Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression. Objective: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month. Interventions: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. Main Outcomes and Measures: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS). Results: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]). Conclusions and Relevance: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS. Trial Registration: ClinicalTrials.gov Identifier: NCT04248465.

Correction to: Eculizumab improves fatigue in refractory generalized myasthenia gravis.

The article "Eculizumab improves fatigue in refractory generalized myasthenia gravis", written by "Henning Andersen, Renato Mantegazza, Jing Jing Wang, Fanny O'Brien, Kaushik Patra, James F. Howard Jr. and The REGAIN Study Group" was originally published electronically on the publisher's internet portal (currently SpringerLink) on 23 March 2019 without open access.

Eculizumab improves fatigue in refractory generalized myasthenia gravis.

PURPOSE: To evaluate the effect of eculizumab on perceived fatigue in patients with anti-acetylcholine receptor antibody-positive, refractory, generalized myasthenia gravis (MG) using the Quality of Life in Neurological Disorders (Neuro-QOL) Fatigue subscale, and to evaluate correlations between improvements in Neuro-QOL Fatigue and other clinical endpoints. METHODS: Neuro-QOL Fatigue, MG Activities of Daily Living (MG-ADL), Quantitative MG (QMG), and the 15-item MG Quality of Life (MG-QOL15) scales were administered during the phase 3, randomized, placebo-controlled REGAIN study (eculizumab, n = 62; placebo, n = 63) and subsequent open-label extension (OLE). Data were analyzed using repeated-measures models. Correlations between changes in Neuro-QOL Fatigue and in MG-ADL, QMG, and MG-QOL15 scores were determined at REGAIN week 26. RESULTS: At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderate, and weak, respectively, for placebo-treated patients. CONCLUSIONS: Compared with placebo, eculizumab was associated with improvements in perceived fatigue that strongly correlated with improvements in MG-specific outcome measures. Trial ID Registration: NCT01997229, NCT02301624.

Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.

BACKGROUND: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. OBJECTIVES: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. METHODS: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. RESULTS: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. CONCLUSION: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study.

BACKGROUND & AIMS: MEDI2070 is a human monoclonal antibody that selectively inhibits interleukin 23 (IL23), a cytokine implicated in the pathogenesis of Crohn's disease (CD). We analyzed its safety and efficacy in treatment of CD in a phase 2a study. METHODS: We conducted a double-blind, placebo-controlled study of 119 adults with moderate to severe CD failed by treatment with tumor necrosis factor antagonists. Patients were randomly assigned (1:1) to groups given MEDI2070 (700 mg) or placebo intravenously at weeks 0 and 4. Patients received open-label MEDI2070 (210 mg) subcutaneously every 4 weeks from weeks 12 to 112. The CD Activity Index was used to measure disease activity. RESULTS: The primary outcome, clinical response (either a 100-point decrease in CD Activity Index score from baseline or clinical remission, defined as CD Activity Index score <150) at week 8 occurred in 49.2% of patients receiving MEDI2070 (n = 59) compared with 26.7% receiving placebo (n = 60; absolute difference, 22.5%; 95% confidence interval, 5.6%-39.5%; P = .010). Clinical response at week 24 occurred in 53.8% of patients who continued to receive open-label MEDI2070 and in 57.7% of patients who had received placebo during the double-blind period and open-label MEDI2070 thereafter. The most common adverse events were headache and nasopharyngitis. Higher baseline serum concentrations of IL22, a cytokine whose expression is induced by IL23, were associated with greater likelihood of response to MEDI2070 compared with placebo. CONCLUSIONS: In a phase 2a trial of patients with moderate to severe Crohn's disease who had failed treatment with tumor necrosis factor antagonists, 8 and 24 weeks of treatment with MEDI2070 were associated with clinical improvement. ClinicalTrials.gov ID: NCT01714726.

A Bayesian paradigm for decision-making in proof-of-concept trials.

Decision-making is central to every phase of drug development, and especially at the proof of concept stage where risk and evidence must be weighed carefully, often in the presence of significant uncertainty. The decision to proceed or not to large expensive Phase 3 trials has significant implications to both patients and sponsors alike. Recent experience has shown that Phase 3 failure rates remain high. We present a flexible Bayesian quantitative decision-making paradigm that evaluates evidence relative to achieving a multilevel target product profile. A framework for operating characteristics is provided that allows the drug developer to design a proof-of-concept trial in light of its ability to support decision-making rather than merely achieve statistical significance. Operating characteristics are shown to be superior to traditional p-value-based methods. In addition, discussion related to sample size considerations, application to interim futility analysis and incorporation of prior historical information is evaluated.

Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study.

