Alfred Sandrock

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study

BACKGROUND Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis. METHODS 257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701. FINDINGS Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. INTERPRETATION The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

Anti-JC Virus Antibodies: Implications for PML Risk Stratification

A study was undertaken to establish an enzyme‐linked immunosorbent assay (ELISA) to detect JC virus (JCV)‐specific antibodies in multiple sclerosis (MS) patients, and to evaluate its potential utility for identifying patients at higher or lower risk (ie, risk stratification) of developing progressive multifocal leukoencephalopathy (PML).

Benefit of interferon β-1a on MSFC progression in secondary progressive MS

BackgroundInterferon &bgr;-1a (IFN&bgr;-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFN&bgr; preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFN&bgr;-1a slowed disease progression in SP-MS. MethodsA total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFN&bgr;-1a (60 &mgr;g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). ResultsMedian MSFC Z-score change was reduced 40.4% in IFN&bgr;-1a subjects (−0.096 vs −0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFN&bgr;-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFN&bgr;-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFN&bgr;-1a–treated subjects. ConclusionsIFN&bgr;-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS.

Background: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. Methods: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. Results: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. Conclusion: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite

Background: Visual dysfunction is one of the most common causes of disability in multiple sclerosis (MS). The Multiple Sclerosis Functional Composite (MSFC), a new clinical trial outcome measure, does not currently include a test of visual function. Objective: To examine contrast letter acuity as a candidate visual function test for the MSFC. Methods: Binocular contrast letter acuity testing (Sloan charts) was performed in a subgroup of participants from the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT Substudy) and in MS patients and disease-free control subjects from a cross-sectional study of visual outcome measures (Multiple Sclerosis Vision Prospective cohort [MVP cohort]). High-contrast visual acuity was measured in both studies; MVP cohort participants underwent additional binocular testing for contrast sensitivity (Pelli–Robson chart), color vision (D-15 desaturated test), and visual field (Esterman test, Humphrey Field Analyzer II). Results: Contrast letter acuity (Sloan charts, p < 0.0001, receiver operating characteristic curve analysis) and contrast sensitivity (Pelli–Robson chart, p = 0.003) best distinguished MS patients from disease-free control subjects in the MVP cohort. Correlations of Sloan chart scores with MSFC and Expanded Disability Statue Scale (EDSS) scores in both studies were significant and moderate in magnitude, demonstrating that Sloan chart scores reflect visual and neurologic dysfunction not entirely captured by the EDSS or MSFC. Conclusions: Among clinical measures, contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli–Robson chart) demonstrate the greatest capacity to identify binocular visual dysfunction in MS. Sloan chart testing also captures unique aspects of neurologic dysfunction not captured by current EDSS or MSFC components, making it a strong candidate visual function test for the MSFC.

Interferon β‐1a for early multiple sclerosis: CHAMPS trial subgroup analyses

The objective of this work was to assess the effect of interferon β‐1a (Avonex®) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High‐Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30μg interferon β‐1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem–cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon β‐1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem–cerebellar syndromes, and spinal cord syndromes.

Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS

Natalizumab (Antegren™, Elan Corp. plc.; Biogen Idec.) is the first α4-integrin antagonist in the class of selective adhesion molecule inhibitors and is in Phase III clinical trials for the treatment of multiple sclerosis. After a 300 mg intravenous infusion, natalizumab has an elimination half-life of 6 to 9 days, but α4-integrin receptors expressed on the surface of peripheral blood leukocytes are more than 80% saturated approximately 1 month postinfusion. Therefore, natalizumab is given as a 300 mg dose administered monthly. Preliminary efficacy results showed a marked reduction (~90%) in the formation of new gadolinium-enhancing lesions and reduced the number of patients with relapse by 50% in patients with relapsing–remitting or secondary progressive multiple sclerosis receiving natalizumab versus those receiving placebo over a 6-month period. In clinical studies, natalizumab has demonstrated a favorable safety profile. Pivotal Phase III studies of natalizumab as monotherapy and in combination with intramuscular interferon-β-1a are underway in patients with relapsing–remitting multiple sclerosis. Natalizumab may be an important addition to the therapeutic armamentarium for multiple sclerosis.

Anti‐John Cunnigham virus antibody prevalence in multiple sclerosis patients: Baseline results of STRATIFY‐1

A study was undertaken to define the prevalence of anti‐JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false‐negative rate of a 2‐step anti‐JC virus antibody assay.

LINGO-1 and its role in CNS repair

LINGO-1 is selectively expressed in the CNS on both oligodendrocyte precursor cells (OPCs) and neurons. Its expression is developmentally regulated in the normal CNS, as well as up-regulated in human or rat models of neuropathologies. LINGO-1 functions as a negative regulator of oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration. Across diverse animal CNS disease models, targeted LINGO-1 inhibition was found to promote neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and improved functional recovery. The targeted inhibition of LINGO-1 therefore presents a novel therapeutic approach for the treatment of neurological diseases.