Sandra Richman

Anti–JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy

The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti–JC virus (JCV) antibodies. We analyzed whether anti‐JCV antibody levels, measured as index, may further define PML risk in seropositive patients.

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.

A Novel PEGylated Interferon Beta-1a for Multiple Sclerosis: Safety, Pharmacology, and Biology

This study clinically evaluated a novel PEGylated form of interferon beta‐1a (PEG‐IFN beta‐1a), a potential first‐line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single‐dose study (n = 60) comparing subcutaneous or intramuscular PEG‐IFN beta‐1a (63, 125, or 188 μg) with intramuscular unmodified IFN beta‐1a 30 μg and a multiple‐dose study (n = 69) comparing subcutaneous PEG‐IFN beta‐1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2′,5′‐OAS) measures, exploratory immune assessments, safety, and tolerability. A dose‐proportional increase in PEG‐IFN beta‐1a exposure was observed, with a 4‐fold greater exposure at 63 μg (6 million international units [MIU]) of PEG‐IFN beta‐1a than with 30 μg (6 MIU) intramuscular unmodified IFN beta‐1a. Increases in neopterin and 2′,5′‐OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG‐IFN beta‐1a than with unmodified IFN beta‐1a. PEG‐IFN beta‐1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu‐like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG‐IFN beta‐1a as a potentially effective treatment for patients with relapsing multiple sclerosis.

Outcome and survival of asymptomatic PML in natalizumab‐treated MS patients

As of 3 September 2013, 399 cases of natalizumab‐associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab‐treated MS patients who were asymptomatic at PML diagnosis.

Anti‐JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC virus (JCV) infection due to combined host and viral factors. Anti‐JCV antibodies provide a means to assess JCV exposure and stratify PML risk. The reported seroprevalence of anti‐JCV antibodies varies from 39% to 91% depending on assay methodology and population studied. A two‐step anti‐JCV antibody assay (STRATIFY JCV™; Focus Diagnostics, Cypress, CA, USA) detected anti‐JCV antibodies in approximately 55% of multiple sclerosis (MS) patients. This study describes the prevalence of anti‐JCV antibodies in a large, multinational MS population.

PEGylated Interferon Beta-1a: Meeting an Unmet Medical Need in the Treatment of Relapsing Multiple Sclerosis

Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex®, Rebif®, and Betaseron/Betaferon®), glatiramer acetate (Copaxone®), and an anti-VLA4 monoclonal antibody (Tysabri®). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patients decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125 microg administered via the subcutaneous route every 2 or 4 weeks.

Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies

BACKGROUND Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index). METHODS Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort. FINDINGS 156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00-0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8-4·0) in patients with previous immunosuppressant use and 1·7% (1·4-2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00-0·03) in year 1 (1-12 infusions) to 0·6 (0·0-1·5) in year 6 (61-72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0-0·2) in year 1 to 3·0 (0·2-5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0-0·5) in year 1 to 10·0 (5·6-14·4) in year 6 for those with an index of more than 1·5. INTERPRETATION Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit-risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants. FUNDING Biogen.

1009 Evaluation of the Incidence of Anti-JC Virus Antibodies in a Cohort of Natalizumab-Treated Patients

States collecting patient history, effi cacy as assessed by the Harvey Bradshaw Index (HBI), Health Related Quality of Life outcomes, and serious adverse events (SAE) in CD patients. TYGRIS is a voluntary global observational study evaluating the long-term safety of natalizumab in MS. Post-marketing surveillance data from countries that do not participate in TOUCHTM or TYGRIS are also collected. Th is abstract provides updates on natalizumab utilization and safety data from these programs in both indications. Results: As of the end of March 2010, ~67,700 patients have been exposed to natalizumab in the post-marketing setting, predominately for MS. As of 6 May 2010, 49 confi rmed cases of PML had been reported in the post-marketing setting (all in MS patients). Th ere were 11 deaths; 38 of the 49 (78%) natalizumab-treated patients who developed PML have survived and exhibit varying levels of disability. CD INFORM has enrolled 84 patients with an average HBI at time of entry of 8.3 as of 23 May 2010. Of the 51 CD patients with an HBI assessment following 6 months of natalizumab therapy, the average score was 4.7, a mean decrease of 2.8 points from baseline. Th e overall SAE incidence in CD INFORM was 16.7% (n=14), though only 2.4% (n=2) was considered treatment related. As of 23 February 2010, there were 198 women (including 1 woman with CD) enrolled prospectively in the pregnancy registry where the outcome of the pregnancy was unknown at time of enrollment. Follow-up was ongoing in 51 cases and 151 outcomes have been reported (4 patients with twins resulted in 2 outcomes for each pregnancy). Th e most current exposure and safety data from patients receiving natalizumab worldwide will be presented. Conclusion: Cumulative data from both indications suggest a safety profi le consistent with the product labeling of natalizumab. Disclosure: Drs Anthony Pepio and Lori Taylor are employees of Elan Pharmaceuticals, Inc. Drs Mariska Kooijmans, Lynda M. Cristiano, and Carmen Bozic are employees of Biogen Idec, Inc. Dr Grainne Quinn is an employee of Elan Pharma International Ltd.