BACKGROUND: Systemic sclerosis (SSc) is a clinically heterogeneous, life-threatening disease characterized by fibrosis, microvasculopathy, and autoimmunity. Extensive nonclinical and clinical data implicate B cells in the pathogenesis of SSc. MEDI-551 is an investigational humanized monoclonal antibody that targets the B cell surface antigen CD19 and mediates antibody-dependent, cell-mediated cytotoxicity of B cells. This clinical study evaluated the safety and tolerability, pharmacokinetics, and pharmacodynamics of MEDI-551 in subjects with SSc. METHODS: This phase I multicenter, randomized, double-blind, placebo-controlled, single escalating dose study enrolled adult subjects with either limited or diffuse cutaneous SSc. A single intravenous dose of MEDI-551 was administered, and safety and tolerability were evaluated. MEDI-551 pharmacokinetics (PK), pharmacodynamics, and immunogenicity were also assessed. Safety assessments included the incidence of adverse events and changes in clinical and laboratory results. MEDI-551 serum concentrations, effects on circulating and tissue B cells and plasma cells (PCs), and antidrug antibodies were analyzed. Modified Rodnan skin score (MRSS) and pulmonary function tests were used to explore the clinical effect of MEDI-551. RESULTS: The study enrolled 28 subjects with SSc (mean age, 47.3 years; 67.9 % female). Twenty-four received a single dose of MEDI-551 (0.1-10.0 mg/kg) and four received placebo. Treatment-emergent adverse events (TEAEs) occurred in 95.8 % of subjects in the MEDI-551 group and in 75.0 % of subjects in the placebo group; the majority of TEAEs were mild or moderate in severity. Two serious adverse events were considered possibly related to the study drug. One death, deemed not related to the study drug, occurred in a MEDI-551-treated subject. MEDI-551 exhibited linear PK in the dose range of 1.0 to 10.0 mg/kg, and more rapid clearance at lower doses. Dose-dependent depletion of circulating B cells and plasma cells was observed. MRSS assessments suggest a possible clinical effect of MEDI-551 on affected skin. CONCLUSIONS: A single escalating dose of MEDI-551 was tolerable and safe in this subject population. B cell depletion was achieved and was dose dependent. A signal of clinical effect was observed. Based on these results, further investigation of MEDI-551 as a disease-modifying treatment for SSc is warranted. TRIAL REGISTRATION: www.clinicaltrials.gov identifier, NCT00946699 ; registered 23 July 2009.

Statistical Considerations for an Adaptive Design for a Serious Rare Disease.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare, disabling autoimmune disorder of the central nervous system. Clinical trials in NMOSD present unique design and statistical challenges to adequately determine treatment effect and to minimize risk. METHODS: The N-MOmentum trial (NCT02200770) is evaluating the efficacy and safety of MEDI-551, an anti-CD 19 B-cell depleting monoclonal antibody, in patients with NMOSD and employs a number of unique design features. Patients are randomized (3:1) to receive MEDI-551 or placebo for up to 197 days. NMOSD attacks are evaluated by the investigator and confirmed by an independent adjudication committee. The primary endpoint is time to first relapse as determined by adjudication committee. Sample size re-estimation and futility analyses are planned interim analyses. Novel multiplicity adjustment methods are developed to control the study-wise type I error. Methods for assessing inter- and intrarater reliability are proposed. CONCLUSIONS: The N-MOmentum study minimizes exposure to placebo for individual patients. The application of several statistical methods in the N-MOmentum trial is novel in NMOSD and aims to achieve a balance between minimizing risk and maintaining scientific integrity.

Placebo-controlled study in neuromyelitis optica-Ethical and design considerations.

BACKGROUND: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. OBJECTIVE: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical-scientific integrity. METHODS: We assessed the "standard of care" for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. RESULTS: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. CONCLUSION: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.

Clinical consequences of delayed addition of adalimumab to methotrexate therapy over 5 years in patients with rheumatoid arthritis.

