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Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study

Multiple Sclerosis and Related Disorders, Voluma 11, January 2017, Pages 25 - 31

Abstract

Background

Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS).

Objective

To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients.

Methods

This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300 mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed.

Results

New active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients.

Conclusions

In Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

Highlights

  • Natalizumab is an antibody treatment for relapsing-remitting multiple sclerosis.
  • This study investigated natalizumab efficacy and safety in Japanese patients.
  • New brain lesion development rate was lower with natalizumab than placebo (p<0.001).
  • Annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001).
  • Natalizumab had a favorable safety and tolerability profile in Japanese patients.

Abbreviations: AE - adverse event, ARR - annualized relapse rate, AUC - area under the concentration time curve, AUC0–last - area under the curve to the last measurable concentration of a dosing interval, AUC0–∞ - area under the curve to infinity, AUC0–672 - area under the curve for dosing interval, CI - confidence interval, CL - systemic clearance, Cmax - maximum concentration, Ctrough - trough concentration, EDSS - Expanded Disability Status Scale, ELISA - enzyme-linked immunosorbent assay, Gd - gadolinium, IFNβ - interferon beta, IV - intravenously, IVIG - intravenous immunoglobulin, JCV - John Cunningham virus, N/A - not assessed, NMO - neuromyelitis optica, NMOSD - neuromyelitis optica spectrum disorder, PD - pharmacodynamics, PK - pharmacokinetics, PML - progressive multifocal leukoencephalopathy, RRMS - relapsing-remitting multiple sclerosis, SD - standard deviation, SE - standard error, T1/2 - half-life, Tmax - time to maximum concentration, VAS - visual analog scale, Vd - volume of distribution, VLA-4 - very late antigen-4.

Keywords: Multiple sclerosis, Japanese, Natalizumab, Randomized clinical trial, Pharmacokinetics.

1. Introduction

Natalizumab (Tysabri®, Biogen), a humanized anti-α4 integrin monoclonal antibody, blocks lymphocyte adhesion to endothelial cells, thereby preventing their migration to the CNS and reducing inflammation (Yednock et al., 1992). In patients with relapsing-remitting MS (RRMS), natalizumab reduced annualized relapse rates by 68%, accumulation of new or enlarging hyperintense lesions by 83%, 12-week sustained disability progression by 42%, and 24-week sustained disability progression by 54% in the 2-year, phase 3 AFFIRM study (Polman et al., 2006). Recent reports indicate that these benefits extend over four to five years of natalizumab treatment (Butzkueven et al, 2014 and Kappos et al, 2012; O’Connor et al., 2014). These studies included predominantly Caucasian (white) patients with MS. Because clinically important differences may exist between ethnic groups, the effects of natalizumab in Japanese patients with MS require confirmation in clinical studies. This 2-part study was conducted to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese patients with RRMS.

2. Materials and methods

2.1. Study design

Part A was an open-label study of patients who received natalizumab 300 mg intravenously (IV) every 4 weeks for 24 weeks to assess safety, tolerability, PK, and PD. An interim analysis of 10 patients who completed 4 weeks of natalizumab treatment and at least 5 patients with PK data was conducted to determine safety and PK of the dosage regimen in Japanese patients prior to initiating study part B.

The double-blind, placebo-controlled study (part B) randomized patients in a 1:1 ratio to receive natalizumab 300 mg IV every 4 weeks or placebo for 24 weeks. Randomization of patients to treatment was stratified using a computer-generated randomization schedule and a multi-digit identification number, which was implemented by an interactive voice and web response system. All study personnel, patients, sponsor personnel involved in the conduct of the study, and the investigator advisory committee were unaware of treatment assignments throughout the study. Following completion of study assessments at Week 24, patients from parts A and B could enroll in a long-term, open-label extension study to receive natalizumab.

This study was conducted at 25 sites in Japan between April 2010 and August 2012 in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, applicable local regulations (including Japanese Ministry of Health, Labour, and Welfare regulations), and the ethical principles outlined in the Declaration of Helsinki. Ethics committee approvals of the study protocol were obtained from each participating site. The study was registered at ClinicalTrials.gov (NCT01440101).

