walk) of at least 20 percent.

The primary endpoint was met, with 12.6 percent of patients in the MD1003 arm showing an improvement of EDSS or T25FW at nine months and confirmed at 12 months, compared to none of the patients in the placebo arm. The primary endpoint was supported by secondary analyses showing evidence for a decrease in the risk of disease progression. These numbers are encouraging, although it is important to note that the decrease in disability experienced by the MD1003 group, and the disease progression seen in the placebo group, were both so small, they would be virtually undetectable in clinical practice. MD1003 was well tolerated. The overall incidence of adverse events was similar across the two groups. One patient treated with MD1003 died from suicide; however, this event was not considered to be related to the drug.

These results suggest a possible therapeutic effect of high-dose biotin in progressive MS, and merit further study. Though this trial gives initial support for its potential use, a larger trial will need to be done to truly understand whether biotin is an effective treatment in progressive MS. Noting that the dose of biotin studied would require taking hundreds of commercially-available pills of this vitamin, it is certainly not recommended that patients begin such a regimen at the present time. Studies also need to determine if any toxic effects could result from taking such high doses of this vitamin.

Neuroprotection in Optic Neuritis

Anti-LINGO-1 – The RENEW Trial

Anti-LINGO-1 is an agent under investigation for its potential remyelinative properties, after animal studies showed that it blocks this protein responsible for stopping the growth of myelin. Agents aimed at remyelination would repair or regrow myelin, the protective covering of the nerves, which is damaged by MS.

RENEW was a Phase II, randomized, double-blind, placebo-controlled, study of Anti-LINGO-1 in subjects experiencing their first episode of acute optic neuritis (AON). An equal number of subjects were randomized to receive either a placebo or anti-LINGO-1 (100 mg/kg) once every four weeks for six total doses. Follow-up extended 12 weeks after the last dose.

The primary outcome of RENEW was an assessment of recovery of optic-nerve function measured by the speed at which the nerve conducts visual signals. This was studied by evaluating a test called Full Field Visual Evoked Potential (FF-VEP) in participants treated with anti-LINGO-1, compared with placebo. Patients who were treated with at least five of the six doses of anti-LINGO-1 showed a 34-percent improvement in optic-nerve conduction latency (delay in the speed of the visual signal) at week 24, compared with placebo. Further recovery in optic-nerve conduction was observed at the last study visit (week 32), with a statistically significant 41-percent improvement. Together, the data demonstrate evidence of treatment effect with continuous improvement observed 12 weeks following the last study dose. There was no effect on key secondary endpoints, including actual recovery of visual function.

These data are the first evidence of functional remyelination in patients treated with anti-LINGO-1, and justify further study in the ongoing SYNERGY trial, in which 396 subjects with active RRMS or SPMS will be randomized to intravenous (IV) infusions of this experimental medication or placebo. All subjects will also receive once-weekly injections of Avonex. Results will provide clinical information about this drug’s efficacy for neuroprotection or repair within the central nervous system (CNS), which consists of the brain, spinal cord, and optic nerves. The results will also address two fundamental questions: 1) Are the effects seen in the optic neuritis study replicable in other areas of the nervous system? And 2) Does this translate to improved function in patients with MS either in the short or long term?

Phenytoin in Acute Optic Neuritis

Phenytoin is an anti-epileptic medication that has been available for decades. It has also been shown to be neuroprotective in experimental models of inflammatory demyelination. A Phase II clinical trial assessed whether phenytoin could be neuroprotective in acute optic neuritis (AON). The study was comprised of 86 people with AON randomized within two weeks of symptom onset to receive either phenytoin (4 mg/kg/day) or placebo for three months. The primary outcome of this AON study was an evaluation of the structure of the retinal nerve fiber layer (RNFL) and macular volume (MV) at six months. Visual function, optic-nerve imaging, and visual evoked potentials were also measured.

Of the original 86 participants, 81 were followed to study end. In these patients, the average adjusted affected eye RNFL thickness at six months was higher in the active group versus placebo, resulting in a 30-percent protective-treatment effect. Adjusted MV (macular volume) showed a 34-percent protective-treatment effect. Vision generally recovered well, with no significant difference in visual outcomes between the treatment groups.

This is an intriguing study that may have broad implications, as it found that the administration of a well-known, relatively safe drug seemed to be neuro-protective in the period directly following optic neuritis. Similar to anti-LINGO-1, further studies will need to be done to clarify whether this effect is translatable to other areas of the nervous system and whether this will, in turn, lead to preservation of neurologic function.

