Post-COVID-19 Multisystem Inflammatory Syndrome in Adults (MIS-A) With Elevated Levels of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Treated With Anakinra: A Case Report

Article

作者: Milionis, Haralampos ; Konstantopoulou, Revekka ; Christaki, Maria ; Samanidou, Valentini ; Liontos, Angelos

The COVID-19 pandemic has brought attention to a newly identified syndrome of multisystem inflammation. This potentially fatal complication of the disease was initially observed in children and later in adults. It affects primarily unvaccinated patients and may manifest within a timeframe of 2-12 weeks following infection. Soluble urokinase plasminogen activator receptor (suPAR), a novel biomarker, highlights the severity of inflammation and the degree of immune system activation. Herein, we report a case of a patient with multisystem inflammatory syndrome in adults (MIS-A) and markedly elevated suPAR levels, successfully treated with interleukin-1 (IL-1) receptor antagonist. A 59-year-old female was admitted to our hospital due to febrile illness (up to 40°C) with chills, vomiting, non-bloody diarrhea, and abdominal pain for four days prior to her admission. She tested positive for SARS-CoV-2 12 weeks before her presentation. During hospitalization, the patient deteriorated clinically with multiorgan involvement and hemodynamically instability, with concomitant markedly elevated inflammatory markers. Extensive workup with high suPAR levels led to post-COVID-19 MIS-A diagnosis, and treatment with dexamethasone and an interleukin-1 receptor antagonist (IL-1ra), anakinra, was administered. The subcutaneous injection of anakinra effectively and safely deterred MIS-A. Further research is needed to investigate the role of interleukin-1 inhibitors for the management of this potentially life-threatening condition.

2024-10-01·Annals of the Rheumatic Diseases

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX

Article

作者: Samson, Maxime ; Kosmider, Olivier ; Garnier, Alice ; Bourguiba, Rim ; Campochiaro, Corrado ; Martis, Nihal ; Outh, Roderau ; Nguyen, Yann ; Antoine, Carole ; Karam, Jean-Denis ; de Maleprade, Baptiste ; Dumain, Cyril ; Faucher, Benoit ; Puigrenier, Sebastien ; Campagne, Julien ; Abisror, Noemie ; Dor-Etienne, Anais ; Fayard, Damien ; Nicolas, Barbara ; Chasset, Francois ; Audia, Sylvain ; Maria, Alexandre ; Mathian, Alexis ; Antoine, Pascale ; Mouloudj, Dalila ; Jachiet, Vincent ; Aouba, Achille ; Marianetti, Paola ; Meyer, Aurore ; Fain, Olivier ; De Sainte-Marie, Benjamin ; Jamilloux, Yvan ; Lobbes, Hervé ; McAvoy, Chloe ; Coustal, Cyrille ; Roux-Sauvat, Murielle ; Broner, Jonathan ; Georgin-Lavialle, Sophie ; Lartigau-Roussin, Celine ; Hadjadj, Jerome ; Carpentier, Benjamin ; Aloui, Hassina ; Woaye-Hune, Pascal ; Castel, Brice ; Mekinian, Arsène ; Arnaud, Laurent ; Crickx, Etienne ; Terrier, Benjamin ; Dossier, Antoine ; Grobost, Vincent ; Hirsch, Pierre ; Chazal, Thibaud ; Levavasseur, Matthieu ; Martellosio, Jean-Philippe ; Sujobert, Pierre ; Bouaziz, Jean-David ; Comont, Thibault ; Nguyen, Alexandre ; Heiblig, Mael ; Dumont, Anael ; Le Guenno, Guillaume ; Deligny, Christophe ; Lifermann, Francois ; Moulinet, Thomas ; Lacombe, Valentin ; Decker, Paul ; Volle, Geoffroy ; Lacout, Carole ; Hermine, Olivier ; Lazaro, Estibaliz ; Fenaux, Pierre ; Giraud, Jean-Thomas ; Ardois, Samuel

ObjectivesVacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies.MethodsMulticentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose.Results110 patients (median age 71 (68–79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors.ConclusionsThis study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

2024-09-01·Rheumatology

Long-term use of interleukin-1 inhibitors reduce flare activity in patients with fibrodysplasia ossificans progressiva

Article

作者: Matteo, Valentina ; Prencipe, Giusi ; Moshe, Veronica ; Uziel, Yosef ; Rabinowicz, Noa ; Ziv, Amit ; Haviv, Ruby ; De Cunto, Carmen Laura ; Zeitlin, Leonid ; De Benedetti, Fabrizio ; Hsiao, Edward C

AbstractObjectivesFibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy.MethodsPreviously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres.ResultsAll 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales.ConclusionThis case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO.FundingRH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III.

项与 CLC-1 inhibitors(NMD Pharma) 相关的新闻（医药）

2024-10-11

·BioSpace

NMD Pharma to Present Data on its Skeletal Muscle Targeted Therapy for Rare Neuromuscular Diseases at the 2024 AANEM Annual Meeting

NMD Pharma to Present Data on its Skeletal Muscle Targeted Therapy for Rare Neuromuscular Diseases at the 2024 AANEM Annual Meeting Aarhus, Denmark, 11 October 2024 – NMD Pharma A/S, a clinical-stage biotech company dedicated to developing novel and improved treatments for patients living with neuromuscular diseases, today announces that three abstracts have been accepted for oral presentation, and a fourth abstract selected for poster presentation, at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) annual meeting taking place from 15-18 October in Savannah, Georgia. The presentations will include preclinical and clinical data and provide an update on the design and progress of NMD Pharma’s Phase 2b generalized myasthenia (gMG) clinical trial. Oral presentations will take place during the Myasthenia Gravis Foundation of America (MGFA) Scientific Sessions, which will be held in Chatham Ballroom A in the Savannah Convention Center on Tuesday, 15 October from 8:00 am – 12:00 pm. Details of NMD Pharma’s oral and poster presentations are below: Oral Presentation: “NMD670, a First-in-Class Skeletal Muscle ClC-1 Inhibitor in MG: The SYNAPSE-MG Dose-Finding Study” Presenter: Vera Kiyasova, Director of Clinical Development Time: 10:17 am ET Oral Presentation: “ClC-1 Inhibition Improves Skeletal Muscle Function in Rat Models and Patients with MG” Presenter: Martin Skov, Innovation Manager Time: 10:45 am ET Oral Presentation: “ClC-1 inhibition improves QMG score and skeletal muscle function in patients with myasthenia gravis” Presenter: Vera Kiyasova, Director of Clinical Development Time: 10:50 am ET A fourth abstract highlighting the results of a large US physician quantitative survey on the level of MG patient unmet need that exists despite being on physicians’ preferred treatments recognized by US