2.2. Patients

Japanese patients aged 18–65 years were eligible for study enrollment if they had a diagnosis of RRMS as defined by the revised McDonald criteria (Polman et al., 2005). All other neurological diagnoses, including primary or secondary progressive MS, neuromyelitis optica (NMO), and NMO spectrum disorder (NMOSD), were excluded. Patients with a history of a long spinal cord lesion extending over three or more vertebral bodies on T2-weighted spinal MRI or a positive test for AQP4 antibodies were excluded. The negativity of anti-AQP4 antibody by cell-based assay was reconfirmed at the time of study registration by the central laboratory. Patients had to have experienced at least one clinical MS exacerbation within the previous year and to have an Expanded Disability Status Scale (EDSS) score of 0.0–6.0 for part A or 0.0–5.5 for part B. The EDSS upper limit for inclusion was set at 6.0 for part A to allow inclusion of Japanese MS patients with high disease activity in part A. For part B, patients with EDSS scores 0.0–5.5 were included so that the study population would be comparable with another Japanese double-blind clinical trial (Saida et al., 2016).

Patients who had received prior treatment with natalizumab or immunosuppressants were excluded, and treatment with immunomodulatory drugs (e.g. interferon beta [IFNβ] or glatiramer acetate) was not permitted within 2 weeks of enrollment or during the study. Corticosteroids were not permitted within 30 days of enrollment or during the study with the exception of short courses for treatment of clinical relapses. Written informed consent was obtained from each patient before study evaluations were performed.

2.3. Study assessments

Efficacy assessments were included in part B only. Brain MRI scans with T2 and fluid attenuated inversion recovery sequences and T1 sequences with and without gadolinium (Gd) were performed every 4 weeks to determine the number of Gd-enhancing lesions and non-enhancing T2 hyperintense lesions. All MRI scans were read at a blinded central facility. Clinical relapses were defined as new or recurrent neurological symptoms not associated with fever or infection and lasting for at least 24 h. EDSS scores were recorded by an independent rater neurologist, and global assessment of well-being was measured using a visual analog scale (VAS) ranging from 0 to 100 points, where 0 denotes “poor” and 100 denotes “excellent.”

Adverse events were monitored throughout the study, and assessment of vital signs occurred every 4 weeks. Physical and neurological exams, laboratory testing, PK, and patients’ self-rating of global well-being on a VAS were collected every 12 weeks. Serum samples were evaluated for antibodies to natalizumab using a bridging enzyme-linked immunosorbent assay (ELISA) (Vennegoor et al., 2013). Anti–JC virus (JCV) antibody testing for progressive multifocal leukoencephalopathy (PML) risk assessment (Gorelik et al, 2010 and Lee et al, 2013) became available during part B and was included at screening and Week 24 for those patients who had not been screened or had not completed the study. Anti-JCV antibodies were detected using the STRATIFY JCV® two-step ELISA (Focus Diagnostics, Cypress, CA, USA), as previously described (Gorelik et al, 2010 and Lee et al, 2013) and results are provided for patients tested in part B and the open-label extension study.

Samples for PK/PD assessment were collected from all patients in part A pre-dose, at the end of infusion, and 4, 24, 48, and 96 h and 1, 2, and 3 weeks after the first and sixth doses. Additional pre-infusion samples were collected at Weeks 4, 8, 12, 16, and 24. For patients in part B, samples were collected before natalizumab infusion at baseline and Weeks 12 and 24. Natalizumab concentrations in blood samples were determined by ELISA.

PD activity was assessed by measuring the degree of saturation of the VLA-4 (or α4 integrin) receptor on peripheral blood mononuclear cells. Cells were stained with phycoerythrin conjugated anti-human IgG4 antibody to label the cell-bound natalizumab, and detection and quantification were performed by flow cytometry.

2.4. Statistical analysis

Demographics, baseline characteristics, and safety data were summarized separately for the two discrete populations enrolled in parts A and B. For part A, PK and PD parameters were summarized using descriptive statistics.

