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Long-term efficacy and safety of intramuscular interferon beta-1a: Randomized postmarketing trial of two dosing regimens in Japanese patients with relapsing-remitting multiple sclerosis
Multiple Sclerosis and Related Disorders, Volume 7, May 2016, Pages 102 - 108
To evaluate the efficacy and safety of 2 years of treatment with intramuscular interferon beta-1a (IM IFN beta-1a) in Japanese patients with relapsing-remitting multiple sclerosis, with an exploratory analysis of the impact of initial dose titration on tolerability.
Japanese patients with relapsing-remitting multiple sclerosis were randomized to receive IM IFN beta-1a at dosages of either 30 mcg once weekly (full-dose group, n=50) or 15 mcg once weekly for 2 weeks then 30 mcg once weekly thereafter (titration group, n=50). Key outcomes included annualized relapse rate (ARR) at 2 years (primary endpoint), change in disability measured using the Expanded Disability Status Scale (EDSS), safety, and tolerability.
The ARR (95% CI) decreased from 1.540 (1.381–1.718) at baseline to 0.371 (0.240–0.571) at Year 1 and 0.351 (0.244–0.503) at Year 2. EDSS improvements were apparent from Week 24; the mean change from baseline EDSS score (2.1) at Year 2 was −0.34 (P=0.004). The most frequently reported adverse events were influenza-like illness (92%), nasopharyngitis (57%), relapse of multiple sclerosis (51%), and injection-site reaction (30%). The overall incidence and severity of influenza-like symptoms were similar in the full-dose group and titration group; only 1 participant, in the full-dose group (2%), experienced severe influenza-like symptoms. However, the incidence of influenza-like symptoms was slightly reduced at earlier timepoints in the titration group.
The results of this 2-year study demonstrate that IM IFN beta-1a can be used effectively and safely in Japanese patients with relapsing-remitting multiple sclerosis for an extended period of time.
- Phase IV study of IFN beta-1a (30 mcg/week) in Japanese patients with RRMS.
- ARR decreased and EDSS score improved during the 2-year treatment period.
- There were no new safety concerns noted during the study.
- Dose titration slightly reduced influenza-like symptoms at early timepoints.
- IFN beta-1a can be used effectively and safely in Japanese patients with RRMS.
Abbreviations: ARR - annualized relapse rate, CI - confidence interval, EDSS - Expanded Disability Status Scores, Gd+ - gadolinium-enhancing, IFN beta - interferon beta, IFN beta-1a - interferon beta-1a, IM - intramuscular, MedDRA - Medical Dictionary for Regulatory Activities, MRI - magnetic resonance imaging, MS - multiple sclerosis, MSCRG - Multiple Sclerosis Collaborative Research Group, RRMS - relapsing remitting multiple sclerosis, SD - standard deviation.
Keywords: Clinical trial, Phase IV, Interferon beta-1a, Japan, Multiple sclerosis.
Multiple sclerosis (MS) is a chronic and debilitating autoimmune disorder of the central nervous system. The most common clinical variant, relapsing-remitting MS (RRMS), is characterized by recurrent acute exacerbations of neurologic dysfunction, followed by partial or complete recovery (NIH National Institute of Neurological Disorders and Stroke, 2015). Interferon beta (IFN beta) therapy is widely regarded as a standard therapy for MS, based on a wealth of evidence from a large number of clinical trials involving parenteral treatment with different formulations and dosages across diverse types of MS (Goodin et al, 2002, Multiple Sclerosis Advisory Committee of the Neurological Association of South Africa, 2004, and Wiendl et al, 2008). Meta-analyses and systematic reviews have demonstrated significant improvements in relapse rate and disability associated with IFN beta therapy, particularly in early and relapsing-remitting forms of MS (Clerico et al, 2008, Mantia et al, 2013, Nikfar et al, 2010, and Oliver et al, 2011).
Intramuscular (IM) IFN beta-1a (Avonex®, Biogen) was first approved for treatment of RRMS in the United States in 1996 and in Japan in 2006; it is now approved in more than 80 countries (Nikfar et al., 2010). In the pivotal Multiple Sclerosis Collaborative Research Group (MSCRG) study, once-weekly IM IFN beta-1a 30 mcg treatment resulted in a significant beneficial impact in patients with RRMS by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity detected by brain magnetic resonance imaging (MRI) scans (Jacobs et al., 1996). An average of 15 years after randomization into the MSCRG study, patients continuing treatment with IM IFN beta-1a had less disability and a better quality of life than patients who were not being treated with IM IFN beta-1a (Bermel et al., 2010).