Long-Term Extension Studies

Lemtrada® (alemtuzumab) – Update from the Care MS II Extension for RRMS

Lemtrada is a monoclonal antibody given by IV infusion that was approved by the FDA in 2014 for the treatment of relapsing MS. In the CARE-MS II trial, Lemtrada had superior benefit versus subcutaneous interferon beta-1a, including improved MRI outcomes over two years, in RRMS patients who had relapsed on prior therapy. A total of 393 (92.9 percent) CARE-MS II Lemtrada-treated patients entered the extension study; data are available through four years from the first treatment, and follow-up is ongoing. Through four years, 67.7 percent of patients received only the initial two courses of treatment, 24.2 percent received the initial two treatments plus one additional course, and 7.4 percent received the initial two treatments plus two additional courses. In Year 3 and Year 4, almost 90 percent of patients were free of new gadolinium-enhancing lesions, and two-thirds of patients did not have new T2 lesions.

Aubagio®’s (teriflunomide) 14-Year Extension Study for RRMS

Aubagio is a once-daily oral immunomodulator approved for the treatment of RRMS. In the core Phase II study, patients with relapsing MS were randomized equally to Aubagio 14mg, Aubagio 7mg, or placebo. After completing the 36-week core study, patients could enter the long-term open-label extension. In the extension, patients who were taking one of the two doses of Aubagio continued on their same therapy; those previously treated with placebo were reallocated in equal numbers to Aubagio 14mg or 7mg.

Of the 179 patients originally randomized, 147 entered the extension study. Including treatment in the core and extension studies, patients received Aubagio for up to 576 weeks (11 years). During the study, annualized relapse rates (ARR) remained low in both groups, and the percentage of patients free from relapse during the extension was greater in the 14-mg group (51.5 percent) versus the 7-mg group (39.5 percent). Patients had minimal increases in EDSS score following up to 528 weeks (more than 10 years) of treatment. No new/unexpected adverse events were identified following long-term Aubagio treatment, and the safety and tolerability profile was consistent with other clinical studies.

Although long-term extension trials are always limited by the fact that patients who are doing well on a particular treatment are more apt to stay on it, this study provides support for the use of Aubagio — one of the more recently approved therapies — over the long term. Relapse rates remained low in both treatment groups that were followed up to 12 years, and patients in both groups had minimal progression, similar to what was seen in the Phase III trials.

Data on Treatment Decisions

Anti-JCV Antibody Index in Tysabri® (natalizumab)-Treated Patients

Multiple risk factors are now known for developing Tysabri-associated progressive multifocal leukoencephalopathy (PML), a viral brain infection caused by the JC virus. These risk factors include the presence of anti-JCV antibodies, prior immunosuppressant use, and duration of Tysabri treatment — especially beyond two years. In previous analyses, the anti-JCV antibody index was able to differentiate the risk of PML in patients who were positive for the anti-JCV antibody, but without a history of immunosuppressant use.

This current analyses involved data from clinical studies and post-marketing sources as of March 2014. Data were available for 101 Tysabri-treated PML patients with blood samples collected six months prior to PML diagnosis. For patients with no history of immunosuppressant use, with anti-JCV antibody index at or below thresholds of 0.9 to 1.5, PML risk was approximately 0.1 to 0.2 per 1,000 patients during the first two years of Tysabri treatment; it ranged from 0.5 to 1.1 per 1,000 patients who had taken Tysabri for more than two years and up to four years; and from 0.6 to 1.4 per 1,000 patients who had taken Tysabri for more than four years and up to six years. For patients with no history of immunosuppressant use with an index greater than 1.5, PML risk was approximately 1.2 per 1,000 patients during the first two years of Tysabri treatment, 8.8 per 1,000 patients between two and four years, and 10.1 per 1,000 patients between four and six years.

Consistent with previous findings, this updated analysis suggests the anti-JCV antibody index may differentiate PML risk in anti-JCV antibody positive patients with no history of immunosuppressant use. Patients with a JC index less than 1.5 maintained a low risk for developing PML over the course of the study, as opposed to those with a high index where the risk was seen to increase greatly over time.

Data on Discontinuing Treatment

“Doctor, can I stop my medicine?” – Analysis of disease course after stopping disease-modifying therapy in stable MS patients

Little data are available on MS disease course after disease-modifying treatment (DMT) discontinuation. MSBase, a 30,000-patient global, observational MS registry, provides a unique opportunity for such a study. Patients were included who, at the time of DMT discontinuation, were: 40 years of age or older; had no relapses and a stable EDSS for five or more years; were on DMT continuously for three or more years; and, after stopping DMT, were followed for three or more years. Predictors of when patients would restart their DMT, as well as time-confirmed progression of disability, were analyzed.