For part B, the efficacy population included all patients who received at least one infusion of study treatment and who had at least one post-baseline efficacy assessment (intent-to-treat). The primary endpoint was the rate of development of new active lesions over 24 weeks. New active lesions were the sum of Gd+ lesions and any new or newly enlarging T2-hyperintense lesions that did not enhance. The rate of development was calculated for each patient as the slope of the cumulative new active lesions over time where the calculation used the values at all the time points between Weeks 0 and 24. In the subset of patients with RRMS in a previous report (Miller et al., 2003), the mean rate of development of new active lesions over 24 weeks for the placebo group was 0.909 with a standard deviation (SD) of 1.462. If all MRIs taken more than 34 days after the final infusion are excluded from the calculations, the mean rate of development of new active lesions over 24 weeks for the placebo group was 0.887 with an SD of 1.408. An 80% reduction in the mean rate was considered to be clinically meaningful. This reduction applied to the estimated mean in the placebo group yielded a mean rate in the active group of 0.177. Using the coefficient of variation of 265% observed in the natalizumab-treated patients in the previous report (Miller et al., 2003), the SD for this rate was estimated to be 0.471, yielding a pooled SD of 1.050. Assuming a normal approximation, the means of 0.887 and 0.177 and the pooled SD of 1.050 generate a probability of 0.316 that an observed rate from the placebo group was less than one from the natalizumab group. Using this probability, the sample size of 78 patients (39 per group) will provide 80% power to detect an 80% reduction in rate of new lesion development using the Wilcoxon rank-sum test. To account for early withdrawals, 45 patients were randomized to each treatment group in order to ensure 39 evaluable patients per group.

The rates were compared by treatment group using the Mann-Whitney U-test stratified by the presence or absence of Gd-enhancing lesions at baseline. Missing data were imputed using linear interpolation between two adjacent non-missing values. Secondary efficacy endpoints included the cumulative number of new active lesions at Week 24, annualized relapse rate (calculated as the total number of relapses experienced in a treatment group over 24 weeks divided by the number of days followed in the study and multiplied by 365), and the proportion of patients who were relapse-free at Week 24. Annualized relapse rate and proportion relapse-free were analyzed using a Poisson regression model and Fisher exact test, respectively. Changes from baseline in EDSS and VAS scores at Weeks 12 and 24 were summarized descriptively and treatment-group comparisons performed using analysis of covariance.

3. Results

3.1. Patients

Twelve Japanese patients were included in part A and 94 Japanese patients were randomized in part B (Fig. 1). As shown in Table 1, most patients in part A (11 of 12; 92%) and part B (83 of 94; 88%) had received prior disease-modifying therapy, most commonly IFNβ-1b or IFNβ-1a. In part A, 12 patients received at least 1 infusion and 10 patients received all 6 infusions. In part B, 47 patients in each treatment group received at least 1 dose of study medication; 46 (98%) and 43 (91%) patients completed the 6-month study in the natalizumab and placebo groups, respectively.

Fig. 1

Fig. 1

Patient disposition.

 

Table 1

Baseline characteristics of patients by study part and treatment group.

 

Characteristic Part A Part B
Natalizumab (n=12) Natalizumab (n=47) Placebo (n=47)
Age, years
 Mean±SD 41.6±9.9 37.7±8.6 35.1±8.2
 Median (range) 39.0 (26–62) 37.0 (22–62) 35.0 (19–52)
Female, n (%) 7 (58) 34 (72) 32 (68)
Body weight, kg
 Mean±SD 57.6±11.2 55.4±9.7 62.6±15.8
 Median (range) 53.0 (46.0–84.0) 53.7 (38.0–82.0) 53.7 (38.3–96.0)
Time from first MS symptoms to randomization, years
 Mean±SD 11.3±5.8 8.7±5.7 6.8±5.5
 Median (range) 12.0 (2–22) 7.0 (1–22) 6.0 (0–25)
Time since MS diagnosis, years
 Mean±SD 9.6±6.2 5.9±5.0 5.1±4.9
 Median (range) 8.5 (1–22) 4.0 (0–18) 4.0 (0–19)
Prior MS therapy, n (%)1 11 (92) 43 (91) 40 (85)
 IFNβ-1a 7 (58) 29 (62) 23 (49)
 IFNβ-1b 9 (75) 26 (55) 28 (60)
 Azathioprine 3 (25) 1 (2) 1 (2)
 Fingolimod 1 (8) 2 (4) 1 (2)
Number of relapses in previous year
 Mean±SD 1.7±0.8 2.0±1.2 1.9± 1.0
 Median (range) 1.5 (1–3) 2 (1–5) 2 (1–4)
EDSS score
 Mean±SD 3.7±1.0 2.5±1.6 2.1±1.5
 Median (range) 3.5 (2.5–6.0) 2.5 (0.0–5.5) 2.0 (0.0–5.5)
Number of Gd-enhancing lesions
 Mean±SD N/A 0.9±2.7 0.7±1.9
 Median (range) N/A 0 (0–13) 0 (0–9)

