Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054.

BACKGROUND: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE: This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS: A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS: Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS: BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial.

BACKGROUND: Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years. METHODS: Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall. RESULTS: Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p < 0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p < 0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p < 0.0001). CONCLUSION: Peginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00906399 ; Registered on: May 20, 2009.

Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE.

OBJECTIVE: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study. METHODS: Patients were randomized to placebo or 125 µg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. RESULTS: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated. CONCLUSIONS: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1.Clinicaltrials.gov REGISTRATION NUMBER: NCT00906399.

Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis in the randomized ADVANCE study.

AIMS: To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS) in the phase 3 ADVANCE study (n = 1512). METHODS: During year 1, patients were randomized (1:1:1) to placebo or peginterferon beta-1a 125 µg every 2 or 4 weeks. After year 1, patients randomized to placebo were re-randomized to 125 µg peginterferon beta-1a administered every 2 weeks or every 4 weeks for year 2. Patients randomized to peginterferon beta-1a in year 1 remained on the same dosing regimen in year 2. Intensive blood samples for PK and PD (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) measurements were collected from 44 patients pre-dosing and at intervals over 240 h post-dosing at weeks 4 and 24. Sparse samples were collected from all patients after each dosing at weeks 4, 12, 24, 56 and 84. RESULTS: The PK profile of peginterferon beta-1a did not change over time or between dosing regimens. No accumulation was observed. Peak serum concentrations were reached 1-1.5 days post-dosing, with a mono-phasic decline and a median half-life of approximately 2-3 days. Dosing every 2 weeks provided approximately two-fold greater monthly cumulative area under the curve than every 4 weeks. Neopterin elevation was sustained for 10-14 days following each dose, indicating doubled cumulative duration of pharmacological activity for dosing every 2 weeks vs. every 4 weeks. CONCLUSIONS: These PK/PD profiles potentially explain the enhanced efficacy of dosing every 2 weeks in patients with RRMS.

Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis.

BACKGROUND: Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1. METHODS: RRMS patients (18-65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 µg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted. RESULTS: 1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p < 0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p < 0.0001), as well as the volume of T2 and T1 lesions (p < 0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p < 0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity. CONCLUSION: During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00906399.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson's disease.

Epidural motor cortex stimulation has been reported to be effective in treating some movement disorders. Nevertheless, clinical results have been variable and no double-blinded evaluations have been reported. The aim of this study was to investigate efficacy and safety of unilateral subdural motor cortex stimulation in patients with essential tremor and Parkinson's disease. Six patients with essential tremor and five parkinsonian patients were selected. Craniotomy was performed under local anaesthesia with conscious sedation. A four contact electrode (Resume II model 3587, Medtronic, Inc) was positioned on the motor cortex, after identification of the area with direct monopolar cortical stimulation. Soon after surgery, a variety of different settings of stimulation were assessed using standard rating scales to select the optimal stimulation parameters. The effects of chronic stimulation were evaluated in both groups of patients after 3 months (double-blinded fashion) and 1 year (open fashion). In essential tremor, contralateral hand tremor scores significantly improved (P = 0.04) with stimulation during the double-blinded study, whereas in Parkinson's disease, there were no changes in the OFF medication/on stimulation motor scores compared with off stimulation. At 1 year, tremor was improved by stimulation in two out of three patients with essential tremor available at follow-up, whereas no improvement was observed in the five parkinsonian patients. One parkinsonian patient had a cortical venous infarct. Three other patients had self-limiting seizures with aggressive trials of stimulation in the period of dosage selection. These findings suggest that unilateral subdural motor cortex stimulation may be useful for contralateral hand tremor in selected patients with essential tremor but was not effective in improving parkinsonian signs in our series.

Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease.

BACKGROUND: The huntingtin gene (HTT) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments. OBJECTIVE: This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions. METHODS: Across 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing. RESULTS: Heterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the mHTT allele in 61% (95% high density interval: 55%, 67%) of individuals. CONCLUSIONS: These results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD.

Long-term outcomes of peginterferon beta-1a in multiple sclerosis: results from the ADVANCE extension study, ATTAIN.

BACKGROUND: ADVANCE was a phase III trial of the efficacy and safety of subcutaneous peginterferon beta-1a 125 µg every 2 or 4 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). ATTAIN was a 2-year extension study of ADVANCE. The aim was to evaluate the long-term safety, tolerability, and efficacy of peginterferon beta-1a 125 µg every 2 or 4 weeks in ATTAIN. METHODS: ADVANCE dosing schedules were maintained in ATTAIN, except that every-4-weeks dosing patients were switched to every-2-weeks dosing after conversion of the study to an open-label protocol. ATTAIN was considered complete when the last patient completed the 96-week extension study. Primary endpoints included adverse event (AE) and serious AE (SAE) incidence. Secondary endpoints included relapse, magnetic resonance imaging, and disability outcomes. RESULTS: Of the 1512 patients randomized in ADVANCE, 1076 (71%) continued treatment in ATTAIN; of these, 842 (78%) completed the open-label extension study. During ATTAIN, 478 patients (87%) in the every-2-weeks group and 471 patients (89%) in the every-4-weeks group experienced an AE; SAEs were reported in 90 patients (16%) in the every-2-weeks group and 113 patients (21%) in the every-4-weeks group. The most frequent AEs reported were injection site reactions and flu-like symptoms, both of which numerically decreased over time. Peginterferon beta-1a every 2 weeks versus every 4 weeks significantly reduced the adjusted annualized relapse rate over 6 years (0.188 versus 0.263, p = 0.0052) and the risk of relapse over 5 years (36% versus 49%, p = 0.0018). Fewer new T1, new/newly enlarging T2, and gadolinium-enhancing magnetic resonance imaging lesions were observed with every-2-weeks dosing than every-4-weeks dosing over 4 years. CONCLUSIONS: Results from the ADVANCE extension study, ATTAIN, confirm the favorable long-term safety and tolerability profile of peginterferon beta-1a in patients with RRMS and provide additional evidence for the clinical and radiological benefits associated with this therapy.

Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

BACKGROUND: In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). METHODS: In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. RESULTS: Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. CONCLUSIONS: Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399].

Subgroup and sensitivity analyses of annualized relapse rate over 2 years in the ADVANCE trial of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis.

ADVANCE was a 2-year, double-blind, placebo-controlled, Phase 3 study in 1512 patients aged 18-65 years with relapsing-remitting multiple sclerosis, which demonstrated that peginterferon beta-1a 125 mcg administered subcutaneously every 2 or 4 weeks led to significant reductions in annualized relapse rate (ARR) compared with placebo. This analysis examined ARR over 2 years in ADVANCE across subgroups. Patients were treated with peginterferon beta-1a every 2 weeks or every 4 weeks, or placebo during Year 1. Thereafter, patients on placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks (delayed treatment). Subgroup analyses were conducted by demographics and baseline disease characteristics. The following results compared ARR in these subgroups for patients in continuous 2-week treatment versus continuous 4-week treatment. ARR was similar in most demographic and baseline disease characteristic subgroups evaluated within the peginterferon beta-1a every-2-week arm or every-4-week arm over 2 years. Although for both doses some differences in the point estimates for ARR were noted among the subgroups, considerable overlap in the confidence intervals suggested that the efficacy of peginterferon beta-1a is similar in all patients irrespective of gender, age, body weight, geographical region, and disease activity at initiation of treatment. Within each peginterferon beta-1a dosing group, ARR was generally similar across most subgroups.

Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial.

BACKGROUND: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity. OBJECTIVE: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. METHODS: Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 µg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. RESULTS: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. CONCLUSION: The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.

Improvement in relapse recovery with peginterferon beta-1a in patients with multiple sclerosis.

BACKGROUND: Subcutaneous peginterferon beta-1a every 2 weeks significantly affects clinical outcomes in patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To explore relationships between relapses and worsening of disability in patients with RRMS, and assess the treatment effect of peginterferon beta-1a on relapse recovery. METHODS: Post-hoc analysis of the 2-year, randomized, double-blind, parallel-group, Phase 3 ADVANCE study. The severity of relapses, proportion of patients with relapses associated with residual disability (onset of 24-week confirmed disability progression (CDP) within 90 days following a relapse), and persistence of changes in Functional Systems Scores, were compared between treatment groups. RESULTS: Subcutaneous peginterferon beta-1a every 2 weeks significantly reduced the proportion of patients experiencing relapse associated with CDP over 2 years (6.6%, compared with 15.1% of patients who received placebo in Year 1; p = 0.02). Reduction in relapses associated with residual disability was greater than the treatment effect on overall relapse rate, and occurred despite similar relapse severity across treatment groups. CONCLUSIONS: The beneficial effect of peginterferon beta-1a on risk of CDP may be attributable to the combination of an overall reduction in the risk of relapses and improvement in recovery from relapses, thus limiting further disability progression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00906399.

Pharmacokinetics, pharmacodynamics, and safety of peginterferon beta-1a in subjects with normal or impaired renal function.

Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 µg (n = 5) or 125 µg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC [30-53%]) and peak serum concentration (Cmax [26-42%]) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment.

Single-use autoinjector for peginterferon-ß1a treatment of relapsing-remitting multiple sclerosis: safety, tolerability and patient evaluation data from the Phase IIIb ATTAIN study.

OBJECTIVES: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-ß1a (a pegylated interferon-ß1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study. METHODS: Over 8 weeks, patients self-administered peginterferon-ß1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials. RESULTS: In 39 patients, the safety profile of peginterferon-ß1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high. CONCLUSION: The safety and tolerability profile of peginterferon-ß1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient's quality of life and adherence.

Pegylated interferon ß-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study.

BACKGROUND: Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. METHODS: We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 µg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. FINDINGS: We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. INTERPRETATION: After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. FUNDING: Biogen Idec.