ARTICLE IN BRIEF
MS experts recommended as noteworthy new papers on MS pathology, an assay on detection of JC virus antibodies, dalfampridine for improved gait, and the effectiveness of alemtuzumab compared to standard interferon treatment.
TORONTO—How can MRI lesions help clinicians predict a possible course of multiple sclerosis (MS) progression? How far along is an assay to detect JC virus in people taking natalizumab? How effective is a new oral therapy to improve gait? And how does alemtuzumab compared to standard interferon therapy? These were among the questions addressed in new papers, which MS experts identified as most “noteworthy” from this year's AAN annual meeting in April.
PATHOLOGY OF LESIONS
In a pathology study, Claudia F. Lucchinetti, MD, chair and professor of neurology at the Mayo Clinic in Rochester, MN, reported that active lesions in the brain are uncommon in chronic MS, while inactive lesions predominate in chronic progressive disease.
“This study provides important new information about the relationship between the type of plaque and duration and course of MS,” said John Corboy, MD, professor of neurology at the University of Colorado-Denver and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus, who selected this as a clinically important paper.
The investigators reported that heterogeneous immunopatterns of lesions are evident early in the course of disease when active plaques are more frequent, but are also observed in established active MS, whereas chronic progressive disease is characterized by homogeneity in immunopattern of MS lesions.
Using paraffin tissue from 143 MS autopsies, the investigators characterized demyelinated activity lesions as one of four types: active, smoldering, inactive, and shadow. They identified 2,479 plaques: 881 active, 379 smoldering, 863 inactive, and 356 shadow. A retrospective review was conducted on course of disease and correlation with plaque type.
“Smoldering plaques were more likely to be associated with progressive MS and longer disease duration, while active plaques were associated with relapsing MS,” he continued. The strong negative correlation between active plaques and disease duration supports the concept that inflammation cools off over time in MS. The larger question is the relationship between active inflammation and disease progression. This is a big controversy among MS experts, Dr. Corboy said.
BLOOD ASSAY FOR JC VIRUS
Dr. Corboy also highlighted as important a study of a Biogen-developed assay that detects the presence of JC virus antibodies in the serum and plasma of MS patients. About 40- to 50 percent of blood samples from 800 MS patients were seronegative and 40- to 50-percent were seropositive for anti-JC virus antibodies. The presence of distinct populations who are seropositive and seronegative for the virus is consistent with reports in healthy volunteers, Leonid Gorelik, PhD, a scientist at Biogen Idec, reported here. The study also showed that blood samples of all 11 MS patients who developed progressive multifocal leukoencephalopathy (PML) on natalizumab treatment and had sera stored before the use of natalizumab were seropositive for JC virus antibodies before treatment with natalizumab.
Commenting on this abstract, Dr. Corboy said: “The ultimate utility of this test, if it is validated and performs well, would be for risk stratification of MS patients being considered for natalizumab treatment. If they are seronegative, they would be at no, or little risk for PML, but if they are seropositive, they may have a risk of PML that is substantially higher than the 1:1,000 presently noted in the package insert,” Dr. Corboy explained.
Aaron E. Miller, MD, medical director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai School of Medicine and professor of neurology at the Mount Sinai School of Medicine in New York, cited as important a pooled analysis of three placebo-controlled studies (one Phase II study and two Phase III studies) that found that treatment with dalfampridine 10 mg twice daily improved performance on the Timed 25-foot Walk test by an average of 25 percent from baseline in patients with severe gait impairment. The three studies enrolled a total of 806 MS patients with severe impairment as measured by the EDSS. The analysis presented at the AAN meeting included 631 patients (394 on dalfampridine and 237 on placebo). The primary endpoint of the study was Timed Walk Response (TWR).
“This drug is effective for walking in some patients with significant gait impairment, and it maintained its effect in an extension trial,” Dr. Miller commented.
Andrew D. Goodman, MD, director of the MS Center at the University of Rochester, reported at the meeting that “TWR was sensitive to the treatment effect of dalfampridine. The effect was consistently reproducible across all three studies.” Dr. Goodman, who led some of the clinical trials that led to the drug's FDA approval, said the TWR rate was 37.3 percent in the dalfampridine-treated group versus 8.9 percent in the placebo group (p>.001). In responders, average improvement from baseline was 25.3 percent, while non-responders performed similarly to placebo. “This indicates that the TWR criterion effectively separates treatment effects from unrelated changes,” Dr. Goodman said.
Serious adverse events were reported in 5.5 percent of those who received dalfampridine and 2.1 percent of the placebo group. One patient in the active treatment group suffered a seizure.
Anecdotally, Dr. Goodman said that patients with weakness and spasticity are more likely to respond preferentially to dalfampridine than those with ataxia, but this has not been studied.
Timothy L. Vollmer, MD, professor of neurology at the University of Colorado Health Sciences Center, co-director of the Rocky Mountain MS Center at Anschutz Medical Center, and medical director of the Rocky Mountain MS Center in Aurora, highlighted four-year data on alemtuzumab as clinically important.
The data from the randomized CAMMS223 [Campath-1H in Multiple Sclerosis] trial were strikingly positive for the benefits of alemtuzumab in patients with relapsing-remitting MS. Those data showed superiority for alemtuzumab versus standard treatment with interferon beta-1a (Rebif) for freedom from clinically active MS — patients were relapse-free and had no progression on the Expanded Disability Status Scale (EDSS) throughout the study. Among patients on alemtuzumab at four years, 71 percent were free from clinically active MS versus 35 percent on interferon beta-1a (p<.001).
Looking at these parameters separately, at four years, 91 percent of alemtuzumab-treated patients were free of sustained accumulation of disability compared to 68 percent of those in the standard treatment arm, and 77 percent of those treated with alemtuzumab were relapse-free compared to 48 precent of those taking standard treatment.
“These data may set a new bar for clinical outcomes in MS,” according to the lead investigator of CAMMS223, Omar Khan, MD, professor of neurology at Wayne State University School of Medicine in Detroit, MI.
“Alemtuzumab continues to appear to be one of the most effective drugs we have to stop the inflammatory attack on the central nervous system that characterizes MS. However, it looks like this drug will be complicated to use, because it can trigger other autoimmune disorders,” Dr. Vollmer said.
He pointed out that the known consequences of alemtuzumab include autoimmune thyroiditis in up to 30 percent of MS patients, and rare cases of Goodpasture's syndrome [acute glomerulonephritis and pulmonary alveolar hemorrhage] and idiopathic thrombocytopenic purpura including at least one death. •