Safety and Efficacy of Natalizumab in Japanese Patients with Relapsing-Remitting Multiple Sclerosis: Open-Label Extension Study of a Phase 2 Trial

Introduction The efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) in a 24-week, phase 2 bridging study. An open-label, 2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients. Methods A total of 97 patients (43 previously on placebo; 54 previously on natalizumab) who had completed the bridging study were treated with 300 mg natalizumab every 4 weeks. Multiple sclerosis relapses, changes in Expanded Disability Status Scale (EDSS) scores, and adverse events were assessed at regular intervals. Anti-natalizumab and anti-JC virus (JCV) antibodies were measured. Results After 2 years of natalizumab treatment, the mean adjusted annualized relapse rate was 0.30 (95% confidence interval [CI]: 0.18–0.52) among previously-on-placebo patients and 0.13 (95% CI: 0.05–0.29) among previously-on-natalizumab patients. The mean change in EDSS score from baseline to week 120 was −0.03 among previously-on-placebo patients and −0.18 among previously-on-natalizumab patients. In both groups, >90% of patients experienced ≥1 adverse event. Two previously-on-placebo patients developed persistently positive anti-natalizumab antibodies. Approximately 65% of all patients tested positive for anti-JCV antibodies at open-label treatment initiation. No deaths or progressive multifocal leukoencephalopathy cases were reported. Conclusions The efficacy and safety findings from this 2-year open-label extension study are comparable to and confirm the results of other clinical trials of natalizumab conducted in non-Asian patient populations, and provide longer-term evidence of efficacy and safety in Japanese patients. Trial registration ClinicalTrials.gov identifier NCT01416155. Funding Biogen.

2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients. (EDSS) scores, and low rates of confirmed EDSS worsening with natalizumab treatment after 4-5 years of follow-up [3]. These results have been supported by results from studies conducted in the clinical practice setting [4][5][6][7]. More recently, the safety and efficacy of natalizumab in Japanese patients with RRMS was demonstrated in a 24-week phase 2 study [8]. After 24 weeks of double-blind treatment, the adjusted ARR was significantly lower in natalizumab-than placebo-treated patients Here, we report results from the 2-year open-label extension study of patients who completed the phase 2 bridging study. The primary objective of this study was to evaluate the 2-year safety and tolerability of natalizumab in Japanese patients with RRMS. The secondary objective was to evaluate the 2-year efficacy of natalizumab in this patient population.

Study Design and Patient Population
This study was a 2-year open-label extension study of patients who successfully completed part A or part B of the phase 2 bridging study [8]. Briefly, Japanese patients (aged 18-65 years) were eligible for the phase 2 bridging study if, prior to enrollment, they had a diagnosis of RRMS as defined by the revised McDonald criteria [9], C1 exacerbation within the previous year, and an EDSS score [10] between 0.0 and 6.0 (inclusive) for part A and between 0.0 and 5.

Assessment of Safety and Tolerability
For the open-label extension, physical examinations were performed and vital signs were measured every 4 weeks, and neurological examinations and laboratory testing were conducted every 12 weeks. A 12-lead electrocardiogram was performed at week 24.
Blood samples were taken at baseline and every 12 weeks thereafter to assess serum anti-natalizumab antibodies using a bridging enzyme-linked immunosorbent assay (ELISA) [11]. Anti-JC virus (JCV) antibody testing for progressive multifocal leukoencephalopathy (PML) risk assessment was conducted every 24 weeks. Anti-JCV antibodies were detected using the STRATIFY JCV Ò two-step ELISA (Focus Diagnostics, Cypress, CA, USA) [12,13].
The immunogenicity population included all patients who received C1 infusion of study treatment, had a negative baseline antibody screening result, and had C1 post-baseline antibody assessment. Patients were considered persistently positive for anti-natalizumab antibodies if they had two positive results separated by C6-12 weeks. During the 24-week bridging study, the protocol was amended to include anti-JCV antibody testing at screening and week 24. Because this testing was begun when the study was already in progress, not all patients were tested for anti-JCV antibodies. During the open-label extension study, anti-JCV antibodies were tested at the open-label baseline (week 24 of the bridging study) and every 24 weeks thereafter.
Treatment-emergent adverse events (TEAEs) were monitored throughout the study. A TEAE was defined as any untoward medical occurrence regardless of its relationship to study medication. Severity (mild, moderate, or severe) and the possible relationship to study treatment (related or not related) were determined for each TEAE. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in death, was considered by the investigator to be life-threatening, required hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability or a congenital abnormality/birth defect, or was considered by the investigator to jeopardize the patient's well-being.