1 Only continuous MS therapies used by ≥2 patients in any treatment group are shown.

EDSS: Expanded Disability Status Scale; Gd: gadolinium; IFNβ: interferon beta; IVIG: intravenous immunoglobulin; MS: multiple sclerosis; N/A: not assessed; SD: standard deviation.

3.2. Efficacy

The mean rate of development of new active lesions over 24 weeks was significantly higher in the placebo group (0.35) than in the natalizumab group (0.06; p<0.001) (Table 2). Natalizumab treatment reduced rates of new lesions by 84% compared with placebo. The mean cumulative number of new active lesions increased over time in the placebo group but remained stable in the natalizumab group (Fig. 2). The difference in treatment groups was significant starting at Week 8 and continued through Week 24. At Week 24, the mean cumulative number of new active lesion was 8.5 in the placebo group and 1.5 in the natalizumab group (p<0.001) (Table 2). The mean cumulative number of new Gd-enhancing lesions was 7.4 in the placebo group and 1.2 in the natalizumab group (p<0.001) at Week 24, and the mean number of new or newly enlarging T2 lesions was 1.1 in the placebo group and 0.3 in the natalizumab group (p=0.006) at Week 24.

Table 2

Part B: MRI and clinical endpoints at Week 24 by study treatment.

 

Endpoint Natalizumab (n=47) Placebo (n=47) p value
Primary and MRI endpoints
 Rate of development of new active lesionsa 0.06 0.35 <0.001
 Mean cumulative number of new active lesionsa 1.5 8.5 <0.001
 Gd-enhancing lesions 1.2 7.4 <0.001
 T2 lesions 0.3 1.1 0.006
Clinical endpoints
 ARRb 0.53 1.73 0.001
 Proportion of patients relapse-freeb 79% 38% <0.001

a New active lesions defined as the sum of Gd-enhancing and new or newly enlarging, non-enhancing T2-hyperintense lesions over 24 weeks.

b Clinical relapses were defined as new or recurrent neurological symptoms, not associated with fever or infection, lasting for at least 24 h.

ARR: annualized relapse rate; Gd: gadolinium.

Fig. 2

Fig. 2

Cumulative number of new active lesions* over time by treatment group. *New active lesions are the sum of gadolinium-enhancing lesions and any new or newly enlarging non-enhancing T2-hyperintense lesions. SE: standard error.

 

Clinical relapses were experienced by 27 patients in the placebo group and 9 patients in the natalizumab group, with 8 and 2 patients, respectively, having more than one relapse. At Week 24, the annualized relapse rate was 1.73 (95% confidence interval [CI], 1.22–2.45) for placebo and 0.53 (95% CI, 0.29–0.99) for natalizumab (p<0.001), representing a reduction of 69% with natalizumab treatment (Table 2). Twice as many patients in the natalizumab group (37 [79%]) compared with patients in the placebo group (18 [38%]) were relapse-free at Week 24 (p<0.001) (Table 2). EDSS scores improved from baseline in the natalizumab group (mean change, −0.16 at Week 12 and −0.22 at Week 24) and worsened in the placebo group (mean change, 0.19 at Week 12 and 0.19 at Week 24). Comparison between the treatment groups in the mean EDSS change from baseline to Week 24 showed statistical significance favoring natalizumab (p=0.019), although this analysis was not pre-specified (Table 3).

Table 3

EDSS change from baseline.

 

Natalizumab (n=46) Placebo (n=44) p value
Baseline EDSS scorea 2.5±1.6 2.1±1.5
Mean EDSS change (baseline to Week 12)a −0.16±0.7 0.19±0.8 0.050
Mean EDSS change (baseline to Week 24)a −0.22±0.7 0.19±0.9 0.019

a Values are mean±standard deviation (SD).