Patients participating in the initial IM IFN beta-1a 30 mcg study by the MSCRG (Jacobs et al., 1996) and in the long-term follow-up study (Bermel et al., 2010) were predominantly Caucasian. In one small study conducted in 25 Japanese patients with RRMS, the efficacy of IM IFN beta-1a 30 mcg, based on MRI measures, was similar to that reported in Caucasians (Saida et al., 2012). Relapse and disability outcomes were evaluated; however, the duration of treatment was relatively short (24 weeks) (Saida et al., 2012). Here, we evaluate the efficacy and safety of 2 years of treatment with IM IFN beta-1a in Japanese patients with RRMS. We also present an exploratory analysis of the effect of dose titration on the severity and incidence of influenza-like symptoms, which were reported by 80% of patients in our initial study (Saida et al., 2012).
2.1. Study population
This open-label, multicenter (35 sites, predominantly major hospitals), 2-year study enrolled Japanese patients aged 18 to 55 years with a confirmed diagnosis of RRMS (McDonald criteria, 2005 revisions) (Polman et al., 2005). Patients were included in the study if they had an Expanded Disability Status Scale (EDSS) score between 0.0 and 5.5 (MS symptoms ranging from normal neurological function to disability impairing full daily functions) (Kurtzke, 1983), experienced at least 1 relapse in the year before consenting to participate or at least 2 relapses in the previous 2 years, had no relapse during the previous 4 weeks, and had not been treated with corticosteroids or IFN beta within 4 weeks of the first dose of study drug. All participants were required to provide written informed consent. The use of concomitant nonsteroidal anti-inflammatory drugs was permitted for the management of influenza-like symptoms.
2.2. Study design
Eligible patients were randomized 1:1 to receive IM IFN beta-1a 30 mcg once weekly from study start (the full-dose group) or IM IFN beta-1a 15 mcg once weekly for 2 weeks and then IM IFN beta-1a 30 mcg once weekly thereafter (the titration group). Two treatment arms were included to compare the incidence and severity of adverse events, including influenza-like symptoms, in an exploratory manner. The study protocol was approved by the Institutional Review Board of each institution. The study was conducted in accordance with Good Clinical Practice and Good Post-marketing Study Practice of the Pharmaceutical Affairs Law of Japan and the Declaration of Helsinki.
Scheduled assessments included EDSS scores recorded at baseline, at Weeks 24, 48, 72, and 104, and at study termination, in addition to brain MRI imaging (of gadolinium-enhancing [Gd+] and T2-weighted [T2] lesions) conducted at baseline, at Weeks 24, 48, and 104, and at study termination. Serum levels of anti-IFN beta-1a neutralizing antibodies were determined at baseline and in samples taken at least 48 hours after each dose at Weeks 24, 48, 72, and 104, and at study termination.
2.3. Outcome measures
Relapses were defined as new neurological symptoms or worsening of pre-existing neurological symptoms not associated with fever, which lasted at least 48 hours in participants who were neurologically stable or improving for the previous 30 days, and accompanied by worsening of ≥0.5 point in EDSS score or >1.0 point in the pyramidal, cerebellar, brainstem, or visual Functional System Score (Kurtzke, 1983). Relapses were treated by administration of methylprednisolone 500 mg/day via intravenous infusion for 3–5 days or 1000 mg/day via intravenous infusion for 3 days, followed (if necessary) by oral methylprednisolone 60 mg/day, then at tapered doses for up to 3 weeks. Disability (EDSS) was evaluated before initiating steroid treatment for a suspected relapse.
The primary efficacy endpoint was the annualized relapse rate (ARR) at 2 years. Other efficacy endpoints included time to first relapse, time to development of sustained progression of disability, and the number of Gd+ and T2 lesions detected by brain MRI. Sustained progression of disability was defined as an increase in EDSS score sustained for at least 24 weeks of ≥1.0 point in participants with a baseline score of ≥1.0, or ≥1.5 points in participants with a baseline score of 0.