A total of 198 (65.4 percent) of 303 eligible patients restarted DMT following discontinuation after only one month, on average. The rate of restarting DMT decreased by 25 percent for every 10-year increase in age, meaning that the older patients were less likely to restart their DMT as quickly as the younger ones. Patients who restarted DMT experienced a 46-percent reduction in the rate of subsequent three-month confirmed disability progression, versus those who did not restart their treatment.

Overall, the authors concluded that high rates of DMT restart occurred in this group of stable, older MS patients who discontinued DMT. Younger age (within this group of older MS patients) and lower EDSS predicted an increased rate of restarting treatment. Importantly, even in this group of stable patients, DMT restart was associated with reduced rates of disability progression.

It is important to note that in the years following DMT discontinuation, there was evidence in a large percentage of patients for either relapse or progression despite five previous years of good disease control. Knowing the time when someone who is clinically stable “no longer needs to be treated” remains elusive, and more work will need to be done before evidence can guide a decision to stop a DMT.

Epidemiology, Environmental Factors, and Disease Course

The GEMS Project – Genetics and Environment in MS

Investigation of MS prevention requires early identification and understanding of the incidence in the high-risk population. The Genes and Environment in Multiple Sclerosis (GEMS) project has a goal of early detection in first-degree relatives of MS patients. Each subject submits saliva for targeted genotyping and completes detailed web-based questionnaires that capture demographics and risk factors. For each subject, a weighted genetic and environmental risk score (GERS) was calculated. It includes 64 genetic variants, as well as the individual’s gender, whether or not he or she had infectious mononucleosis, and if the person has a history of smoking.

By leveraging patient-advocacy groups and social media, the GEMS investigators were able to recruit more than 2,600 first-degree relatives from across the United States. In an analysis of the initial 1,696 subjects (1,583 without symptoms and 113 with MS at enrollment), investigators found that 27 percent of the individuals with MS and 25 percent of the asymptomatic subjects have a history of infectious mononucleosis, both doubling that of the general population. This higher proportion of infectious mononucleosis in asymptomatic family members is not attributable to known MS-genetic susceptibility. MS subjects have a significant excess of current smokers than asymptomatic subjects. Four out of the initial 1,583 asymptomatic subjects developed MS after enrollment, providing an incidence estimate (123 cases per 100,000 first-degree relative annually) 30-times greater than the incidence of sporadic MS in the United States. The average follow-up duration of the study was two years.

The GEMS study highlights the role of electronic communication, e.g., using social media and web-based questionnaires, in rapid and large-scale subject recruitment of first-degree relatives. It also provides a first estimate of the incidence of MS among this high-risk population, critically informing the design of a prospective study of high-risk family members. Identification of patients at the highest risk for MS may lead to opportunities for intervention before the condition becomes clinically apparent.

The Microbiome and MS

The vast collection of organisms that inhabit the human gut, the microbiome, has been demonstrated to influence immune responses and modulate susceptibility to chronic diseases. Recent studies have related gut dysbiosis (an imbalance of bacteria) to Crohn’s disease, type 1 diabetes, obesity, and autism. Additionally, animal model work suggests an important role in MS.

The Multiple Sclerosis Microbiome Consortium (MSMC) is a multi-disciplinary collaboration composed of two translational MS Centers (Mount Sinai and UCSF). Together, they have initiated a microbiome-oriented basic/experimental program and sequencing/bioinformatics Core. The MSMC is currently analyzing hundreds of samples by bacterial DNA sequencing aimed at identifying group differences at the genus-level. Tracked variables include demographics, Body Mass Index (BMI), medical history, MS clinical course and phenotype, disease-modifying therapy, and diet. The MSMC has successfully implemented IRB-approved protocols to recruit MS patients and controls, as well as to process and analyze their blood and stool samples.

Initial results show significant genus-level differences in the microbiomes of patients treated with Copaxone® (glatiramer acetate) compared to untreated subjects. Female patients showed significant enrichment of members of the Enterobacteriaceae family of bacteria, compared to gender-matched controls. Geographical differences were noted as well. Strikingly, when transferred into germ-free mice, gut microbiota from an MS patient resulted in more severe EAE (a mouse model of MS) than microbiota from a healthy control. This may be the most intriguing result from this project to date. Observed differences between cases and controls suggest a biological effect and warrant further investigation, as do effects of geographic, demographic, and dietary factors. Study of the human microbiome has the potential to yield important insights in understanding the pathophysiology of MS as well as possible treatment strategies.

