Qunming Dong

Statistical analysis of PML incidences of natalizumab-treated patients from 2009 to 2016: outcomes after introduction of the Stratify JCV® DxSelect™ antibody assay

In January 2012, the presence of John Cunningham virus (JCV) antibodies was incorporated into the US prescribing information for Tysabri® (natalizumab) as a third independent risk factor for progressive multifocal leukoencephalopathy (PML) development in natalizumab-treated patients (Tysabri 2016). The assay used to detect the presence of JCV antibodies, Stratify JCV® DxSelectTM (Focus Diagnostics, Cypress, CA, USA), reports a binary output of positive or negative. Additional research described in 2013 (Plavina et al. 2013) and published in 2014 (Plavina et al. 2014) demonstrated that JCV index values could further stratify PML risk in natalizumab-treated anti-JCV antibody positive patients without prior exposure to immunosuppressants. The estimated US incidence of PML risk table (Tysabri 2016) helps to inform health care providers (HCPs) and thei r pa t ients about PML risk on natalizumab treatment. It is based on three identified risk factors: the presence of anti-JCV antibodies, the duration of treatment (especially beyond 2 years), and prior treatment with an immunosuppressant. Benefit/risk assessment is complex and varies among HCPs and patients. The algorithm exists to assist HCPs in risk stratification of PML based on the established risk factors. On the assumption that risk stratification has altered patient management, the outcome of potentially changing behavior can only be assessed retrospectively and after a significant period of time. Dr. Werner has reported (Werner and Huang 2016) that in the nearly 4 years since the antibody test became available as a means of risk stratification, there has been only a modest reduction in the incidence of PML arising from natalizumab treatment (based on data from February 2011 to January 2016). Using a broader data set of PML incidence extending from November 2009 to June 2016 (Biogen, data on file), we generated a new graphical representation of PML incidence in natalizumab-treated patients (Fig. 1). While our analysis is similar to that of Dr. Werner, we also applied a statistical method to approximate the plotted curve, as described below. The two lines drawn in red and green were found to be the best-fit lines. (The statistical method demonstrated that the best fit is not substantially improved by approximating the curve with three or more lines.) The differences between the associated slopes are statistically significant (p < 0.0001). As shown on the graph, PML incidence increased at a rate of 0.067 per month from December 2009 to September 2013. From September 2013 to June 2016, the slope of the line increased at a rate of 0.027 per month, representing a more than 50 % decrease in the slope after September 2013. The mathematically derived break point, which can be tested at any point along the curve, was optimized at the September 2013 time point, approximately 18 months after introduction of the JCV antibody assay. While it is not possible to assign causal relationships for the slope reduction, a significant reduction in PML * Denise Campagnolo denise.campagnolo@biogen.com

Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients

Objective: To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. Methods: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule–1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule–1 (VCAM-1) binding were assessed using flow cytometry. Results: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 109 to 3.5 × 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 109 vs 3.5 × 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. Conclusions: Natalizumabs effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumabs biological effects may help clinicians make treatment sequencing decisions. Classification of evidence: This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.

Matching-Adjusted Comparisons Demonstrate Better Clinical Outcomes with SC Peginterferon Beta-1a Every Two Weeks Than with SC Interferon Beta-1a Three Times per Week