Evaluation of the safety and tolerability of IM IFN beta-1a included analysis of adverse events, laboratory parameters, and vital signs. Influenza-like symptoms, adverse events of special interest (Saida et al., 2012), were investigated as a composite term encompassing the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms influenza-like illness, myalgia, pyrexia, hyperpyrexia, intermittent pyrexia, and fatigue.
2.4. Statistical methods
The study population size of 100 was selected as the minimum sample size based on the feasibility of comparing the study outcomes with those of other studies, taking into account the number of available patients in Japan from the target population and access to other drugs in the same class. Treatment adherence was determined by the proportion of study drug taken, calculated as 100×the total number of doses received divided by the number of weeks in the study. Baseline demographics and disease characteristics were analyzed using summary statistics for continuous variables and frequency distributions for categorical variables.
Efficacy analyses included all participants receiving at least one dose of IM IFN beta-1a and undergoing at least one efficacy assessment after baseline. The study was not designed to compare efficacy between the randomization groups; therefore, efficacy results were analyzed for the overall study population. The primary efficacy endpoint, ARR, was evaluated using Poisson regression (log-likelihood ratio test, assuming the number of relapses followed a Poisson distribution). Changes in EDSS scores from baseline were evaluated using t-tests. Other outcomes were analyzed using descriptive statistics.
Safety data were also analyzed using descriptive statistics for all participants receiving at least one dose of IM IFN beta-1a.
A total of 100 Japanese patients with RRMS were randomized to either the full-dose group (n=50) or the titration group (n=50) (Fig. 1). All 100 randomized participants received IM IFN beta-1a and were included in efficacy and safety analyses. Treatment adherence was high, with 43 of 50 (86%) participants in the full-dose group and 41 of 50 (82%) participants in the titration group receiving >90% of study drug. In total, 67 participants (67%) completed the 2-year study, including 37 of 50 (74%) participants in the full-dose group and 30 of 50 (60%) participants in the titration group. The most common reason for discontinuation was an adverse event or worsening of MS symptoms, and only 5 participants (1 from the full-dose group and 4 from the titration group) discontinued due to lack of efficacy. None of the participants discontinued within the first 2 weeks, and only 1 participant from each study group discontinued during Weeks 3 or 4 of the study. The mean (standard deviation [SD]) time on study drug was 609.9 (218.79) days in the full-dose group and 574.2 (226.71) days in the titration group.
The majority of participants (79 of 100) were female; on average, participants had experienced 1.5 relapses in the year before study entry, and had a mean (SD) baseline EDSS score of 2.1 (1.53) (Table 1), indicating the presence of minimal disability in 1 of 8 functional (central nervous) systems (Kurtzke, 1983). All participants had RRMS, with MS diagnosed approximately 4.5 years before the study, and 21 participants had received prior treatment with IFN beta-1b, taken for a mean (SD) of 2.4 (2.19) years. Thirty-four participants (34%) had Gd+ lesions at baseline.
|Characteristic||Full-dose group ( n =50)||Titration group ( n =50)||Total ( N =100)|
|Age, mean (SD), years||34.8 (8.63)||36.6 (8.06)||35.7 (8.35)|
|Female, n (%)||41 (82)||38 (76)||79 (79)|
|Time since first RRMS symptoms, mean (SD), years||6.5 (6.68)||7.3 (7.25)||6.9 (6.95)|
|Time since RRMS diagnosis, mean (SD), years||3.7 (5.24)||5.3 (5.93)||4.5 (5.63)|
|Prior relapses, mean (SD)|
|In year before study entry||1.5 (0.71)||1.6 (0.9)||1.5 (0.86)|
|In 2 years before study entry||2.1 (1.10)||2.3 (1.43)||2.2 (1.27)|
|Relapses in year before study entry, n (%)|
|0||1 (2)||2 (4)||3 (3)|
|1||29 (58)||26 (52)||55 (55)|
|2||15 (30)||15 (30)||30 (30)|
|3||5 (10)||6 (12)||11 (11)|
|≥4||0 (0)||1 (2)||1 (1)|