EDSS: Expanded Disability Status Scale.

VAS assessment showed high variability between patients and over time. The mean change in VAS score from baseline to Week 24 was −2.9 points in the placebo group and −4.8 points in the natalizumab group (p=0.942).

3.3. Safety

Adverse events for part A and B are shown in Table 4. For the 12 patients in part A, most adverse events were mild or moderate in severity and considered not related to study treatment. Two patients discontinued study treatment due to adverse events (MS relapse and asthma). The patient who discontinued study treatment due to asthma had received 4 doses of study treatment. This patient was also found to be positive for anti-natalizumab antibodies, but a second test was not possible, so it could not be determined if the antibody response was transient or persistent. Three patients had at least 1 adverse event considered to be related to treatment and 2 patients had 3 serious adverse events. One patient experienced retinal detachment, which was considered moderate in severity and related to study drug, 75 days after the first dose of natalizumab. This patient also experienced a non-serious MS relapse 47 days after the first natalizumab dose and discontinued study treatment (18 and 46 days prior to MS relapse and retinal detachment, respectively). Another patient experienced 2 severe relapses of MS that were considered not related to study drug. The events occurred 40 and 127 days after the first dose of natalizumab, and the patient continued to participate in the study.

Table 4

Adverse events (AEs) by study part and treatment.

 

AE, n (%) Part A Part B
Natalizumab (n=12) Natalizumab (n=47) Placebo (n=47)
All events
 At least one AE 8 (67) 34 (72) 41 (87)
 AE leading to study withdrawal 2 (17) 0 1 (2)
Serious AEa 2 (17) 7 (15) 11 (23)
 MS relapse 1 (8) 4 (9) 10 (21)
Frequent AE (≥10% [part A] or ≥5% [part B] of patients)
 MS relapseb 3 (25) 11 (23) 25 (53)
 Headache 3 (25) 1 (2) 2 (4)
 Nasopharyngitis 3 (25) 9 (19) 14 (30)
 Pharyngitis 2 (17) 3 (6) 2 (4)
 Cystitis 2 (17) 1 (2) 2 (4)
 Insomnia 1 (8) 3 (6) 1 (2)
 Eye strain 0 0 3 (6)
 Eczema 1 (8) 2 (4) 3 (6)
 Back pain 0 0 3 (6)
Other infectionsc
 Herpes zoster 0 2 (4) 0
 PML 0 0 0

a Part A: Two patients had three serious AEs: one patient had retinal detachment and one patient had two events of MS relapse. Part B: Other serious adverse events in natalizumab-treated patients were considered not related to study treatment: Asperger's disorder, mild diarrhea, and moderate basal cell carcinoma (occurred in a patient who had a light lentigo lesion that was growing and hemorrhagic before study enrollment); no other malignancies were reported.

b MS relapse reported as an AE at the discretion of the investigator; events fitting the definition of clinical relapse were evaluated for efficacy.

c No severe or serious infections were reported.

MS: multiple sclerosis; PML: progressive multifocal leukoencephalopathy.

For the 94 patients in study part B, most adverse events were mild or moderate in severity, including infusion-related reactions. No hypersensitivity reactions occurred, and the number of infections was similar between natalizumab- and placebo-treated patients. Two natalizumab-treated patients had herpes zoster infections; 1 of these events was assessed to be unrelated to natalizumab treatment, and both were mild or moderate in severity. No suspected cases of PML were reported. Natalizumab was associated with an increase in circulating leukocytes as expected based on its mechanism of action. Overall, no notable trends in physical examination findings, laboratory results, ECG, or vital sign measurements were observed. The most frequently reported serious adverse event was MS relapse (seen in 4 natalizumab-treated patients [9%] and 10 placebo-treated patients [21%]). In addition, 3 patients in the natalizumab group had serious adverse events of Asperger disorder, diarrhea, and moderate basal cell carcinoma, and 1 patient in the placebo group had serious adverse events of somatoform disorder and pyelonephritis. There were no patients in the natalizumab group who discontinued treatment or withdrew from part B of the study for adverse events. One patient (2%) in the placebo group discontinued study treatment and withdrew from part B of the study due to an adverse event (somatoform disorder).

