Highlights from The American Academy of Neurology’s Annual Meeting

Held in New Orleans (April 21-28, 2012)

Editor’s note: For easier reading, certain definitions have been included within the text and are often repeated throughout the article. Additionally, for easier reading, a brand name of an approved drug is used versus the generic name wherever possible.

Introduction

This year’s American Academy of Neurology (AAN) meeting was especially exciting for multiple sclerosis (MS) clinicians and researchers. Results were presented from clinical trials that have been ongoing for the past three-to-four years, many of which focus on the "new generation" of oral drugs for managing MS progression. Studies have looked at the effectiveness and safety of the new agents, particularly as compared to the standard injectible drugs that became available starting in the early 1990’s. Data on these new agents have been released gradually as the studies progressed through the clinical trials process, and anticipation of the details from completed studies has been building.

BG-12 (oral fumarate)
In the DEFINE Phase III study, BG-12 previously demonstrated significant reductions in the proportion of patients who experienced a relapse, in annualized relapse rate (ARR), and in disability progression, when compared to placebo in patients with relapsing-remitting MS (RRMS). These data were presented in late 2011 at the ECTRIMS/ACTRIMS meeting. (Please refer to MSAA’s online article for an overview of the ECTRIMS/ACTRIMS joint meeting highlights.)

MRI results from the DEFINE study were presented at this year’s AAN meeting and focused on brain atrophy (shrinkage) as well as lesion volume as seen on MRI. After two years, brain atrophy, as measured by a decrease in the volume of brain tissue, was much less extensive in the groups receiving BG-12 twice or three times per day ("BID" and "TID"), with reductions in brain atrophy of 30 percent and 17 percent versus placebo. There was also a significant reduction in MS-related lesion activity in the treated groups.

Clinical results were presented for the CONFIRM two-year Phase III study of 1,417 patients. The study compared BG-12 (given either twice per day or three times per day) against placebo and Copaxone® (glatiramer acetate) against placebo. The primary endpoint was the a

ARR (relapse rate) at two years; secondary clinical endpoints included the proportion of patients who experienced a relapse, and disability progression as measured by the Expanded Disability Status Scale ( EDSS). Both dosing regimens of BG-12 significantly reduced the ARR compared to individuals taking a placebo, by 44 percent and 51 percent, respectively. BG-12 reduced the risk of relapse by 34 percent (when taken twice per day) and 45 percent (when taken three times per day) versus placebo, while Copaxone reduced the risk of relapse by 29 percent versus placebo.

BG-12’s side effects were generally mild. These included skin flushing, stomach cramps, diarrhea, and vomiting, mostly during the first few weeks of treatment.

These clinical and MRI data further support the earlier clinical data from the DEFINE study. They suggest that BG-12 has the potential to be a valuable treatment option for people with RRMS.

Alemtuzumab (Lemtrada)
The much-awaited full results of the Phase III CARE-MS 1 and CARE-MS 2 studies were presented at the AAN. Early results were first released in the fall of 2011 at the ECTRIMS/ACTRIMS joint meeting.

   CARE-MS I:
The CARE-MS I study compared the clinical and MRI results of treatment with alemtuzumab, to treatment with subcutaneous interferon beta-1a (Rebif®) in patients with RRMS who had not received prior treatment with any disease-modifying therapies. Rebif was given according to the regular dosing of three times per week, while alemtuzumab was given intravenously for five days, and then a second time one year later for three days. CARE-MS I was a multicenter international trial. Data were collected for each patient during a two-year period from the time of the first infusion.

Clinical Results: The ARR (relapse rate) was 0.18 (or slightly less than one relapse every five years) for alemtuzumab-treated patients. This was as compared with 0.39 (or slightly less than one relapse every two-and-a-half years) for Rebif-treated patients. This means that alemtuzumab reduced the ARR 55-percent more than Rebif. The proportion of patients who were relapse-free was 77.6 percent with alemtuzumab compared to 58.7 percent with Rebif.