|Mean (SD)||1.9 (1.44)||2.3 (1.60)||2.1 (1.53)|
|Median (range)||2.0 (0.0–5.5)||2.0 (0.0–5.5)||2.0 (0.0–5.5)|
|EDSS score at baseline, n (%)|
|0–1.5||22 (44)||19 (38)||41 (41)|
|2.0–3.5||23 (46)||23 (46)||46 (46)|
|≥4.0||5 (10)||8 (16)||13 (13)|
|Number of Gd+ lesions, n (%)|
|0||32 (64)||34 (68)||66 (66)|
|1–3||15 (30)||10 (20)||25 (25)|
|≥4||3 (6)||6 (12)||9 (9)|
|Mean (SD) lesion number||0.9 (2.01)||0.8 (1.49)||0.8 (1.76)|
|Volume of T2 lesions, mean (SD), mm3||761.1 (916.88)||800.3 (727.76)||780.7 (823.78)|
|Prior treatment with IFN beta-1b, n (%)a||9 (18)||12 (24)||21 (21)|
|Treatment for RRMS in year before study entry, n (%)||39 (78)||37 (74)||76 (76)|
|Methylprednisolone sodium succinate||31 (62)||33 (66)||64 (66)|
|Prednisolone||21 (42)||15 (30)||36 (36)|
|Steroid pulse (unknown type)||6 (12)||3 (6)||9 (9)|
|Azathioprine||1 (2)||1 (2)||2 (2)|
|Betamethasone sodium phosphate||1 (2)||1 (1)|
|Dexamethasone sodium phosphate||1 (2)||1 (1)|
|Dexamethasone||1 (2)||1 (1)|
|Fingolimod||1 (2)||1 (1)|
a Other formulations of IFN beta were not available in Japan at the time of the study.
EDSS, Expanded Disability Status Scores; Gd+, gadolinium-enhancing; IFN beta-1b, interferon beta-1b; RRMS, relapsing-remitting multiple sclerosis; SD, standard deviation; T2, T2-weighted
Important protocol deviations were recorded for 15 participants, all relating to concomitant medications and therapies; 12 participants received prophylactic treatment with steroid preparations (for prophylaxis of acute exacerbation in 10 participants, after relapse recovery in 1 participant, and for symptoms other than MS in 1 participant). One participant received IFN beta-1b preparation during the post-study period, before the final MRI scan. Two participants discontinued IM IFN beta-1a treatment: one because of a lymphoma that required treatment with an immunosuppressive agent and one because of a malignant cardiac neoplasm that required treatment with gamma globulin. The possibility that steroid therapy may have affected the efficacy assessment in this study cannot be excluded.
The unadjusted ARR was 1.540 for the year before study entry, decreasing to 0.401 in Year 1 and 0.371 at Year 2. The adjusted ARR (95% confidence interval [CI]), calculated using Poisson regression analysis, was 1.540 (1.381–1.718) before study entry. Following 1 year of treatment, the ARR (95% CI), after adjusting for the number of acute exacerbations in the year before study entry, had decreased to 0.371 (0.240–0.571), with a further decrease to 0.351 (0.244–0.503) at the end of Year 2.
Of the 100 participants included in the efficacy analysis, 43 participants experienced a relapse during the 2-year study (with 1, 2, 3, and ≥4 relapses experienced by 30, 8, 4, and 1 participants, respectively). The proportion (95% CI) of participants who relapsed at 2 years, estimated by the Kaplan–Meier method, was 0.47 (0.38–0.58) for the overall population, with an estimated median time to first relapse of 1.64 years (Fig. 2).
Adjusted for number of acute exacerbations in the year before the study, the ARR (95% CI) for requiring steroid treatment at 2 years, calculated from Poisson regression analysis, was 0.276 (0.193–0.396), and the ARR (95% CI) for requiring hospitalization at 2 years was 0.078 (0.035–0.173).
Overall, 3 participants had sustained confirmed disability progression; the proportion of participants experiencing sustained confirmed disability progression at 2 years estimated using the Kaplan–Meier method was 0.04. The EDSS score improved from baseline at Week 24, with further improvements at subsequent timepoints (Fig. 3); the mean (SD) change from baseline at Year 2 (Week 104) was −0.34 (0.958; P = 0.004).
3.2.3. MRI outcomes
MRI outcomes indicated that the mean number of Gd+ lesions decreased from baseline by Week 24, and continued to decrease further until Week 104 (Fig. 4). Although there was an increase in the mean number (from 0.45 to 0.80) of new or newly enlarging T2 lesions between Weeks 24 and 104, 48 of 100 of participants remained free of new or newly enlarging lesions at 104 weeks. Reductions from baseline were observed in the overall volume of T2 lesions from Week 24 to Week 104.