OBJECTIVE: This Year 5 analysis of an open-label extension (OLE) study assessed radiographic progression, clinical efficacy, and safety of adalimumab with concomitant methotrexate (MTX) for patients with active rheumatoid arthritis. METHODS: In a double-blind study (DE019, NCT00195702), inadequate responders to MTX were randomized to MTX plus either adalimumab 40 mg eow, adalimumab 20 mg weekly, or placebo for 52 weeks. Eligible patients entered an ongoing OLE and received adalimumab 40 mg eow plus MTX. Longterm efficacy and safety were evaluated. RESULTS: Of 457 patients who had enrolled in the OLE, 304 remained in the study at Year 5, including 112, 107, and 85 from the original adalimumab 40 mg, adalimumab 20 mg, and placebo groups, respectively. Year 5 radiographs demonstrated mean changes in modified total Sharp score for the original adalimumab 40 mg eow and 20 mg weekly groups of 0.8 and 2.6, respectively, versus 3.9 for placebo; 58% from the adalimumab 40 mg eow group had no radiographic progression versus 40% of those who initially received placebo. Of patients who received adalimumab 40 mg eow for 5 years, 26.1% achieved clinical remission (Disease Activity Score 28-joint count < 2.6), had no radio graphic progression (change in modified total Sharp score ≤ 0.5), and had normal function (Health Assessment Questionnaire ≤ 0.5), versus 11.9% of those who initially received placebo. Serious infection rate for 553 patients who received at least one dose of adalimumab was 4.4/100 patient-years. CONCLUSION: A 52-week delay in adding adalimumab to MTX led to worse radiographic, functional, and clinical outcomes at Year 5 for most patients who initially received placebo instead of adalimumab.

Disease activity, physical function, and radiographic progression after longterm therapy with adalimumab plus methotrexate: 5-year results of PREMIER.

OBJECTIVE: To evaluate the efficacy and safety of initial combination treatment with adalimumab (ADA) and methotrexate (MTX) versus monotherapy with ADA or MTX during an open-label extension of PREMIER. METHODS: Patients with early rheumatoid arthritis (RA) received blinded ADA plus MTX, ADA alone, or MTX alone for 2 years in PREMIER. At Year 2, patients could enroll in an open-label extension and receive ADA monotherapy; MTX could be added at the investigator's discretion. Longterm efficacy results are presented as observed data. RESULTS: In the open-label period, 497 of the original 799 randomized patients had ≥ 1 dose of ADA (by original randomization: ADA plus MTX, n = 183; ADA, n = 159; MTX, n = 155). In the completers cohort [patients with available Year-5 ACR responses and modified total Sharp scores (mTSS)], the Year-5 mean change from baseline in mTSS for the ADA+MTX arm (n = 124) was 2.9, compared with 8.7 and 9.7 in the ADA (n = 115) and MTX (n = 115) arms. Comprehensive disease remission, defined as the combination of DAS28 remission, normal function (Health Assessment Questionnaire ≤ 0.5), and radiographic nonprogression (ΔmTSS ≤ 0.5), was achieved by more patients in the initial ADA+MTX arm (35%) than in the ADA (13%) or MTX (14%) arms. CONCLUSION: Initial combination treatment with ADA plus MTX, followed by open-label ADA, led to better longterm clinical, functional, and radiographic outcomes than either initial ADA or MTX monotherapy during 5 years of treatment.

Less radiographic progression with adalimumab plus methotrexate versus methotrexate monotherapy across the spectrum of clinical response in early rheumatoid arthritis.

OBJECTIVE: To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) in the PREMIER study. METHODS: Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state [tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100] at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (DeltaTSS), and percentages of progressors (DeltaTSS > 0.5). RESULTS: Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally intermediate. A strong, proportional relationship was observed between clinical response and radiographic efficacy only for MTX monotherapy. The monotherapies approximated the radiographic efficacy of adalimumab plus MTX only among remission-like responders, although progression was significantly greater with MTX monotherapy versus adalimumab plus MTX for patients with TJC = 0. Concurrent clinical (DAS28 < 2.6) and radiographic (DeltaTSS

Adalimumab response in patients with early versus established rheumatoid arthritis: DE019 randomized controlled trial subanalysis.

In recent years, there has been a shift in the therapeutic approach to rheumatoid arthritis (RA), with emphasis on early therapy. The DE019 trial demonstrated adalimumab efficacy in patients with RA. This subanalysis compares response to adalimumab based on clinical, functional, and radiographic outcomes in patients with early versus established RA. Patients enrolled in the DE019 trial were divided into two groups based on disease duration (3 years=established RA). Data from 407 patients with RA were included, with 78 early (41 adalimumab, 37 placebo) and 329 established (166 adalimumab, 163 placebo) patients. Patients with early disease achieved slightly greater American College of Rheumatology 20 (20% or more improvement or ACR20), 50, and 70 responses of 61%, 46.3%, and 24.4%, respectively, at 52 weeks, compared with those with established disease, with ACR20, 50, and 70 responses of 56%, 37.3%, and 19.9%, respectively. The Health Assessment Questionnaire score improvement between adalimumab and placebo in patients with early disease (0.44) was greater than that for those with established disease (0.25). With adalimumab treatment, there was a statistically significant mean reduction in total Sharp score progression relative to placebo (5.32) in early disease compared with established disease (2.06). While adalimumab is effective for RA of all disease durations, there is a trend toward superior clinical, functional, and radiographic outcomes in patients with early disease.