Alemtuzumab’s relapse reduction was significantly greater beginning the first year of study, with a relapse rate of 22 percent among alemtuzumab patients compared with 46 percent among individuals receiving Rebif. This relapse reduction further increased during the second year of study. Supportive analyses of the risk of severe relapses found that the risk was lower with alemtuzumab. Individuals taking alemtuzumab had a 64-percent reduction in severe relapses, and a 59-percent reduction in relapses requiring steroid treatment. The significant reduction in relapses with alemtuzumab compared with high-dose, high-frequency Rebif suggest that there is potential for alemtuzumab to be a meaningful addition to treatment options for RRMS.

MRI Results: These clinical data were supported by MRI outcomes. Through Year 2, fewer alemtuzumab patients developed new gadolinium-enhancing lesions (areas of active inflammation and myelin damage in the brain) than Rebif-treated patients (15.2 percent versus 27.2 percent). Additional positive MRI data favoriting alemtuzumab include the finding that alemtuzumab reduced median T1-hypointense lesion volume (lesions with lower intensity) more than Rebif from baseline to Year 2. The volume of lesions with lower intensity was reduced by 21.6 percent with alemtuzumab, versus 1 percent with Rebif. This MRI data supports the clinical benefits of alemtuzumab over Rebif seen in previous comparative studies.

   CARE-MS II:
CARE-MS II is the third study to compare alemtuzumab with Rebif (interferon beta-1a given subcutaneously). It was designed to evaluate the effect of alemtuzumab on relapse and disability as compared to Rebif in people with RRMS who had relapsed on prior therapy. The study design was the same as that in CARE-MS I. The co-primary efficacy endpoints were the ARR and time to six-month sustained accumulation of disability as measured by the EDSS disability scale.

The group treated with alemtuzumab showed a decrease in the mean EDSS score, versus a slight worsening of disability in those treated with Rebif. Approximately 29 percent of patients treated with alemtuzumab experienced a six-month sustained reduction in disability, as compared to 13 percent with Rebif.

Relapse data showed that 65 percent of patients treated with alemtuzumab were relapse-free at two years, as compared to 47 percent with Rebif. These data also showed a 49-percent reduction in relapse rate as compared to Rebif.

The adverse event profile was consistent with previous studies. A program to monitor for development of thyroid issues and immune thrombocytopenia was successful in early detection of these known complications from alemtuzumab. (Immune thrombocytopenia is a condition where the number of circulating platelets in the blood is reduced; symptoms include a tendency for bleeding and bruising.)

Based on the data from these studies, it is expected that alemtuzumab will be submitted to the United States Food and Drug Administration (FDA) as well as the EMA (the European equivalent of the FDA) to approve its use in treating RRMS. [Update: On June 12, 2012, the parent company announced that alemtuzumab had been submitted to both the FDA and the EMA for approval in treating relapsing forms of MS.]

Gilenya (fingolimod)
The Phase III TRANSFORMS study of 1,153 patients with RRMS compared Gilenya to interferon beta-1a. Clinically, 83 percent of those on Gilenya® were free of relapses as compared to 69 percent of the interferon beta-1a patients. There was no statistical difference between the groups in terms of disability progression. MRI measures showed 56 percent versus 49 percent to be free of new/enlarging T2 (more intense) lesions, and 90 percent versus 81 percent were free of Gd-enhancing T1 (less intense) lesions.

As has been the case for the interferons and Copaxone, a pregnancy registry is ongoing to determine the effects of Gilenya treatment on maternal, fetal, and infant health. This six-year multinational study will include up to 500 women who were exposed to Gilenya shortly before or at any time during pregnancy.

Based on data about cardiovascular risks, the United States prescribing information for Gilenya has been updated, adding new contraindications to treatment. These include a history or presence of cardiac conditions (such as myocardial infarction or stroke in the previous six months, second-and third-degree atrioventricular block, or other serious cardiac rhythm disturbances) or in patients treated with certain antiarrhythmic drugs. The updated prescribing information recommends that all patients starting treatment should undergo electrocardiography immediately before the first dose and at the end of the initial six-hour observation period, along with hourly measurement of blood pressure and heart rate.

(For more information on Gilenya, please refer to MSAA’s online news article, "New Prescribing Information for Gilenya.")