One patient in part B became persistently positive for anti-natalizumab antibodies during the study. The first positive anti-natalizumab antibody test occurred on the day of the fourth infusion of natalizumab, and the patient remained positive for anti-natalizumab antibodies one month later (last infusion of study) and at the Week 24 visit. The patient completed part B and was enrolled into the long-term extension study because the patient's anti-natalizumab antibody status was unknown at the time of extension study enrollment. The patient had mild pyrexia twice during the extension study and discontinued the study due to being persistently positive for anti-natalizumab antibodies after the second infusion. The patient's relevant medical history included allergic rhinitis.

Of 103 patients who were tested for anti-JCV antibodies in part B and the extension study, 65 (63%) were seropositive based on the first available result.

3.4. PK/PD

Table 5 presents a summary of the PK parameters from the first and sixth doses. Each successive dose of natalizumab led to accumulation of the drug in serum, with patients at or near steady-state by the end of the sixth dose. Comparisons of area under the curve to infinity (AUC0–∞), systemic clearance (CL), and volume of distribution (Vd) values from the first dose with AUC0–672, CL, and Vd values from the sixth dose, respectively, show nearly identical values. Comparison of maximum concentration values between the first dose and the sixth dose showed an accumulation of natalizumab. Mean α4 integrin saturation over the dosing interval was greater than 69% for both the first and sixth doses (Fig. 3). Natalizumab PK parameters in Japanese patients were overlapping and similar to those observed in PK studies of natalizumab in Caucasian patients (Supplemental Tables 1 and 2).

Table 5

Pharmacokinetic parameters.

 

Parametera Dose 1 Dose 6
Cmax (μg/mL) 121.4±22.3 148.6±37.5
AUC0–last (μg·h/mL) 32,379.3±8,026.6 48,165.1±15,250.9
AUC0–∞ (μg·h/mL) 45,203.3±14,152.2 N/A
AUC0–672 (μg·h/mL) N/A 48,323.0±15,081.4
Tmax (h) 3.0±6.0 3.0±2.2
T1/2 (h) 365.4±132.4 397.1±108.7
Vd (L) 3.5±0.8 3.7±1.1
Steady-state Vd (L) 4.8±1.9 3.6±1.0
CL (mL/h) 7.3±2.3 N/A
Steady-state CL (mL/h) N/A 6.7±2.0

a Values are mean±standard deviation (SD).

AUC0–last: area under the curve to the last measurable concentration of a dosing interval; AUC0–∞: area under the curve to infinity; AUC0–672: area under the curve for dosing interval; CL: systemic clearance; Cmax: maximum concentration; N/A: not assessed; T1/2: half-life; Tmax: time to maximum concentration; Vd: volume of distribution.

Fig. 3

Fig. 3

Mean α4 integrin saturation over the entire dose collection period. Arrows indicate natalizumab dose administration. The spike in saturation shown with the sixth dose of natalizumab is evident because of more frequent sampling intervals (4, 24, 48, and 96 h) after dose administration (similar to after the first dose).

 

4. Discussion

This study demonstrated that the efficacy and safety of natalizumab in Japanese RRMS patients were very similar to that previously demonstrated in Caucasian patients (Polman et al, 2006, Miller et al, 2003, and Rudick et al, 2006). Natalizumab administered every 4 weeks for 24 weeks resulted in a statistically significant decrease in the mean rate of development of new active MRI lesions compared with placebo. The effect of natalizumab was observed as early as Week 8, which is consistent with the onset of effect in prior studies (Miller et al., 2003), and was also evident when Gd-enhancing lesions and new or newly enlarging T2 hyperintense lesions were evaluated separately. There was a statistically significant decrease in the annualized relapse rate with natalizumab compared with placebo even though the study lasted only 24 weeks. This finding is consistent with the efficacy of natalizumab demonstrated in phase 3 clinical trials in Caucasian patients (Polman et al, 2006 and Rudick et al, 2006). Disease activity at baseline in this study was higher than that seen in a similar phase 2 study on fingolimod in Japanese patients (Saida et al., 2012). Moreover, the short study duration may have produced a seemingly higher ARR than that seen in other studies.