3.2.4. Correlations between brain MRI and clinical outcomes
As may be expected given the small number of participants with relapses and new brain lesions, correlations between brain MRI and clinical findings were weak; the correlation coefficients ranged from 0.133 (P=0.470) to 0.260 (P=0.150). Among the 27 participants with Gd+ lesions, the mean (SD) relapse rate was 1.107 (3.8585) and the time to first relapse was 296.4 (217.99) days (n=14 with relapse). Among the 73 participants without Gd+ lesions, the mean (SD) relapse rate was 0.495 (0.9260), with a mean (SD) time to relapse (n=29) of 256.9 (204.87) days. There was no correlation between Gd+ lesions and relapse rate (correlation coefficient, 0.156, P=0.182).
Similarly, among the 36 participants with new or newly enlarging T2 lesions, the mean (SD) ARR was 0.9 (3.35) and the mean (SD) time to first relapse was 318.6 (212.62) days (n=19 with relapse). Among the 64 participants without new or newly enlarging T2 lesions, the mean (SD) ARR was 0.5 (0.98) and the mean (SD) time to first relapse was 231.1 (199.21) days (n=24 with relapse).
3.3. Safety and tolerability
3.3.1. Adverse events
All participants enrolled in the study experienced one or more adverse events (Table 2). The most frequently reported adverse event was influenza-like illness, reported by 46 participants (92%) in each group. The incidence of adverse events leading to study discontinuation was 10% in the full-dose group and 16% in the titration group. No clinically significant differences were observed between the full-dose and titration groups in the timing or severity of adverse events.
|Event,n(%) of participants||Full-dose group ( n =50)||Titration group ( n =50)||Total ( N =100)|
|Any adverse event|
|Within 2 weeks after first dose||47 (94)||45 (90)||92 (92)|
|Within 4 weeks after first dose||49 (98)||48 (96)||97 (97)|
|At any time in the study||50 (100)||50 (100)||100 (100)|
|Most commonly reported eventsa,b|
|Influenza-like illness||46 (92)||46 (92)||92 (92)|
|Nasopharyngitis||31 (62)||26 (52)||57 (57)|
|MS relapse||19 (38)||32 (64)||51 (51)|
|Injection-site reaction||13 (26)||17 (34)||30 (30)|
|Headache||14 (28)||13 (26)||27 (27)|
|Pyrexia||17 (34)||9 (18)||26 (26)|
|Insomnia||5 (10)||7 (14)||12 (12)|
|Injection-site pain||10 (20)||8 (16)||18 (18)|
|Malaise||6 (12)||10 (20)||16 (16)|
|Dizziness||7 (14)||8 (16)||15 (15)|
|Constipation||7 (14)||8 (16)||15 (15)|
|Eczema||6 (12)||6 (12)||12 (12)|
|Injection-site erythema||7 (14)||4 (8)||11 (11)|
|Diarrhea||4 (8)||6 (12)||10 (10)|
|Nausea||5 (10)||5 (10)||10 (10)|
|Abnormal hepatic function||5 (10)||5 (10)||10 (10)|
|Back pain||3 (6)||7 (14)||10 (10)|
|Serious adverse eventb||7 (14)||9 (18)||16 (16)|
|MS relapse||5 (10)||5 (10)||10 (10)|
|Otherc||2 (4)||4 (8)||6 (6)|
|Adverse events leading to study drug discontinuation||5 (10)||8 (16)||13 (13)|
|MS relapse||2 (4)||3 (6)||5 (5)|
|Depression||2 (4)||0 (0)||2 (2)|
|Otherd||1 (2)||5 (10)||6 (6)|
a Reported by ≥10% of participants in the overall population.
b Participants may have had more than 1 event.
c Comprising 1 case each of diverticulitis, rectal adenoma, hypoesthesia, postural dizziness, visual impairment, muscular weakness, neurogenic bladder, and/or ovarian mass in the full dose group and 1 case each of malignant cardiac neoplasm, lymphoma, abnormal hepatic function, osteonecrosis, and/or meniscus lesion in the titration group.
d Comprising 1 case of abnormal hepatic function in the full dose group and 1 case each of malignant cardiac neoplasm, lymphoma, hypertonia, abnormal hepatic function, and/or arthralgia in the titration group.