New S1P Receptor Modulators
Data were presented on two new investigational oral agents now in Phase II trials that have a mechanism similar to that of Gilenya (fingolimod). Both drugs were well tolerated and reduced lesions related to RRMS. It is hoped that these agents, ONO-4641 and siponimod (BAF312), will maintain or improve on the efficacy and safety of Gilenya. However, both were still associated with cardiovascular effects, such as bradycardia (slowed heart rate). No direct comparison to Gilenya has been reported as yet for these new agents.

  ONO-4641
In the Phase 2 DreaMS trial, led by the University of Colorado in Denver, 407 patients with RRMS were randomly assigned to placebo or one of three different doses of ONO-4641 (0.05 mg, 0.10 mg, or 0.15 mg once daily for 26 weeks). Patients were included if they had EDSS disability scores of up to 5.5, had two or more relapses during the two years before the trial, or one or more in the previous year, or one or more gadolinium-enhancing (active) lesions within the previous three months.

The primary endpoint was the number of T1 (less intense) gadolinium-enhancing lesions on MRI; secondary endpoints included new and enlarging T2 (more intense) lesions. All three treatment groups showed a substantial decrease in MRI disease activity as measured both by gadolinium-enhancing lesion numbers and new or enlarging T2 lesions. A reduction in the number of cumulative T1 lesions was seen from weeks 10 to 26 with each of the three drug doses relative to placebo. Compared to placebo, lesion counts were reduced by 82 percent in the 0.05 mg/day group; 92 percent in the 0.10 mg/day group, and 77 percent in the 0.15 mg/day group.

The study was not designed to evaluate relapse rates or disability progression, but there was a statistically significant decrease in relapse rate with the 0.10-mg dose. Most of the patients have gone on to an open-label safety extension phase (where everyone is taking the active drug and no one is on a placebo). More safety data will be gathered and the drug is expected to advance to a Phase III study.

Adverse events were similar to those seen with Gilenya, including bradycardia and lymphopenia (a reduction in circulating lymphocytes) in some patients. These were dose-related.

  Siponimod (BAF312)

Researchers at the University of Texas Southwestern in Dallas reported data from a Phase II dose-finding study of siponimod in patients with RRMS. Siponimod has a relatively short half-life compared to Gilenya, which means that the drug does not stay in the body as long. Researchers hope that this will minimize cardiac issues.

The trial had a complex design whose goal was to determine the most appropriate dosing regimen. One group of 188 patients received placebo or once-daily siponimod in doses of 10 mg, 2 mg, or 0.5 mg for six months. A second group of 109 patients were given one of two additional intermediate doses of 1.25 mg or 0.25 mg for three months. Patients completing the core study were eligible for a three-month extension.

At six months, the proportion of relapse-free patients as compared to placebo was 84 percent for the 10-mg group, 92 percent for the 2-mg group, and 77 percent for the 0.5-mg group. In the placebo group, 72 percent were relapse-free.

After six months, the ARR (relapse rate) was lower with the three higher doses than the two lower doses and placebo. Additionally, MRI findings indicated that treatment with siponimod was associated with a reduction in active lesions on MRI. The 2-mg dose reached statistical significance versus placebo, with a reduction in active lesions of approximately 80 percent.

Tysabri (natalizumab)
Tysabri is one of the eight FDA-approved disease-modifying therapies for relapsing forms of MS. A very small percentage of patients (approximately one in one thousand) taking this drug may develop progressive multifocal leukoencephalopathy (PML), a serious and potentially fatal condition. PML is caused by the activation of the JC virus (JCV), which typically remains dormant in those exposed to the virus, but may become active when the immune system is weakened (such as when taking a medication that suppresses the immune system). A blood test is now available to see if an individual has been exposed to the JC virus.

Three risk factors have been identified for developing PML. The risk factors (now added to Tysabri’s label) are:

• The presence of anti-JCV antibodies, which identifies a previous exposure to the JC virus
• Longer duration of Tysabri treatment, especially for more than two years
• Prior treatment with an immunosuppressant medication, such as mitoxantrone (Novantrone®), azathioprine (Imuran®), methotrexate, cyclophosphamide (Cytoxan®), or mycophenolate.

In a study of nine patients who discontinued the drug after testing positive for the JC virus, five experienced relapses within six months. Of those, three who returned to Tysabri and one who used an alternative therapy failed to return to the functional level they had while taking Tysabri.