Statistical Analysis
All variables were analyzed using the intent-to-treat population, which included all patients who received C1 infusion of study treatment and had C1 post-baseline assessment of the variable of interest. In the extension study, efficacy variables (ARR, the proportion of relapse-free patients, and the change in EDSS score from baseline) were analyzed only for patients who had participated in the randomized double-blind placebo-controlled portion of the bridging study (part B). ARR was calculated as the total number of relapses experienced in a treatment group divided by the total number of days in the study multiplied by 365. Using a Poisson regression model, ARRs were adjusted for baseline relapse rate (i.e., the number of relapses in the year prior to screening for the 24-week bridging study) and reported with their 95% confidence intervals (CIs). EDSS scores and changes from baseline were summarized using descriptive statistics. Safety variables were assessed in patients enrolled in the extension study who had participated in either part A or B in the bridging study and were summarized using descriptive statistics.

Patient Disposition
Ninety-seven patients who completed the 24-week double-blind treatment period of the bridging study were enrolled in the open-label extension, including 43 patients who had received placebo and 54 (10 from part A and 44 from part B) who had received natalizumab ( Fig. 1) previously-on-natalizumab patients, which includes patients who withdrew from the study and did not experience a relapse prior to withdrawal.
The mean change in EDSS score from baseline to week 120 was -0.03 in the previously-on-placebo group and -0.18 in the previously-on-natalizumab group.  Table 3).

Safety and Tolerability
Sixteen of 43 patients (37%) in the previously-on-placebo group and 17 of 54 patients (31%) in the previously-on-natalizumab group experienced TEAEs that were considered related to study treatment (Table 4).

Anti-Natalizumab Antibody Status
In the immunogenicity population, two patients in the previously-on-placebo group were persistently positive for anti-natalizumab antibodies. One of these patients experienced an infusion reaction, and both patients withdrew
Overall, changes in EDSS scores during the extension study were small in both the previously-on-placebo and previously-on-natalizumab groups, consistent with changes observed during the double-blind study [8]. The trend of EDSS score reduction in both groups and the slightly larger reduction observed in the previously-on-natalizumab group suggest that natalizumab, on average, also prevents disability progression in Japanese patients. In terms of safety and tolerability, MS relapse and nasopharyngitis were the most frequently reported events in both groups. With MS relapse excluded from the incidence rate of TEAEs, 39 of 43 patients (91%) in the previously-on-placebo group and 52 of 54 patients (96%) in the previously-on-natalizumab group experienced a TEAE. These results were generally similar to the results that included MS relapse as a TEAE.
Although the bridging study was only 24 weeks in duration, similar results were observed: 87% of placebo patients and 72% of natalizumab patients reported C1 TEAE, with MS relapse and infections the most commonly reported TEAEs in both groups [8]. The incidence of testing persistently positive for anti-natalizumab antibodies was 2% (2 of 96 patients in the immunogenicity population) in the extension study, which is slightly lower than the 3-6% incidence that has been reported in non-Asian populations [1,3,11]. One of the two patients who were positive for anti-natalizumab antibodies experienced an  [16]. No cases of PML    [8].

CONCLUSIONS
The efficacy and safety findings from the double-blind bridging study [8] and the open-label extension study are comparable to and confirm results reported from other clinical trials of natalizumab conducted in non-Asian patient populations [1,2,17], and provide longer-term evidence of the efficacy and safety of natalizumab treatment in Japanese patients with RRMS.
contribution to data validation. Sponsorship and article processing charges for this study were funded by Biogen. All named authors met the International Committee of Medical Journal Editors criteria for authorship for this manuscript. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data, the accuracy of the data analysis, and the work as a