MS: multiple sclerosis.
A total of 16 participants experienced at least 1 serious adverse event, with similar incidence in the full-dose and titration groups (Table 2). The most frequently reported serious adverse event was MS relapse, reported by 5 participants in each group, with half of these events (2 in the full-dose group and 3 in the titration group) resulting in study drug discontinuation. No deaths were reported during the study.
3.3.2. Influenza-like symptoms
The incidence of the composite influenza-like symptoms was similar in the full-dose group (50 of 50, 100%) and the titration group (46 of 50, 92%), with similar numbers of participants having mild (32 versus 30), moderate (17 versus 16), or severe (1 versus 0) symptoms. The overall incidence of influenza-like symptoms was very high in both groups and not affected by dose titration at 1 or 2 years but was slightly reduced at earlier timepoints in the titration group. At Weeks 2, 4, and 12, influenza-like symptoms were reported in 45, 46, and 48 participants in the full-dose group compared with 37, 42, and 45 participants in the titration group.
3.3.3. Neutralizing antibodies
Only 2 of 100 participants, both in the titration group, developed persistent anti-IFN beta-1a neutralizing antibodies starting at 48 weeks after treatment initiation. Neither of these participants experienced a relapse.
3.3.4. Other safety measures
There were no clinically significant changes in other safety measures, including laboratory measurements and vital signs (data not shown).
This 2-year study has demonstrated the efficacy and safety of IM IFN beta-1a therapy for Japanese patients with RRMS. The ARR was reduced within the first year of treatment and remained low in the second year, accompanied by improvements in disability progression as assessed by EDSS score. In addition, MRI outcomes demonstrated reductions in the number of Gd+ lesions and the volume of T2 lesions. Few participants developed anti-IFN beta-1a antibodies, and their occurrence was not associated with relapse in those participants. The most commonly reported adverse events were influenza-like symptoms, and no new safety signals emerged during the study. Overall, this 2-year study demonstrates that IM IFN beta-1a is effective in the treatment of Japanese patients with RRMS. However, titration of IFN beta-1a (15 mcg once weekly for 2 weeks then 30 mcg once weekly thereafter) does not improve tolerability compared with once-weekly treatment with 30 mcg IFN beta-1a.
The data from this study are important given the paucity of other published clinical trial data on IFN beta in Japanese patients with RRMS. Although study comparisons should be interpreted with caution, the results of this study were similar to those of a smaller, 24-week, phase 2 study of IM IFN beta-1a in 25 Japanese patients with MS (Saida et al., 2012). However, differences in treatment duration and in study populations (with the phase 2 study not including participants with EDSS score <1.0), as well as the use of steroids by 12 participants (a protocol violation) in the present study, may have contributed to the lower unadjusted ARR in the present study (0.40 at Year 1 and 0.37 at Year 2) than in the phase 2 study (0.81 at 24 weeks) (Saida et al., 2012). Regarding the safety, the results of this study were similar to those of a phase 2 study of subcutaneous IFN beta-1b in Japanese patients with RRMS (Saida et al., 2005). The only major difference in safety was that serious injection-site reactions were reported in the subcutaneous IFN beta-1b study, but not in the present study.
Although the mean number of Gd+ lesions decreased over the course of the 2-year study, there was an apparent increase in the mean number of new or newly enlarging T2 lesions. This discrepancy may be partly attributable to the difficulties in interpreting MRI scans, especially in the identification of enlarging T2 lesions (Erbayat Altay et al., 2013). In addition, the relatively small number of participants, especially by the end of the study, may have contributed to this discrepancy. Indeed, as the number of participants with new or newly enlarging T2 lesions decreased during the study, there may have been a few participants with numerous new or enlarging T2 lesions, which resulted in an increase in the mean number per participant.
The efficacy and safety profiles of IM IFN beta-1a in this study of Japanese participants with RRMS are consistent with data reported in studies of predominantly Caucasian patients, such as the pivotal phase 3 trial of IM IFN beta-1a (Jacobs et al., 1996), and are supported by extensive long-term therapy experience (Bermel et al., 2010). Regarding efficacy, the unadjusted ARR for 2 years in the present study (0.371) was lower than that in the pivotal phase 3 trial (0.90 for placebo and 0.61 for IFN beta-1a treatment; Jacobs et al., 1996). However, this should be interpreted with caution, given that patients in the present study might have relatively low disease activity level. Nevertheless, the absence of any meaningful differences in outcomes between Japanese and Caucasian patients suggest that continued benefit may also be expected during long-term IM IFN beta-1a therapy in Japanese patients.
