Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis. METHODS: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18-74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II-IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871). FINDINGS: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change -4·39 [95% CI -5·28 to -3·50] vs -2·30 [-3·17 to -1·43]; least squares mean difference -2·09 [-3·24 to -0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug. INTERPRETATION: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study. FUNDING: UCB Pharma.

Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

Importance: Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective: To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions: Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures: The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results: The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance: Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration: ClinicalTrials.gov Identifier: NCT03315130.

Treatment Patterns of Newly Diagnosed Rheumatoid Arthritis Patients from a Commercially Insured Population.

INTRODUCTION: To describe treatment patterns in newly diagnosed rheumatoid arthritis (RA) patients in a large, nationally representative managed-care database. METHODS: Newly diagnosed RA patients were identified from 07/01/2006-08/31/2014. Patients had ≥ 1 RA diagnosis by a rheumatologist, or ≥ 2 non-rheumatologist RA diagnoses ≥ 30 days apart, or RA diagnosis followed by a disease-modifying antirheumatic drug (DMARD) prescription fill within 1 year. Patients were ≥ 18 years old at index (earliest date fulfilling diagnostic criteria) and had ≥ 6 and 12 months of pre- and post-index health plan enrollment, respectively. Patterns of DMARD treatment, including conventional synthetic DMARDs (csDMARD), tumor necrosis factor inhibitors (TNFi), non-TNFi, and Janus kinase inhibitors (JAKi), were captured during follow-up. RESULTS: Of the 63,101 RA patients identified, 73% were female; mean age was 57 years. During an average of 3.5 ± 2.1 years of follow-up, 45% of patients never received a DMARD, 52% received a csDMARD (94 ± 298 mean ± SD days from index), 16% a TNFi (315 ± 448 days), 4% a non-TNFi (757 ± 660 days), and < 1% a JAKi. Among DMARD recipients, the most common treatment patterns were: receiving csDMARDs only (68%), adding a TNFi as second-line therapy after initiation of a csDMARD (12%), and receiving only a TNFi (6%) during follow-up. Among those not on DMARDs, the all-cause usage of an opioid was 56% and 19% had chronic opioid use (≥ 180 days supplied). CONCLUSIONS: Despite American College of Rheumatology recommendations for DMARD treatment of RA, nearly half of newly diagnosed RA patients received no DMARD therapy during follow-up. These data identify a treatment gap in RA management. FUNDING: Eli Lilly & Company.

Geophysical Monitoring of Hydrocarbon-Contaminated Soils Remediated with a Bioelectrochemical System.

Efficient noninvasive techniques are desired for monitoring the remediation process of contaminated soils. We applied the direct current resistivity technique to image conductivity changes in sandbox experiments where two sandy and clayey soils were initially contaminated with diesel hydrocarbon. The experiments were conducted over a 230 day period. The removal of hydrocarbon was enhanced by a bioelectrochemical system (BES) and the electrical potentials of the BES reactors were also monitored during the course of the experiment. We found that the variation in electrical conductivity shown in the tomograms correlate well with diesel removal from the sandy soil, but this is not the case with the clayey soil. The clayey soil is characterized by a larger specific surface area and therefore a larger surface conductivity. In sandy soil, the removal of the diesel and products from degradation leads to an increase in electrical conductivity during the first 69 days. This is expected since diesel is electrically insulating. For both soils, the activity of BES reactors is moderately imaged by the inverted conductivity tomogram of the reactor. An increase in current production by electrochemically active bacteria activity corresponds to an increase in conductivity of the reactor.

How to Map Noise.

Noise mapping is a method of presenting complex noise information in a clear and simple way either on a physical map or in a database. This mapping information can be either calculated or measured using a variety of techniques and methods. Furthermore, the results of such exercises can be presented in many different ways and used for a number of different purposes. This paper attempts to examine these issues in the light of the "mapping requirements" outlined in the recently proposed Directive of the European Parliament and of the Council, relating to the Assessment and Management of Environmental Noise (Comm (2000) 468 final). This proposed Directive was laid before the Parliament and Council in the autumn of 2000. The First Reading of the proposal was successfully negotiated just before Christmas 2000. The Second Reading is likely to commence shortly.