physicians was accepted for a poster presentation. Poster Presentation: “Unmet Needs in Myasthenia Gravis: Patient and Physician Perspectives” Author: Martin Skov, Innovation Manager Time: 12:00 pm – 12:45 pm ET NMD670 is a first-in-class, orally administered small molecule inhibitor of the skeletal muscle specific ClC-1 chloride ion channel. By inhibiting the CIC-1 channels, NMD670 amplifies muscle responsiveness, enabling consistent contractions even when the signal transmitted to the muscle is weak. NMD670 is currently being evaluated in a Phase 2b clinical trial in patients with gMG following positive results from a Phase 2a proof-of-mechanism study reported in October 2022 . NMD670 is furthermore being evaluated in two separate Phase 2 trials in patients living with spinal muscular atrophy and Charcot-Marie Tooth Diseases. The gMG Phase2b study, which initiated in June 2024 , is a dose range-finding, double-blinded, placebo-controlled study of NMD670 over 21 days in gMG patients who are anti-acetylcholine receptor (AChR), or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. The study will evaluate changes in the Quantitative Myasthenia Gravis Total Score and the Myasthenia Gravis Activities of Daily Living, among other endpoints, and take place across both US and European clinical sites. Further information on the study can be found here: Study Details | Safety and Efficacy of 3 Dose Levels of NMD670 in Adult Patients With Myasthenia Gravis | ClinicalTrials.gov Generalized myasthenia gravis patients who are AChR or MuSK antibody positive in the US and Europe are encouraged to participate in the study. Further information and a list of currently active investigational sites can be obtained via email at contact@nmdpharma.com . -END- Contacts NMD Pharma A/S Daniel Brennan, SVP Corporate and Commercial Strategy E-mail: contact@nmdpharma.com ICR Consilium Mary-Jane Elliott / Ashley Tapp / Lindsey Neville E-mail: NMDPharma@consilium-comms.com Tel: +44 (0)20 3709 5700 About NMD Pharma NMD Pharma A/S is a clinical-stage biotech company developing a first-in-class platform of small molecule therapies selectively targeting the skeletal muscle chloride ion channel (ClC-1) for the treatment of severe neuromuscular disorders. The Company was founded on more than 15 years of muscle physiology research with a focus on regulation of skeletal muscle excitability under physical activity. NMD Pharma has built a world-leading muscle electrophysiology platform leveraging the in-depth know-how of muscle physiology and muscular disorders, small molecule modulators, enabling technologies and tools as well as in vivo pharmacology models for discovering and developing proprietary modulators of neuromuscular function. The Company has built significant clinical and development expertise as its programmes have progressed through the clinic. NMD Pharma has raised ~€155 million from investors including Novo Holdings, Lundbeckfonden BioCapital, INKEF Capital, Roche Venture Fund, and Jeito Capital. Find out more about us online at .