Although no effect of dose titration on the incidence or severity of influenza-like symptoms beyond the first few months was seen in the exploratory portion of the study, dose titration of IM IFN beta-1a has been shown in other studies to reduce the incidence and severity of influenza-like symptoms (Devane et al, 2014 and Matson et al, 2011). However, these studies were conducted in healthy volunteers, with more protracted 3-week and 6-week titration periods, and did not explore long-term impact. The outcomes of dose titration in these studies were, however, consistent with those reported for dose titration with IFN beta-1b therapy in patients with MS (Wroe, 2005). Other approaches, such as the use of analgesics, may also be helpful in alleviating influenza-like symptoms (Brandes et al., 2007). Given that the incidence of influenza-like symptoms (and most other adverse events) in our study was similar in both the dose-titration and full-dose groups, but the incidence of relapse was higher in the dose-titration group, the dose titration schedule (15 mcg once weekly for 2 weeks and then IM IFN beta-1a 30 mcg once weekly thereafter) in this study may not offer any substantial safety benefit and may be less efficacious than initiating treatment at the full dose. Further studies using different titration schedules will be needed to determine the most optimal treatment with IFN beta-1a.
In the present study, only 2 of 100 (5%) participants developed anti-IFN beta-1a neutralizing antibodies, and neither participant experienced a relapse. This is consistent with data from Caucasian patients with MS and with the findings of a previous study in Japanese patients with MS, in which 4 of 77 (5%) and 46 of 152 (30%) participants developed neutralizing anti-IFN beta antibodies following treatment with IFN beta-1a and IFN beta-1b, respectively (Sato et al, 2012 and Sorensen et al, 2008).
In conclusion, the efficacy and safety results of this 2-year study demonstrate that IM IFN beta-1a can be used effectively and safely in Japanese patients with RRMS for an extended period of time.
Conflicts of interest
Dr Saida has received funding from, held board membership with, spoken at scientific meetings for, prepared manuscripts for, and/or had consulting agreements with Astellas Pharma, Bayer Schering Pharma, Biogen, Daiichi Sankyo, Eisai, Kaketsuken, Merck Serono, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, Ono Pharmaceutical, Sanofi, TDS Japan, Teijin Pharmaceutical. Dr Kira has received payment for lectures or funding from Astellas Pharma Inc., Eisai Co. Ltd, GlaxoSmithKline, Nichii Gakkan Co., Medical Review Co. Ltd, Alexion Pharmaceuticals, Bayer Yakuhin Ltd, Janssen Pharmaceutical K.K., Santen Pharmaceutical Co. Ltd, Ono Pharmaceutical, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma Co. Ltd, Sanofi, Novartis Pharma K.K., Takeda Pharmaceutical Ltd, Pfizer Japan Inc., Mitsubishi-Tanabe Pharmaceutical, Biogen Japan, Daiichi-Sankyo, Boehringer Ingelheim, and Japan Blood Products Organization. Mr Ueno, Mr Harada, and Mr Hirakata are current or former employees of and have equity interests in Biogen Japan.
This study was sponsored by Biogen Japan Ltd. The authors gratefully acknowledge the study investigators for their contributions. Biogen provided funding for editorial support in the development of this manuscript; Mary Goodsell of Infusion Communications and Rebecca Lew, PhD, CMPP and Rose Boutros, PhD of ProScribe – part of the Envision Pharma Group, wrote the first draft of this manuscript based on input from the authors. 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.
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a Kansai Multiple Sclerosis Center and Department of Neurology, Kyoto Min-iren Central Hospital, Kyoto, Japan
b Department of Neurology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
c Biogen Japan Ltd, Tokyo, Japan
⁎ Correspondence to: Kansai Multiple Sclerosis Center, Nishinokyo Kasuga-cho 16-44-409, Nakakyo-ku, Kyoto 604-8453, Japan.
© 2016 Published by Elsevier B.V.