In addition, a significantly higher proportion of natalizumab-treated patients than placebo-treated patients were relapse-free. There was no change in VAS over 24 weeks between treatment groups or over time. The natalizumab group showed a mild but significant improvement in mean EDSS score over the 24-week study period compared with the placebo group, which showed a slight deterioration. Although the size and duration of the study did not allow for definitive conclusions about disability progression, this result is also consistent with the phase 3 clinical trial results (Polman et al, 2006 and Rudick et al, 2006).

Natalizumab was well tolerated in Japanese RRMS patients. The safety profile of natalizumab observed in the 24-week (part B) study was similar to that established in studies of Caucasian patients (Polman et al, 2006 and Rudick et al, 2006). Infections were similar between treatment groups, with no severe or serious infections, including no cases of suspected PML in natalizumab-treated patients. Mild or moderate herpes zoster infections were reported in 2 of 47 patients (4%) treated with natalizumab. Previous reports have also found a slightly higher rate of herpes infection in natalizumab-treated patients compared with placebo-treated patients or healthy controls (Biogen, 2015, Fine et al, 2013, and Kohlmann et al, 2015). However, the frequency of herpes infections does not appear to increase with longer duration of therapy, and the postmarketing reporting rate for herpes infections is consistent with the known safety profile for natalizumab.

In part B, development of persistent antibodies to natalizumab occurred in 1 patient, an incidence of 1%, which is lower than the 6% incidence in the pivotal Western study (Polman et al., 2006). After initiation of this study in Japanese MS patients, the presence of anti-JCV antibodies in serum or plasma was determined to be a risk factor for development of PML, along with long duration of natalizumab treatment, especially beyond 2 years, and the use of immunosuppressants prior to natalizumab treatment (Bloomgren et al., 2012). Testing for anti-JCV antibodies is recommended prior to initiation of treatment or if JCV-antibody status is unknown (Biogen, 2014). Of 103 Japanese MS patients who were tested for anti-JCV antibodies in part B and the extension study, 65 (63%) were seropositive based on the first available result, which is within the prevalence range observed in large (predominantly Caucasian) populations (50–70%) (Bozic et al, 2011, Bozic et al, 2012, Olsson et al, 2013, and Outteryck et al, 2012).

Natalizumab exposure was slightly higher in this Japanese MS population than that reported in Caucasian patients (Keeley et al., 2005), which is consistent with the lower body weight in the general Japanese population. This study is in agreement with previous studies of natalizumab showing that differences in body weight do not result in efficacy or safety concerns (Polman et al, 2006 and Miller et al, 2003). There was no clinically meaningful difference in PD measurements, including α4 integrin saturation and increase in circulating lymphocytes, in Japanese and Caucasian patients (Keeley et al., 2005). The decrease in α4 integrin saturation observed at Weeks 8 and 12 in Fig. 3 may be related to the 1 patient in part A who had anti-natalizumab antibodies when tested after the fourth infusion at Week 12. This patient withdrew before testing at Week 16.

Differences in MS characteristics have been reported between patients in Japan and Western countries. Although previous studies have found MS to be characterized by a higher frequency of optic and spinal cord involvement in Japanese than Caucasian patients (Shibasaki et al., 1981), this seems largely due to the inclusion of a significant proportion of NMO and NMOSD cases in these MS studies (Wingerchuk et al., 2007).

In conclusion, findings from this study are valuable for Japanese MS patients, as the prevalence of MS in Japan, especially in the northern part of the country, is reportedly on the rise (Houzen et al., 2008). Natalizumab showed a high efficacy in Japanese RRMS patients consistent with its high efficacy in phase 3 trials in non-Japanese patients. Natalizumab was also well tolerated in Japanese patients, and no meaningful differences were observed in PK and PD profiles. These findings are important in showing that Japanese patients with RRMS can expect the same therapeutic benefit and adverse event profile with natalizumab therapy as patients of non-Japanese origin.

