J. A. Cohen

Dose comparison trial of sustained-release fampridine in multiple sclerosis

Objective: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS). Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. Results: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more “consistent responders” in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. Conclusions: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.

Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis

Objective: To evaluate concurrent and predictive validity for low-contrast letter acuity (L-CLA) testing as a candidate visual component for the Multiple Sclerosis Functional Composite (MSFC). Methods: L-CLA testing was conducted in two MS patient cohorts. In the MSFC Validation Study, 137 participants from a Phase III trial of inteferon beta-1a (Avonex) for relapsing–remitting MS were followed. A second cohort included 65 patients with secondary progressive MS who participated in a substudy of the International MS Secondary Progressive Avonex Controlled Trial (IMPACT). The total number of letters read correctly at four contrast levels (100, 5, 1.25, and 0.6%) was correlated with Expanded Disability Status Scale (EDSS), MSFC, Sickness Impact Profile, Multiple Sclerosis Quality of Life Inventory, and brain parenchymal fraction (BPF), as determined by MRI. Results: Low- and high-contrast letter acuity scores correlated with BPF at follow-up in the MSFC Validation Study (5%: r = 0.40, p < 0.0001; 100%: r = 0.31, p = 0.0002). L-CLA also correlated with EDSS (5%: r = −0.35, p < 0.0001; 1.25%: r = −0.26, p = 0.0003) and MSFC (5%: r = 0.47, p < 0.0001; 1.25%: r = 0.45, p < 0.0001). In the IMPACT Substudy, change in L-CLA scores from baseline to year 1 predicted subsequent change in the EDSS from year 1 to 2 at the 5% (p = 0.0142) and the 1.25% (p = 0.0038) contrast levels, after adjusting for change in MSFC scores from baseline to year 1. Conclusions: Low-contrast letter acuity (L-CLA) scores demonstrate concurrent and predictive validity in patients with relapsing–remitting and secondary progressive multiple sclerosis (MS). L-CLA testing provides additional information relevant to the MS disease process that is not entirely captured by the Multiple Sclerosis Functional Composite.

Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study

Objective To determine the safety of sustained-release 4-aminopyridine in subjects with mutiple sclerosis (MS) and to examine dose-related efficacy up to 40 mg twice daily. Method Multicenter, randomized, double-blind, placebo-controlled, study. Following a 4-week baseline peroid, subjects were randomly assigned to receive Fampridine-SR (n=25, doses from 10 to 40 mg twice daily, increasing in 5 mg increments weekly) or placebo (n=11). A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, and lower extremity manual muscle testing. Results The most common adverse events were dizziness, insomnia, paresthesia, asthenia, nausea, headache, and tremor. Five subjects were discontinued from Fampridine-SR because of adverse events at doses greater than 25 mg, and these included convulsions in two subjects at doses of 30 and 35 mg twice daily. Improvement were seen in lower extremity muscle strength (prospective analysis) and walking speed (post-hoc analysis) in the Fampridine-SR group compared to placebo (unadjusted p-values of 0.01 and 0.03, respectively). There were no significant differences in other MSFC measure or fatigue scores. Conclusions Future studies should employ doses up to 20 mg twice daily with lower extremity strength and walking speed as potential outcome measures. Multiple Sclerosis 2007; 13: 357-368. http://msj.sagepub.com

Assessing disability progression with the Multiple Sclerosis Functional Composite

Background The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. Objective Evaluate a new method for analyzing disability progression using the MSFC. Methods MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for ≥3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. Results Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. Conclusion MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

ETHICS OF PLACEBO-CONTROLLED CLINICAL TRIALS IN MULTIPLE SCLEROSIS: A REASSESSMENT

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in “resource-restricted” environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes. GLOSSARY: EET = established effective therapy; MS = multiple sclerosis; PPMS = primary progressive MS; SPMS = secondary progressive MS.

Randomized controlled trial of atorvastatin in clinically isolated syndrome: The STAyCIS study

Objective: To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS). Methods: Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon β-1a (IFNβ-1a). Results: Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNβ-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNβ-1a was observed on MRI measures. Conclusion: Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP. Classification of Evidence: This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.

The challenge of follow-on biologics for treatment of multiple sclerosis.

Intellectual property protections for biologic medicinals for multiple sclerosis (MS) are beginning to expire, opening the possibility of development, regulatory approval, and marketing of so-called follow-on biologics, biosimilars, or subsequent entry biologics that might be offered at lower price to consumers and third-party payers, as has been the case for generic drugs. Determining the comparability of a follow-on biologic to its innovator product is more difficult than for small-molecule drugs because of the greater complexity of biologics and the possibility that manufacturing differences can introduce differences in biologic activity and immunogenicity that could result in unpredictable differences in safety or efficacy. We provide a perspective on issues surrounding development, regulatory approval, and potential use of follow-on biologics, with an emphasis on disease-modifying agents for MS.

Change in clinician-assessed measures of multiple sclerosis and subject-reported quality of life: results from the IMPACT study

Background The IMPACT study demonstrated the benefit of interferon beta-1a (IFNβ-1a, Avonex®) two-year change in disability measured by the Multiple Sclerosis Functional Composite (MSFC) in secondary progressive multiple sclerosis (SP-MS) and health-related quality of life (HRQoL) measured by the Multiple Sclerosis Quality of Life Inventory (MSQLI). The IMPACT data permit a detailed assessment of the relation between clinical and self-reported measures. Methods IMPACT was an international randomized, double-blind, placebo-controlled trial of SP-MS patients. As the MSQLI is only in English, this report includes US and Canadian subjects. Subjects were randomized to weekly intramuscular (im) injections of INb-1a (60 mg) or placebo for 24 months. Results At baseline and follow-up, MSQLI correlations were generally stronger with the EDSS than with the MSQLI, MSFC but comparable with MSFC components. Combining the two groups, MSQLI changes for those in the best and worst MSFC change quartiles demonstrated a statistical difference for six of the 11 MSQLI scales. Linear regression demonstrated that EDSS change from baseline to month-24 scores was correlated with change in two MSQLI components. Conclusion These data support the appropriateness of using the MSQLI with individuals who have SP-MS.

Genomic organization and genetic mapping of the neuroimmune gene I2rf5 to mouse chromosome 4

The nervous and immune systems share many functional and molecular similarities, including shared surface antigens, secretions of soluble factors, and cross-modulatory effects. We have identified previously a novel mRNA termed F5, which is expressed only in activated T lymphocytes and mature, postmitotic neurons. Tissue specificity and sequence conservation suggest an important function for F5 in T-lymphocyte proliferation and neuronal maturation. The F5 gene product is an evolutionarily conserved, cytoskeletal-associated phosphoprotein. A full-length mouse genomic clone has been isolated. The protein coding region of the F5 gene is approximately 16 kb in length and is composed of 13 coding exons. The gene encoding F5, termed I2rf5, was mapped using interspecies mouse crosses in close proximity to a number of genes associated with neuronal defects on distal chromosome 4.