This should slow the progression of myasthenia gravis and lessen its symptoms. No change in ongoing therapy was permitted during the 12-week trial, and patients were evaluated at baseline and weeks 1, 2, 4, 8, and 12. UCB will continue the development of zilucoplan, which has been granted orphan drug status by the U.S. Food and Drug Administration (FDA). The monoclonal antibody drug eculizumab (Soliris) has the same mechanism; it was approved for … Ra Pharma is developing zilucoplan and zilucoplan extended release (XR) for generalized myasthenia gravis (gMG), immune-mediated necrotizing … Statistical analysis used an analysis of covariance model and least squares means, with Fisher exact test used to analyze categorical endpoints. Ra Pharmaceuticals is set to launch a Phase 3 trial testing zilucoplan on patients with generalized myasthenia gravis. Zilucoplan is a once-daily self-administered subcutaneous injection that is being positioned as a “pipeline in a product” because it is undergoing clinical development for myasthenia gravis, immune-mediated necrotizing myopathy (IMNM), amyotrophic lateral sclerosis (ALS), atypical hemolytic uremic syndrome and lupus nephritis. Zilucoplan, a macrocyclic peptide that binds complement component C5, showed promise as an effective agent for treatment of generalized myasthenia gravis in a Phase II trial. The product candidate is designed for convenient subcutaneous (SC) self-administration. JAMA Neurol 2020 Feb 17 Zilucoplan, a complement inhibitor, showed promise in a phase 2 study of patients with acetylcholine receptor antibody–positive myasthenia gravis. Generalized myasthenia gravis is an autoimmune disorder in which antibodies against acetylcholine receptors block signals transmitted from nerves to muscles. Ra Pharmaceuticals is preparing to launch a Phase 3 clinical trial to assess the therapeutic potential of zilucoplan for the treatment of patients with generalized myasthenia gravis (gMG). On Dec. 10, Ra Pharmaceuticals Inc., based in Cambridge, Mass., announced positive results from a Phase 2 clinical trial designed to evaluate zilucoplan (RA101495) for treating generalized myasthenia gravis (gMG). Ra Pharma is developing zilucoplan, a self-administered macrocyclic peptide inhibitor of complement component 5 (C5), for the treatment of generalized myasthenia gravis (gMG) and other rare, tissue-based complement-mediated diseases. Conquer Myasthenia Gravis 275 N. York Street, Suite 201 Elmhurst, IL 60126. info@myastheniagravis.org (800) 888-6208 Zilucoplan. Rapid, clinically meaningful, and statistically significant improvement in the QMG score was seen in the 0.3 mg/kg zilucoplan arm compared to placebo, with a score change of -6.0 points in the former, compared to -3.2 in the latter, and improvement beginning after one week. The terminal complement component [membrane attack complex (MAC)] is found at the neuromuscular junctions of patients with MG. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.Â. The Food and Drug Administration (FDA) has granted Orphan Drug designation to zilucoplan (Ra Pharmaceuticals) for the treatment of generalized … The RAISE study is a multicenter, randomized, double-blind, placebo controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in subjects with generalized Myasthenia Gravis. AEs that were more common with zilucoplan than with placebo were nausea (in 2, 2, and 0 patients) and headache (in 2, 4, and 1 patient). Zilucoplan also inhibits the interaction between C5b and C6, thereby further blocking MAC assembly. The study drug was well-tolerated, with a moderate injection-site reaction (ISR) in only one placebo patient, all other ISRs being mild. Professor of Clinical Neurology, Weill Cornell Medical College. Emily is passionate about science communication, and, in her free time, writes and illustrates childrenâs stories. No meningococcal infections, life-threatening adverse events, or deaths occurred during the trial, and no anti-zilucoplan antibodies were detected. It does not provide medical advice, diagnosis, or treatment. MG-ADL showed similar results, favoring zilucoplan over placebo, and 0.3 mg/kg over 0.1 mg/kg, at week 12. A synthetic macrocyclic peptide, zilucoplan binds C5, preventing its cleavage into C5a and C5b, and preventing the production of the membrane attack complex. Complement Inhibitor Therapy for Myasthenia Gravis. Generalized myasthenia gravis (gMG) is a severe form of MG that can include weakness of multiple muscle groups such the limbs, neck, diaphragm, and eye muscles. In myasthenia gravis, the complement system is thought to be involved in stimulating the production of harmful autoantibodies. Myasthenia Gravis News is strictly a news and information website about the disease. Zilucoplan, a macrocyclic peptide that binds C5 with high affinity and specificity, is thus the subject of this study to determine its efficacy in gMG. Zilucoplan is an experimental treatment for myasthenia gravis. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Evidence indicates that these antibodies, as opposed to anti-muscle-specific kinase (MuSK) antibodies, activate the classic complement cascade. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Emily holds a Ph.D. in Biochemistry from the University of Iowa and is currently a postdoctoral scholar at the University of Wisconsin-Madison. 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. Myasthenia gravis (MG) is a rare, chronic, autoimmune, neuromuscular condition characterized by weakness of voluntary muscles that increases with exercise and recovers with rest. Ra Pharmaceuticals’ (Ra Pharma) zilucoplan has succeeded in a phase 2 trial in generalized myasthenia gravis (gMG) by meeting the primary and key secondary end points. Patients will be assigned randomly to receive either 0.3 mg zilucoplan per kg body weight, or placebo, via a daily under-the-skin injection for 12 weeks. Between December 2017 and August 2018, MG patients, ages 18 to 85 years, were recruited from 25 North American study sites to participate in this randomized, double-blind, placebo-controlled, Phase II clinical trial. Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp. SYNOPSIS: Zilucoplan, a macrocyclic peptide that binds complement component C5, showed promise as an effective agent for treatment of generalized myasthenia gravis in a Phase II trial. Subcutaneous Immunoglobulin (SCIg) for Myasthenia Gravis, myasthenia gravis activities of daily living (MG-ADL) scale, Pink, Green, Blue and Purple Lights Illuminated World for Rare Disease Day, Phase 3 Trial of Zilucoplan Enrolling Adults with Generalized MG, FDA Reviewing Efgartigimod as Possible Treatment for Generalized MG, Immunovant Prepares to Launch Phase 3 Trial of IMVT-1401 in MG Patients, Coalition Will Address Racial Disparities in Rare Disease Communities, Rituximab More Beneficial if Given to gMG Patients Early, Study Finds. IVIg or PLEX was allowed in the event of worsening, based on investigator discretion. Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo for 12 weeks. Complement inhibition increases the risk for meningococcal infection since the complement system ordinarily protects against encapsulated bacterial infections, and prior vaccination may be required. The primary outcome measure will be changes in MG-ADL scores from the beginning to the end of the study, with the secondary outcome measure being changes in QMG from the beginning to the end of the study. This multicenter phase II trial compared outcomes in 44 patients with moderate to severe generalized myasthenia gravis (gMG) who were randomized to 12 weeks of daily self-administered subcutaneous injections of placebo, 0.1 mg/kg zilucoplan, or 0.3 mg/kg zilucoplan. Zilucoplan is an experimental treatment for myasthenia gravis. Zilucoplan obtains positive results in moderate to severe generalized myasthenia gravis with anti-RACh autoantibodies 25 March 2020 Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. The treatment was developed originally by Ra Pharmaceuticals, which has been acquired by UCB. Three patients in the placebo arm required rescue therapy with IVIg or PLEX, one patient in the 0.1 mg/kg zilucoplan arm, and none in the 0.3 mg/kg zilucoplan arm. Based on the Phase 2 results, a Phase 3 clinical trial (NCT04115293) called RAISE is now recruiting 130 myasthenia gravis patients at 31 sites worldwide to further test the effectiveness of zilucoplan. All but one received the study drug, with the exception lost to follow-up when he did not return for the dosing visit. About Myasthenia Gravis. Photo: courtesy of ponsulak/Freedigitalphotos.net. A change in QMG score, a 13-item scale evaluating muscle strength, ranging from 0 (normal) to 39 (severe weakness), was the primary endpoint, with improvement of two to three points considered clinically meaningful, depending on baseline disease. Eculizumab, a monoclonal antibody to complement component 5 (C5) inhibitor, was shown to be effective in treating gMG patients previously refractory to other therapies, supporting complement inhibition as a new therapeutic approach in gMG. [Epub ahead of print]. Patients were assigned randomly, in a 1:1:1 ratio, to daily subcutaneous self-injection of zilucoplan 0.1 mg/kg, zilucoplan 0.3 mg/kg, or placebo, for 12 weeks. Generalized Myasthenia Gravis: Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis (RAISE) Phase 3: RA101495-02.301 Ongoing You must have JavaScript enabled to enjoy a limited number of articles over the next 360 days. Like eculizumab, zilucoplan is a terminal complement inhibitor, but, unlike the former, it is administered subcutaneously. Upward of 85% of patients with generalized myasthenia gravis (gMG) have detectable anti-acetylcholine receptor antibodies (AchR-Ab). ReliasMedia_AR@reliasmedia.com, Do Not Sell My Personal Information Privacy Policy Terms of Use Contact Us Reprints Group Sales, For DSR inquiries or complaints, please reach out to Wes Vaux, Data Privacy Officer, DPO@relias.com, Design, CMS, Hosting & Web Development :: ePublishing, Neurology Alert (Vol. Zilucoplan, a subcutaneously self-administered peptide inhibitor of complement component (C5), for the treatment of generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Ãzge has a MSc. Howard JF Jr, Nowak RJ, Wolfe GI, et al. The secondary outcome measured was the patients’ engagement in daily activities using the myasthenia gravis activities of daily living (MG-ADL) scale, a test of daily activities patients are able to perform. The attack by the immune system weakens the junctions, causing nervous signals to be effectively transported to muscles, leading to muscle weakness and fatigue, among other symptoms. 9) - May 2020, Tacrolimus for Treatment of Myasthenia Gravis, Acetylcholine Receptor Antibody Testing in Ocular Myasthenia Gravis, Omega-3s for the AREDS2 Cohort Are Not Beneficial for Preventing Cognitive Decline. Abstract Importance Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. She graduated with a Masters in Chemistry from the Georgia Institute of Technology and holds a Bachelors in Biology and Chemistry from the University of Central Arkansas. Among 57 patients assessed for eligibility, 12 did not meet inclusion criteria, leaving 45 patients for randomization (15 per arm of the trial). A Phase 2 clinical trial (NCT03315130) is evaluating the safety and effectiveness of zilucoplan in treating 44 myasthenia gravis patients. This prevents MAC-mediated lysis and destruction of red blood cells (RBCs) that occurs in complement-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG) and lupus nephritis (LN). The purpose of the study is to evaluate the safety and efficacy of RA101495 in patients with generalized Myasthenia Gravis (gMG). Participants are assigned randomly to receive 0.1 mg zilucoplan per kilogram  (kg) of body weight, 0.3 mg zilucoplan per kg body weight, or placebo, administered under the skin every day for 12 weeks. The key secondary endpoint was the change in MG Activities of Daily Living (MG-ADL) score, an eight-item scale assessing daily functions, ranging from 0 (normal) to 24 (severely affected), by study completion. Unique to early-onset AChR-positive myasthenia gravis, compared with other autoimmune diseases, is the involvement of the thymus that contains lymphoid germinal centers overexpressing proinflammatory cytokines and MHC-II-positive thymic epithelial cells that present AChR subunits to CD4+ T cells leading to upregulation of IL4 and IL6 that stimulate B cells to produce anti-AChR … 39, No. Meaning The findings support a potential therapeutic role for zilucoplan in generalized myasthenia gravis and further evaluation in a phase 3 study. Please click here to continue without javascript.. Special Report from the 2020 International Stroke Conference, Los Angeles, Cognitive Symptoms in Genetic Forms of Parkinson’s Disease May Help in Distinguishing the Various Types. Zilucoplan is delivered as a subcutaneous (under-the-skin) injection and can be self-administered by patients. Ra Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to zilucoplan for the treatment of myasthenia gravis. Ra’s potentially blockbuster therapy Zilucoplan is undergoing a pivotal phase 03 trial for the treatment of generalized myasthenia gravis (gMG) with top-line data expected in early 2021. No significance was found in the analysis of the covariance model for age, sex, duration of disease, treatment history, prior thymectomy, or history of thymoma. Myasthenia Gravis News is strictly a news and information website about the disease. Beginning after four weeks, a less pronounced and slower but clinically meaningful and statistically significant improvement also was appreciated with 0.1 mg/kg zilucoplan. She worked as the Research Communication Officer at a London based charity for almost two years. 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. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. MG-QoL15r and MGC followed a similar pattern, although the former favored the 0.1 mg/kg zilucoplan arm, perhaps because of its higher baseline scores. Copyright © 2013-2021 All rights reserved. The treatment was developed originally by Ra Pharmaceuticals, which has been acquired by UCB. “Zilucoplan is a small molecule complement inhibitor targeting C5 A to C6,” Howard explained. Potential of Zilucoplan for Treating Myasthenia Gravis Jaime Toro, MD reviewing Howard JF Jr et al. Ra Pharmaceuticals is preparing to launch a Phase 3 clinical trial to assess the therapeutic potential of zilucoplan for the treatment of patients with generalized myasthenia gravis … Zilucoplan appears safe and effective for the treatment of AchR-Ab positive gMG. JAMA Neurol 2020; Feb. 17. doi:10.1001/jamaneurol.2019.5125. About Zilucoplan. The therapy is designed to ultimately prevent the formation and assembly of the membrane attack complex in myasthenia gravis. This comes after the company’s completion of End-of-Phase 2 interactions with the FDA The results of this study are promising, and preparations for a Phase III trial are underway. Zilucoplan is a peptide agent that inhibits the C5 complement protein. Only mild adverse side effects not related to treatment were reported. “Designed for subcutaneous self-administration, zilucoplan offers convenience and accessibility, giving it the potential to bring C5 inhibition to the forefront of the … Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Other adverse events were mostly mild, were considered unrelated to study drug, and resolved spontaneously. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. The complement system is made up of a large group of proteins that are involved in activating the immune cells that produce antibodies. Howard JF Jr, Nowak RJ, Wolfe GI, Benatar MG, Duda PW, MacDougall J, et al. SOURCE: Howard JF, Nowak RJ, Wolfe GI, et al. Secondary endpoints included the MG Composite (MGC) and the 15-item Myasthenia Gravis Quality-of-Life Revised Scale (MG-QoL15r). Image: Ra Pharma’s zilucoplan succeeds in phase 2 gMG trial. It does not provide medical advice, diagnosis or treatment. Complement activation as a driver of pathology in myasthenia gravis (MG) has been appreciated for decades. 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. The higher dose of zilucoplan produced more significant improvements. Myasthenia gravis is an autoimmune disease that affects the junction between nerve cells and muscles, the so-called neuromuscular junction. By blocking the complement system, zilucoplan may be able to reduce the release of autoantibodies that attack the neuromuscular junction. Post-synaptic membrane simplification, with associated reduced AchR density, is the ultrastructural correlate of impaired neuromuscular transmission in gMG, and it appears that the terminal complement cascade plays a role. UCB will continue the development of zilucoplan, which has been granted orphan drug status by the U.S. Food and Drug Administration (FDA). Financial Disclosure: Editor in Chief Matthew Fink, MD, Peer Reviewer M. Flint Beal, MD, Editorial Group Manager Leslie Coplin, Editor Jason Schneider, Executive Editor Shelly Morrow Mark, and Accreditations Director Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study. Pyridostigmine was not allowed in the 10 hours prior to QMG measurements. Subjects will be randomized in a 1:1 ratio to receive daily SC … Inclusion criteria required a clinically confirmed diagnosis of MG (Myasthenia Gravis Foundation of America [MGFA] Class II-IVa), AchR-Ab positivity, Quantitative MG (QMG) score of 12 or greater, with no intravenous immunoglobulin (IVIg), plasma exchange (PLEX), or change in therapy for four weeks prior to randomization, and no thymectomy or rituximab in the prior six months. 1-800-370-9210 Ra Pharma is developing zilucoplan and zilucoplan extended release (XR) for generalized myasthenia gravis (gMG), immune-mediated necrotizing myopathy (IMNM), and other tissue-based complement-mediated disorders with high unmet medical need. Zilucoplan for Myasthenia Gravis | 2020-04-22 | Relias Media - Continuing Medical Education Publishing JAMA Neurol. Preliminary, 12-week results from the trial showed that patients treated with zilucoplan had significant improvement in both QMG and MG-ADL compared to those given placebo. Zilucoplan is a small, synthetic molecule that is designed to bind and inhibit portions of the immune system called the complement system. 2020 May 1;77 (5):582-592. doi: 10.1001/jamaneurol.2019.5125. The primary outcome measured is QMG (quantitative myasthenia gravis), a test that assesses a patientâs level of muscle weakness. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London.
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