A separate study of microbiome in MS looked at differences in Vitamin D levels predicting alterations in gut bacteria. Analysis of 43 subjects showed increased abundance of a type of helpful bacteria called Ruminococcaceae in untreated MS patients with a serum Vitamin D level above 40 ng/mL, versus patients with a Vitamin D level below 40. The authors conclude that high levels of Vitamin D in untreated MS patients are associated with increased amounts of Ruminococcaceae in the gut. This has relevance to MS, as a decreased amount of Ruminococcaceae has previously been associated with Crohn’s disease. Hence, lower amounts of Ruminococcaceae might be linked to increased inflammation in MS. Further studies are underway to explain the mechanism by which Vitamin D regulates the composition of the microbiota in MS.

The Association between Coffee and MS

Caffeine intake has been associated with reduced odds (or risk) of Parkinson’s and Alzheimer’s diseases, but previous studies done on caffeine consumption and MS risk have been inconclusive. The study team, led by Ellen Mowry, used two population-based case-control studies – a case-control group from Sweden and a case-control group from Northern California – to look for an association of coffee consumption prior to disease onset with the odds of developing MS.

In the Swedish cohort, consuming at least six cups of coffee daily over the course of one year was associated with an adjusted odds ratio (OR) for MS of 0.67, which represents a modestly reduced risk of developing MS. In the Northern California study, among those who consumed four or more cups of coffee daily prior to the year of the study, the odds ratio for MS was also 0.67. It is important to note that the study finding was only significant at the highest levels of coffee intake. Also, no association was found for other types of caffeine. The study authors postulated that coffee may have a direct immunomodulatory effect, although it is possible that this association is present due to other unmeasurable factors. Further work will be needed to investigate this association, and it is not yet recommended that people (with or without MS) commence drinking six cups of coffee per day.

A New Model of MS Disease Course

The “Topographical Model” of MS was proposed by Dr. Krieger as a way of visualizing disease course in a more individualized way than the typical simple graphs of relapsing or progressive forms of MS. This model is based on the observation that it is difficult to apply our current disease-course categories – RRMS, SPMS, and PPMS – to individual patients, and that even when someone has an apparently progressive disease, progression can take a variety of forms and sometimes stop altogether.

Instead of these separate categories, the Topographical Model proposes encompassing the mix of factors underlying the MS disease course in a unified way across a pattern of relapses, progression, both, or neither. “Topography” refers to mapping the locations in the nervous system where MS has caused damage, and from where an individual’s symptoms are derived.

The model itself was depicted as a series of 3D animated videos, showing the emergence of signs (such as lesions) and symptoms of MS above a “clinical threshold,” where a physician can observe changes… as well as lesions that can be seen on MRI but don’t cause obvious symptoms, as existing “under the threshold,” so that a physician could not observe changes. Progression is depicted as that threshold slowly drops, representing a loss in function that can occur in progressive disease. It also helps to show why during episodes of fever, or being overheated, patients may often experience a worsening or return of many of their same prior MS symptoms. In this model, these symptoms are transiently being “revealed” (in these 3D animated videos) above the clinical threshold during periods of depleted reserve, and then recede back under the threshold when the fever resolves.

The model depicts one’s disease course in a clinically nuanced way that complements the clinical-course categories. It attempts to capture the broad range of experiences of the disease – the unique “disease topography” experienced by an individual person – so that clinical course can be shown and understood to a more personalized degree. The Topographical Model remains to be empirically tested, and may have clinical research implications.

Please see MSAA’s MS Research Update for additional details on the FDA-approved disease-modifying therapies, experimental treatments, and other MS research. For more information or to speak with a trained Client Services Specialist, please call MSAA’s Helpline at (800) 532-7667, extension 154. Questions to MSAA’s Client Services department may also be emailed to MSquestions@mymsaa.org.

Written and compiled by Stephen Krieger, MD and Michelle Fabian, MD
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer
Edited by Susan Wells Courtney, MSAA Senior Writer and Creative Director

Editor’s note: MSAA does not endorse or recommend any specific products or therapies. Readers are advised to consult their physician before making any changes to their medication, diet, exercise, or other treatment regimen. Initial study results from therapeutic agents under investigation should be considered as preliminary, since additional studies and/or evaluations may be needed to prove the safety and efficacy of these agents. Please note that the different lengths of text dedicated to each topic should in no way be considered as favoritism toward any one product. The information given in this article is just a sampling of various highlights from the AAN meeting.