BACKGROUND Subcutaneous (SC) peginterferon beta-1a and SC interferon beta-1a (IFN beta-1a) have demonstrated efficacy in treating relapsing-remitting multiple sclerosis (RRMS) but have never been compared in direct head-to-head clinical trials, the gold-standard comparison. A well-balanced matching-adjusted comparison of weighted individual patient data on SC peginterferon beta-1a, and aggregate data from published phase 3 clinical trials of SC IFN beta-1a, was conducted to provide additional information on the comparative efficacy of these two agents. METHODS Individual patient data from a study of SC peginterferon beta-1a 125 mcg every two weeks (ADVANCE) and pooled summary data from four published studies of SC IFN beta-1a 44 mcg three times per week (OPERA I and II, CARE-MS I and II) with similar populations were utilized. A comparison was conducted by weighting individual peginterferon beta-1a-treated patients, using estimated propensity of enrolling in SC IFN beta-1a treatment to match multiple key aggregate baseline characteristics of SC IFN beta-1a-treated patients. After matching, weighted annualized relapse rate (ARR), 24-week confirmed disability worsening (CDW), and clinical no evidence of disease activity (clinical-NEDA) were calculated and compared for peginterferon beta-1a and SC IFN beta-1a. RESULTS After matching, baseline characteristics were well balanced across treatment groups. At 2 years, ARR after matching was 0.256 for patients receiving peginterferon beta-1a (effective n = 376) and 0.335 for those receiving SC IFN beta-1a (n = 1218) (P = 0.0901). The percentage of patients who were relapse free over 2 years was significantly higher with peginterferon beta-1a than with SC IFN beta-1a (75.1% vs. 57.4% [after matching], P < 0.0001). The peginterferon beta-1a treatment group had a significantly lower proportion of patients with 24-week CDW compared with SC IFN beta-1a (after matching 6.5% vs. 13.2%; P = 0.0007). Clinical-NEDA occurred in a significantly higher proportion of patients treated with SC peginterferon beta-1a versus SC IFN beta-1a (74.1% vs. 48.1%; P < 0.0001). CONCLUSIONS This matching-adjusted comparison using data from four phase 3 trials with SC IFN beta-1a formulations demonstrated that patients with RRMS treated with SC peginterferon beta-1a 125 mcg every two weeks achieved better clinical outcomes than patients who received SC IFN beta-1a 44 mcg three times per week.

Peginterferon β-1a every 2 weeks increased achievement of no evidence of disease activity over 4 years in the ADVANCE and ATTAIN studies in patients with relapsing–remitting multiple sclerosis

Background: No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the therapeutic efficacy of treatments for relapsing–remitting multiple sclerosis (RRMS). Objective: To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes. Methods: ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE. Results: Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p = 0.0063) and MRI NEDA (28.3% versus 15.8%, p = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA (p = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN. Conclusions: Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2–4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes. Clinicaltrials.gov: NCT01332019

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting

BACKGROUND Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. METHODS TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. RESULTS Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0-2.0 to ≥3.0, 2.0-3.0 to ≥4.0, and 4.0-5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). CONCLUSIONS In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0-9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0-5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Background: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses. Objective: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP). Methods: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score. Results: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively). Conclusion: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.

086 The rapid efficacy of natalizumab vs fingolimod in patients with active relapsing-remitting multiple sclerosis (RRMS): results from reveal, a randomised, head-to-head study

Introduction REVEAL was designed as a 1 year, multicentre, randomised, rater- and sponsor-blinded, prospective study comparing natalizumab and fingolimod in patients with active RRMS. Although the study closed early (for non-safety/non-efficacy reasons), data permitted comparison of effects occurring shortly after treatment initiation. This analysis compares onset of efficacy with natalizumab and fingolimod in REVEAL. Methods Patients were randomised to open-label intravenous natalizumab 300 mg every 4 weeks (n=54) or oral fingolimod 0.5 mg once daily (n=54). Magnetic resonance imaging was scheduled every 4 weeks for the first 24 weeks and at weeks 36 and 52. Analyses included Kaplan-Meier and Cox regression, negative binomial regression (annualised relapse rate [ARR] and number of T1 gadolinium-enhancing [Gd+] lesions) and a negative binomial generalised estimating equation (cumulative Gd +lesions over time). Results As expected for a randomised study, patient characteristics and follow-up time (median 39 weeks) were generally similar between groups. Natalizumab patients were less likely than fingolimod patients to develop new Gd +lesions (for ≥1 lesion, cumulative probability 40.68% vs 57.99%; hazard ratio [HR]=1.678 [95% CI: 0.865 to 3.255]; p=0.1258; for ≥2 lesions, cumulative probability 11.54% vs 48.48%; HR=4.053 [95% CI: 1.474 to 11.144]; p=0.007). Natalizumab patients consistently had 63%–72% fewer Gd +lesions than fingolimod patients, with between-group differences apparent within 4 weeks and reaching significance by 12 weeks (p=0.030). ARR was 83% lower with natalizumab than with fingolimod (0.05 vs 0.29; p=0.023), and cumulative probability of relapse was 1.85% with natalizumab vs 22.28% with fingolimod (HR=12.184 [95% CI: 1.552 to 95.634]; p=0.017). Adverse events were consistent with known safety profiles. Conclusion These results suggest that natalizumab reduces disease activity more rapidly and to a greater extent than fingolimod in patients with active RRMS. Given the early study closure, available data did not permit primary endpoint evaluation, and interpretation of these results requires caution. Study Support Biogen.