A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis.

BACKGROUND: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. OBJECTIVE: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. METHODS: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1-4 hours on day 1 and 450-600 mg over 1-3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. RESULTS: In all cohorts (N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1-2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions (p = 0.003) and a 10.6% decrease in T2 lesion volume (p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). CONCLUSION: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.

B cell depletion with ublituximab reshapes the T cell profile in multiple sclerosis patients.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naïve CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naïve T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS.

Prospective, Multicenter, Randomized, Double-Blinded, Partial Crossover Study to Assess the Safety and Efficacy of the Novel Neuromodulation System in the Treatment of Patients With Chronic Pain of Peripheral Nerve Origin.

INTRODUCTION: Currently available central nervous system treatment strategies are often insufficient in management of peripheral neuropathic pain, prompting a resurgence of neuromodulation focused on peripheral pain. A new peripheral nerve stimulation device was investigated in a prospective, randomized, double blind, crossover study, looking specifically at efficacy and safety, with Food and Drug Administration oversight. METHODS: Prospective, multicenter, randomized, double-blind, partial crossover study to assess safety and efficacy. After IRB approval, patients were enrolled, implanted, and then followed for three months to assess efficacy and one year for safety based on Food and Drug Administration guidance. RESULTS: One hundred forty-seven patients were consented and screened for the study. Thirty-five did not meet inclusion or exclusion criteria. Ninety-four patients were implanted and then randomized to the treatment (45) or the Control group (49). The primary efficacy endpoint, three months after randomization to treatment, demonstrated that patients receiving active stimulation achieved a statistically significantly higher response rate of 38% vs. the 10% rate found in the Control group (p = 0.0048). Improvement in pain was statistically significant between the randomized groups, with the Treatment group achieving a mean pain reduction of 27.2% from Baseline to Month 3 compared to a 2.3% reduction in the Control group (p < 0.0001). During the partial crossover period, patients again demonstrated statistically significant improvement in pain relief with active stimulation compared to baseline. Further, the Treatment group had significantly better improvement than the Control group in secondary measures including but not limited to quality of life and satisfaction. Safety, assessed throughout the trial and with follow-up to one year, demonstrated no serious adverse events related to the device. All device-related adverse events were minor and self-limiting. CONCLUSION: The novel peripheral nerve stimulation device is a safe and effective treatment strategy to address neuropathic pain of peripheral nerve origin.

Alleviating flu-like symptoms with dose titration and analgesics in MS patients on intramuscular interferon beta-1a therapy: a pilot study.

OBJECTIVE: To determine the effectiveness of dose titration and choice of analgesic in reducing flu-like side effects of intramuscular interferon beta-1a (i.m. IFNbeta-1a). METHODS: Patients were randomly assigned to receive weekly i.m. IFNbeta-1a, with or without dose titration, plus acetaminophen or ibuprofen. After 27 patients had been randomized, the original formulation of i.m. IFNbeta-1a became unavailable and the remaining patients used a pre-packaged liquid formulation, necessitating a change in protocol from initially quarter-dose to half-dose titration. Patients scored presence and intensity of muscle aches, chills, and weakness, and measured body temperature; information was recorded in diaries. RESULTS: Forty-seven patients were enrolled; 36 completed the study. Fifteen patients received full-dose therapy plus acetaminophen, eight patients received quarter-dose titration and acetaminophen, 10 patients received quarter-dose titration and ibuprofen, eight patients received half-dose titration and acetaminophen, and six patients received half-dose titration and ibuprofen. The mean number of acetaminophen doses taken was not statistically different from the mean number of ibuprofen doses taken per patient per week in any dose-titration group over measured time intervals (p > 0.05). Symptom scores from acetaminophen and ibuprofen dose-titration groups were combined and compared with the no-titration group. The proportion of patients with a mean increase of > or = 2 from baseline in flu-like symptom score trended lower in the titrated group compared with the no-titration group at 4 hours and 12-15 hours post-injection; these differences reached statistical significance only during the first 2 weeks of treatment (p = 0.015, quarter-dose vs. no titration). CONCLUSION: This study supports the findings of previous studies demonstrating no difference in the effectiveness of acetaminophen and ibuprofen in controlling flu-like symptoms associated with IFNbeta treatment in patients with relapsing-remitting MS. Trends in this small pilot study suggest that the combination of initial dose titration and analgesic administration is useful for the reduction of flu-like symptoms with IFNbeta-1a therapy.

Rapid eye movement sleep behavior disorder in children with autism.

We performed nocturnal polysomnography on 11 children with autism who had symptoms of disrupted sleep and nocturnal awakenings. We identified rapid eye movement (REM) sleep behavior disorder in 5 of these 11 patients. Since REM sleep behavior disorder typically affects elderly males with neurodegenerative diseases, the identification of this phenomenon in autistic children could have profound implications for our understanding of the neurochemical and neurophysiologic bases of autism. Further, accurate diagnosis of REM sleep behavior disorder would enable specific treatment with clonazepam and help the family and the child consolidate sleep and improve daytime performance.