(For more information on these risk factors and the test for JCV antibodies, please refer to MSAA’s online news article, "Antibody Test Identifies New Risk Factor for PML.")

Rituximab
Rituximab has previously been shown to be effective in treating RRMS. A small German study of 15 patients (11 with SPMS, one with PPMS, and three with neuromyelitis optica) tested this monoclonal antibody, which selectively depletes a specific subpopulation of B cells (a type of lymphocyte, which are immune-system cells produced to fight infection and disease) .

Primary endpoints were confirmed disease progression as measured by an increase in score on the EDSS disability scale and MRI indicators of progression. Secondary endpoints were ARR (relapse rate) and safety parameters. In all 15 patients, Rituximab reduced inflammatory brain lesions and clinical relapses. It also showed a stabilizing of EDSS and progression as indicated by MRI. This study was too small to provide statistical data, but testing in larger numbers of patients – especially those with PPMS rather than a mixture of diagnoses – would be of interest.

The Results of the CombiRx Trial Show No Added Benefit Over Treatment with the Individual Drugs

The CombiRx trial of Copaxone (glatiramer acetate) and Avonex (interferon-beta-1a given via intermuscular injection) combination therapy in RRMS has been ongoing since 2005, involved 1,008 patients with RRMS, and many have been waiting with much anticipation for the results to be announced. Since the two drugs have quite different mechanisms of action, it was hoped that combining them might yield a significant improvement in clinical response.

For the combination to be considered more effective, it had to be significantly superior to the more effective of the two monotherapy treatments (Copaxone and Avonex), and that was mostly not the case. Clinically, the combination did not outperform the individual drugs in rates of disability progression and time to first relapse. Changes on the Multiple Sclerosis Functional Composite (MSFC) did not differ between groups. (The MSFC is a scale that measures both lower and upper extremity function, as well as cognitive function.)

No differences were seen in the percentage of patients experiencing a relapse over the course of three years, or the time to first relapse, in patients treated with either drug alone or with the combination. In addition, the combination did not show an advantage over either drug alone in several key radiologic (MRI) measures, including brain atrophy, the volume of normal-appearing grey and white matter, and T2 lesions. The only area in which the combination was slightly more effective compared to either drug alone was in terms of new lesion activity visible on MRI and the accumulation of total lesion volume.

Ampyra
Ampyra™ (dalfampridine) is an oral, timed-release medication developed to improve the conduction of impulses between damaged nerves of the central nervous system (CNS). Ampyra was approved by the FDA in January 2010, after Phase III clinical trials showed that a greater number of individuals with MS experienced improvement in walking speed when taking Ampyra, compared to when taking a placebo. Ampyra is the first drug to be approved to increase walking speed in individuals with MS.

Its benefits continue to be observed in clinical trials for up to five years in an extension study. This study has 483 patients, all of whom participated in a late-stage clinical trial with Ampyra.

(For more information on Ampyra, please refer to MSAA’s online news article, "Ampyra™ Approved to Improve Walking for Individuals with MS.")

CCSVI (chronic cerebrospinal venous insufficiency)

The evidence continues to increase that occlusions (obstructions) of the vascular system (CCSVI) in cerebrospinal veins (certain veins located in the head and neck) imaged with ultrasound and magnetic resonance venography do not appear to be related to multiple sclerosis. Reports from an ongoing study at the University of Texas Health Sciences Center in Houston showed that people with and without MS had abnormalities consistent with CCSVI, and that this abnormality was not more common in people with MS. The group used strict ultrasound criteria definitions, and concluded that their tests – neurosonography and magnetic resonance venography – did not support the concept that CCSVI is causally involved in MS.

Shortly after the AAN meeting, the FDA issued an alert about risks, including death, associated with the surgical treatment of CCSVI. Further tests must be approved by the FDA for patient safety monitoring as well as rigorous measurement of any potential treatment effects. Further clinical trials are planned.

(For more information on CCSVI and the recent FDA warning, please refer to MSAA’s online news articles, "FDA Issues CCSVI Treatment Warning" and "CCSVI Update")

Written by Diana M. Schneider, PhD
Reviewed by Jack Burks, MD
Edited by Susan Wells Courtney