临床2期

2024-03-21

·GlobeNewswire-Health Care

NMD Pharma Publishes Comprehensive Data Package for NMD670 in Science Translational Medicine

NMD Pharma Publishes Comprehensive Data Package for NMD670 in Science Translational Medicine ClC-1 is a chloride ion channel specifically expressed in skeletal muscle cells that normally dampens muscle fiber excitability and is involved in regulating muscle fiber excitability during exerciseClinical and preclinical data supports the notion that ClC-1 inhibition is a novel and highly translational therapeutic approach to improve symptoms in myasthenia gravis and, potentially, other diseases with compromised neuromuscular transmissionNMD670, a skeletal muscle targeted ClC-1 inhibitor, is in clinical development for the treatment of patients with generalized myasthenia gravis, spinal muscular atrophy, and Charcot-Marie- Tooth disease Aarhus, Denmark, 21 March 2024 – NMD Pharma A/S, a clinical-stage biotech dedicated to developing novel and improved treatments for patients living with neuromuscular diseases, today announces the peer-reviewed publication of comprehensive data sets demonstrating, for the first time, the ability of CIC-1 inhibition to restore muscle function in patients suffering from myasthenia gravis (MG) and in animal models of MG. These data are published in the journal Science Translational Medicine in a paper titled ‘First in class CIC-1 inhibitor improves skeletal muscle function in animal models and patients with myasthenia gravis.’ ClC-1 is a skeletal muscle specific chloride ion channel that plays important roles for regulating neuromuscular transmission and muscle fiber excitability during exercise. NMD Pharma’s lead development candidate, NMD670, a novel, selective, and orally bioavailable ClC-1 inhibiting small molecule, is used in the preclinical and clinical studies. NMD670 is a muscle-targeted therapy which aims to enhance the activation of skeletal muscle fibers and to improve muscle strength and endurance. Thomas Holm Pedersen, Chief Executive Officer of NMD Pharma and senior author of the paper, commented, “This paper summarizes years of work here at NMD Pharma and Aarhus University, firstly establishing neuromuscular transmission deficits in patients impacted by myasthenia gravis and then demonstrating that ClC-1 inhibition can reverse these deficits and improve the muscle function both in animal models and humans. These data provide important proof-of-mechanism as we progress our Phase 2 trial in spinal muscular atrophy and plan for the initiation of two other Phase 2 trials in AChR and MuSK antibody positive myasthenia gravis and Charcot-Marie-Tooth disease this year.” Dr Jorge A. Quiroz, Chief Medical Officer at NMD Pharma, added, “Myasthenia gravis is a rare neuromuscular disease that compromises the signal transmission between motor neurons and skeletal muscle fibers. As a result, patients have impaired skeletal muscle function and often experience severe muscle weakness and fatigue. Our aim at NMD Pharma is that our development candidates will reduce the burden and improve the lives of patients suffering from these debilitating neuromuscular diseases.” Today's publication in Science Translational Medicine highlights the successful translation of preclinical work with NMD670, which restored skeletal muscle function in a rat model of MG, to meaningful improvements in MG patients. It includes the randomized, placebo-controlled, single-dose, 3-way cross-over Phase 2a clinical study, investigating the efficacy, pharmacodynamics, and safety of a single dose of orally administered NMD670 in 12 patents with MG, showing clinically relevant and statistically significant improvements in the Quantitative Myasthenia Gravis (QMG) total score alongside a favorable safety profile. Access the full paper in Science Translational Medicine online here: www.science.org/doi/10.1126/scitranslmed.adk9109 In October 2022, NMD Pharma announced positive topline data which established the first clinical proof-of-mechanism of NMD Pharma’s novel CIC-1 chloride channel inhibitor approach in patients impacted by MG. In November 2023, NMD Pharma announced that it had raised €75 million (~$80 million) in a Series B financing to complete three Phase 2 studies with NMD670, the Company’s lead ClC-1 inhibitor in AChR and MuSK antibody positive MG, spinal muscular atrophy, and Charcot-Marie-Tooth disease. -END- Contacts NMD Pharma A/SThomas Holm Pedersen, CEOE-mail: contact@nmdpharma.com ICR ConsiliumMary-Jane Elliott / Ashley Tapp / Lindsey Neville E-mail: NMDPharma@consilium-comms.com Tel: +44 (0)20 3709 5700 About NMD PharmaNMD Pharma A/S is a clinical-stage biotech company developing a first-in-class platform of small molecule therapies selectively targeting the skeletal muscle chloride ion channel (ClC-1) for the treatment of severe neuromuscular disorders. The Company was founded on more than 15 years of muscle physiology research with a focus on regulation of skeletal muscle excitability under physical activity. NMD Pharma has built a world-leading muscle electrophysiology platform leveraging the in-depth know-how of muscle physiology and muscular disorders, small molecule modulators, enabling technologies and tools as well as in vivo pharmacology models for discovering and developing proprietary modulators of neuromuscular function. The Company has built significant clinical and development expertise as its programmes have progressed through the clinic. NMD Pharma has raised ~€155 million from investors including Novo Holdings, Lundbeckfonden BioCapital, INKEF Capital, Roche Venture Fund, and Jeito Capital. Find out more about us online at http://www.nmdpharma.com.

临床2期

2024-03-01

·BioSpace

NMD Pharma announces poster and oral presentations on skeletal muscle targeted ClC-1 therapy at two leading neuromuscular disease conferences

