Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study.

BACKGROUND: The low level of disease activity and manageable safety profile seen with fingolimod versus placebo in a 6-month, phase 2, randomized controlled trial in Japanese patients with relapsing multiple sclerosis (MS; ClinicalTrials.gov Identifier NCT00537082) were maintained in the initial 6-month observational study extension. Here, we report long-term safety and efficacy results of the 3-year follow-up to the phase 2 study extension. METHODS: The 6-month core study was completed by 147 patients, of whom 143 entered the extension and took at least one dose of fingolimod. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg (n = 23) or 0.5 mg (n = 27). During the extension, the patients taking fingolimod 1.25 mg (n = 46) were switched to open-label fingolimod 0.5 mg, and those originally randomized to fingolimod 0.5 mg (n = 47) continued with open-label fingolimod 0.5 mg. RESULTS: Continuous fingolimod treatment was associated with a sustained low level of MRI and relapse activity for the duration of the extension phase; 75-100% (range across all assessment time points up to end of study) of patients remained free of Gd-enhanced T1 lesions, 88-100% remained free of new/newly enlarged T2 lesions, and 45-62% remained relapse-free. In patients who switched to the active treatment, a 79.5% decrease in annualized relapse rate (ARR; from 1.131 before switch to 0.232 6-months after switch) was observed in the first 6 months of the extension phase and thereafter remained low until the end of study (0.16-0.31 across all assessment time points after switch up to end of study). The mean number of Gd-enhanced T1 and new/newly enlarged T2 lesions decreased up to month 9 and thereafter remained low until the end of study (0.0-0.1 and 0.0-0.3, respectively, across all assessment time points after switch up to end of study). Fingolimod was generally well-tolerated and the safety profile was consistent with the core and 6-month extension. Serious adverse events were reported in 13.3% of patients during the extension study, with the range in the continuous fingolimod and placebo-fingolimod switch groups (3.7-21.7%) being similar to that reported in the core study for the placebo and fingolimod groups (5.3-20.4%). CONCLUSION: Continuous fingolimod treatment over 36 months was associated with maintained efficacy and a manageable safety profile with no new safety signals. These results indicate that fingolimod provides long-term treatment benefit for Japanese patients with relapsing MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT00670449 (April 28, 2008).

Bimagrumab to improve recovery after hip fracture in older adults: a multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial.

BACKGROUND: Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. METHODS: This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15-35 kg/m2 who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. FINDINGS: Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p<0·0001) and in the bimagrumab 700 mg group 2·8 kg [2·2]; p<0·0001) but not in the bimagrumab 70 mg group (0·6 kg [SD 2·2]; significance not assessed). Changes in habitual gait speed and short physical performance battery scores between baseline and week 24 were not significantly different across the treatment groups, suggesting no enhancement of physical recovery with bimagrumab over placebo. Bimagrumab was safe and well tolerated. The most frequently reported treatment-emergent adverse events were falls (six [18%] of 34 participants in the bimagrumab 70 mg group; 12 [17%] of 69 participants in the bimagrumab 210 mg group; 14 [19%] of 75 participants in the bimagrumab 700 mg group; and 13 [18%] of 72 participants in the placebo group), muscle spasms (two [6%] in the bimagrumab 70 mg group; 17 [25%] in the bimagrumab 210 mg group; 12 [16%] in the bimagrumab 700 mg group; and six [8%] in the placebo group), and arthralgia (five [15%] in the bimagrumab 70 mg group; six [9%] in the bimagrumab 210 mg group; nine [12%] in the bimagrumab 700 mg group; and five [7%] in the placebo group). Six deaths were reported during the study, none of which were considered by investigators as related to the study drug. INTERPRETATION: Bimagrumab treatment for 24 weeks led to dose-dependent, significant increases in lean body mass in older patients recovering from hip fracture surgery when compared with placebo. However, no functional benefit was observed in recovery of mobility or lower extremity function following bimagrumab treatment compared with placebo. FUNDING: Novartis Pharma.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study.

BACKGROUND: Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis. METHODS: In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18-55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00879658. FINDINGS: Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0·0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35% (95% CI 17-57) for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 50% (29-69) for siponimod 0·5 mg (43 patients), 66% (48-80) for siponimod 1·25 mg (42 patients), 72% (57-84) for siponimod 2 mg (45 patients), and 82% (70-90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 43 patients who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 patients who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 (81%) of 16 controls (none serious). INTERPRETATION: Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial. FUNDING: Novartis Pharma AG.