Conflicts of interest

TS (coordinating investigator): has received funding from, held board membership for, spoken at scientific meetings for, prepared manuscripts for, and had consulting agreements with Astellas, Biogen, Bayer-Schering, Daiichi-Sankyo, Eisai, Kaketsuken, Merck Serono, Mitsubishi-Tanabe, Nihon, Novartis, Ono, Sanofi, TDS Japan, and Teijin. JIK (coordinating investigator): consultant for Biogen and Novartis; honoraria from Bayer Healthcare, Biogen, Boehringer Ingelheim, Eisai, Kyowa Kirin, Mitsubishi Tanabe, Otsuka, Pfizer Japan, and Teijin; funding for travel from Bayer HealthCare and Biogen; grants from the Japanese Ministry of Health, Labour and Welfare, the Japanese Science and Technology Agency, and the Japanese Ministry of Education, Culture, Science, Sports and Technology. SK (PML consultant): consultant for Ajinomoto. TY (scientific advisor): member of scientific advisory boards for Biogen and Chugai; received research support from Asahi Kasei Kuraray, Chugai, Mitsubishi Tanabe, Ono, and Teva; received speaker honoraria from Abbot Japan, Astellas, Bayer, Biogen, Dainippon Sumitomo, Eisai, Mitsubishi Tanabe, Nihon, Novartis, and Santen; funded by the Japanese Ministry of Health, Labour and Welfare and the Japan Society for the Promotion of Science. YS, KO, JT, NL, MS: employed by and have equity interests in Biogen.

Funding

This study was funded by Biogen (Study no. 101-MS-203).

Acknowledgments

The authors wish to thank Pei-Ran Ho, MD, of Biogen, and Nobuhisa Ohtsuka, PhD, formerly of Biogen, for providing insightful feedback on the manuscript; Kumar Kandadi Muralidharan, PhD, for insightful discussions on the PK data; and Geoffrey Keusters, PhD, formerly of Biogen, for overseeing and supporting study sample testing.

We thank all patients and staff at participating sites for their contributions to the study. The following sites participated in the study (with principal investigators in parentheses): NCNP (Takashi Yamamura), Kyoto Miniren Center Hospital (Nobuhito Mori, Shinichi Nakamura), Irino Clinic (Takahiko Saida), Kitano Hospital (Sadayuki Matsumoto), Saitama Medical Center (Kyoichi Nomura), Juntendo University Hospital (Kazumasa Yokoyama), Tohoku University (Kazuo Fujihara), Utano National Hospital (Masami Tanaka), Iwate Medical University (Hikoaki Fukaura, Masanori Mizuno), Chiba University (Masahiro Mori), Tokyo Medical and Dental University (Hidehiro Mizusawa), Hokkaido University (Hidenao Sasaki, Makoto Hirotani), Tokyo Women's Med University Hospital (Shinichiro Uchiyama), Hokkaido Medical Center (Massaki Niino), Nigata University (Izumi Kawaichi), Yokohama University Center Hospital (Takehiko Nishiyama, Megumi Shimamura), Ebara Hospital (Chiyoko Nohara), National Defense Medical College Hospital (Kenichi Kaida), Osaka University Hospital (Yuji Nakatsuji), Kyushu University Hospital (Takuya Matsushita, Satoshi Yoshimura), Hiroshima University Hospital (Kazuhide Ochi), Yamaguchi University Hospital (Takashi Kanda), Tsukuba University Hospital (Akira Tamaoka), Kyoto University Hospital (Masafumi Ihara), and Hiroshima City Hospital (Tatsuo Kooriyama).

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Biogen provided funding for editorial support in the development of this manuscript, provided by Michelle McDermott, PharmD, a freelance medical writer and Alison Adams, PhD, of Ashfield Healthcare Communications (Middletown, CT). Chu Kong Liew, PhD, of ProScribe–Envision Pharma Group and Joshua Safran of Ashfield Healthcare Communications copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the manuscript to the authors. The authors had full editorial control of the manuscript and provided their final approval of all content.

Appendix A. Supplementary material

Download file

 

Supplementary material

 

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Footnotes

a Kansai Multiple Sclerosis Center and Kyoto Min-iren Central Hospital, Kyoto, Japan

b Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

c Hakusuikai Hatsuishi Hospital, Chiba, Japan

d National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan

e Biogen Japan, Tokyo, Japan

f Biogen, Cambridge, MA, USA

Correspondence to: Kansai Multiple Sclerosis Center, Nishinokyo-Kasuga-cho 16-44-409, Nakakyo-ku, Kyoto 604-8453, Japan.


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