NMD Pharma announces poster and oral presentations on skeletal muscle targeted ClC-1 therapy at two leading neuromuscular disease conferences ClC-1 is a chloride ion channel specifically expressed in skeletal muscle cells that normally dampens muscle fiber excitability and is involved in regulating muscle fiber excitability during exercise. ClC-1 inhibition could be a possible mechanism to improve muscle fiber activation to address muscle weakness and fatigue in neuromuscular diseases. Presentations include new preclinical data on CIC-1 inhibition and a design and status update on the ongoing Phase 2, SYNAPSE-SMA, trial of NMD670 in spinal muscular atrophy type 3. Aarhus, Denmark, 1 March 2024 – NMD Pharma A/S, a clinical-stage biotech dedicated to developing novel and improved treatments for patients living with neuromuscular diseases, today announces that it will present two posters at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2024 and one poster and one oral presentation at the 4th Scientific International Congress on SMA 2024. The presentations will provide a clinical study design and status update on the Phase II SYNAPSE-SMA trial of NMD670 in ambulatory adults with spinal muscular atrophy type 3. The SYNAPSE-SMA study is a proof-of-concept, Phase II, randomized, double-blind, placebo-controlled, 2-way crossover study to evaluate the efficacy, safety, and tolerability of NMD670. The study is an international multicenter study including sites in North America and Europe and the first subject was enrolled in September 2023. In addition, NMD Pharma will also be presenting a poster outlining pre-clinical results elucidating the mechanism of action for CIC-1 inhibition and its potential to improve neuromuscular transmission in neuromuscular diseases with transmission failure. Jorge A. Quiroz, EVP, and Chief Medical Officer at NMD Pharma: “We are looking forward to sharing updates on the ongoing Phase 2 SYNAPSE-SMA trial for NMD670, along with further insights into the mechanism of ClC-1 inhibition and its potential to enhance neuromuscular transmission improving muscle weakness and fatigue.” “There remains a significant unmet need for new treatments for severe neuromuscular diseases, including patients with SMA. NMD670 has already demonstrated positive clinical study results in a Phase I/II study in patients with myasthenia gravis (MG), and we are confident that it could also be beneficial for the treatment of patients affected by SMA.” The MDA Conference is taking place in Orlando, Florida from 3-6 March. Details of NMD Pharma’s poster presentations are below: Poster number: S114 Location: Poster Exhibit Hall, Hilton Orlando Date and time: Sunday March 3, 6:00pm – 8:00pm ET Poster number: M278 Location: Poster Exhibit Hall, Hilton Orlando Date and time: Monday March 4, 6:00pm – 8:00pm ET The 4th Scientific International Congress on SMA is taking place in Ghent, Belgium, from 14-16 March. : NMD Pharma be presenting one poster and one oral presentation at the congress. Details of NMD Pharma’s oral presentations are below: Oral Presentation: “ClC-1 inhibitor compound improves neuromuscular transmission and enhances skeletal muscle function in pre-clinical animal models of neuromuscular dysfunction” Location: Main Auditorium Date and Time: Saturday 16th March 9:30am CET -END- Contacts NMD Pharma A/S Thomas Holm Pedersen, CEO E-mail: contact@nmdpharma.com ICR Consilium Mary-Jane Elliott / Ashley Tapp / Lindsey Neville E-mail: NMDPharma@consilium-comms.com Tel: +44 (0)20 3709 5700 About NMD Pharma NMD Pharma A/S is a clinical-stage biotech company developing a first-in-class platform of small molecule therapies selectively targeting the skeletal muscle chloride ion channel (ClC-1) for the treatment of severe neuromuscular disorders. The Company was founded on more than 15 years of muscle physiology research with a focus on regulation of skeletal muscle excitability under physical activity. NMD Pharma has built a world-leading muscle electrophysiology platform leveraging the in-depth know-how of muscle physiology and muscular disorders, small molecule modulators, enabling technologies and tools as well as in vivo pharmacology models for discovering and developing proprietary modulators of neuromuscular function. The Company has built significant clinical and development expertise as its programmes have progressed through in the clinic. NMD Pharma has raised ~€155 million from investors including Novo Holdings, Lundbeckfonden BioCapital, INKEF Capital, Roche Venture Fund, and Jeito Capital. Find out more about us online at .

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适应症	最高研发状态	国家/地区	公司	日期
神经肌肉疾病	临床前	-	NMD Pharma A/S初创企业	-
神经肌肉阻滞逆转	临床前	-	NMD Pharma A/S初创企业	-
肌肉减少症	临床前	-	NMD Pharma A/S初创企业	-