AQP4

Immune cells must learn not to attack the body itself. A team of researchers has discovered a previously unknown mechanism behind this: other immune cells, the B cells, contribute to the 'training' of the T cells in the thymus gland. If this process fails, autoimmune diseases can develop. The study confirms this for Neuromyelitis optica, a disease similar to Multiple Sclerosis. Other autoimmune diseases may be linked to the failure of this new mechanism as well. Immune cells must learn not to attack the body itself. A team of researchers from the Technical University of Munich (TUM) and the Ludwig Maximilian University of Munich (LMU) has discovered a previously unknown mechanism behind this: other immune cells, the B cells, contribute to the "training" of the T cells in the thymus gland. If this process fails, autoimmune diseases can develop. The study confirms this for Neuromyelitis optica, a disease similar to Multiple Sclerosis. Other autoimmune diseases may be linked to the failure of this new mechanism as well. In children and adolescents, the thymus gland functions as a "school for T cells." The organ in our chest is where the precursors of those T cells that would later attack the body's own cells are discarded. Epithelial cells in the thymus present a large number of molecules that occur in the body to the future T cells. If any of them reacts to one of these molecules, a self-destruction program is triggered. T cells that attack the body's own molecules remaining intact and multiplying, on the other hand, can cause autoimmune diseases. New mechanism discovered In Nature, the team led by Thomas Korn, Professor of Experimental Neuroimmunology at TUM and a Principal Investigator in the SyNergy Cluster of Excellence, and Ludger Klein, Professor of Immunology at LMU's Biomedical Center (BMC), describe another previously unknown mechanism behind this. In addition to the precursors of T cells, the thymus gland also contains other immune cells, the B cells. They develop in the bone marrow but migrate to the thymus in early childhood. "The function of B cells in the thymus gland has been a mystery that has puzzled immunologists for many years," says Thomas Korn. The researchers have now been able to show for the first time that B cells play an active role in teaching T cells which targets not to attack. MS-like disease due to malfunction in tolerance formation Neuromyelitis optica is an autoimmune disease similar to multiple sclerosis (MS). While it is not yet known which molecules are attacked in MS, it is well-established that T cells respond to the protein AQP4 in neuromyelitis optica. AQP4 is most prominently expressed in cells of the nervous tissue, which then becomes the target of the autoimmune reaction. Frequently, the optic nerve is affected. The researchers were able to show that in the thymus gland of humans and mice not only the epithelial cells but also B cells express and present AQP4 to the T cell precursors. If the B cells were prevented from doing so in animal experiments, AQP4-reactive T cell precursors were not eliminated and the autoimmune disease developed. This was also the case when the epithelial cells still presented the molecule. The team concludes from this that B cells in the thymus are a necessary condition for immune tolerance regarding AQP4. Protection against subsequent interactions between T cells and B cells "We suspect that this previously unknown process has evolved particularly to prevent dangerous interactions between autoreactive T and B cells in the lymph nodes and spleen, the so-called peripheral immune compartment," says Ludger Klein. Once the immune system is developed, B and T cells can communicate and thus trigger highly effective immune reactions. This is useful when it comes to fighting pathogens quickly. On occasion, however, B cells may accidentally present the body's own proteins, such as AQP4. If the T cells that react to AQP4 had not been sorted out in the thymus, this could lead to a sudden and violent large-scale attack on the body. Possible cause of other immune disorders "We assume that problems with the training of T cells by the B cells in the thymus can cause other autoimmune diseases as well," says Thomas Korn. "After all, the B cells in the thymus present a whole range of the body's own proteins. The corresponding interactions must be investigated in further studies." According to the researchers, likely suspects include antiphospholipid syndrome (APS) and certain forms of cerebral amyloid angiopathy. "Looking further into the future, this interaction in the thymus might be exploited to treat existing autoimmune diseases in a very targeted manner," says Thomas Korn.

[16-January-2024] -- First and only anti-CD19 B-cell-depleting monotherapy for the treatment of adult patients with NMOSD who are anti-aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+) – -- NMOSD is a devastating autoimmune disease of severe and recurrent central nervous system attacks which can result in blindness, paralysis and death – TORONTO, Jan. 16, 2024 /CNW/ - Horizon Therapeutics plc, now part of Amgen, announced that on December 15, 2023, Health Canada approved UPLIZNA® (inebilizumab for injection) as a monotherapy for the treatment of adult patients with NMOSD who are AQP4-IgG+. This rare autoimmune disease is caused by inflammation in the central nervous system, resulting in severe and recurrent attacks that can lead to permanent disability, such as vision loss and paralysis.1 An estimated 1,000 people in Canada live with the disease.2,3,4 "Today's approval of UPLIZNA marks a significant milestone for adults living with NMOSD in Canada, bringing a new, targeted treatment option to those living with this devastating disease," said Matt McCarthy, general manager, Canada, Horizon. "Just a single NMOSD attack can have a life-altering impact, including pain, debilitation and irreversible vision loss. We are committed to bringing new medicines to people living with rare and challenging diseases around the world, and today's announcement is an exciting milestone in that effort." Health Canada based its approval of UPLIZNA on results from the N-MOmentum pivotal trial (2014-000253-36), the largest NMOSD clinical trial to date. UPLIZNA demonstrated a significant reduction in the risk of an NMOSD attack with only two infusions per year, following the initial loading doses. Additionally, 87.6% of patients in the AQP4-IgG+ group remained relapse-free during the six-month period post-treatment.5 UPLIZNA also demonstrated an acceptable safety profile. People impacted by NMOSD live with unpredictable attacks; 90% will experience repeat attacks within five years of an initial attack.7 Damage is caused when CD19+-expressing B-cell lymphocytes (plasmablasts and some plasma cells) secrete AQP4-IgG, triggering an escalating autoimmune reaction. Depletion of CD19+ B-cells has proven effective at halting inflammation, lesion formation and astrocyte loss. UPLIZNA offers a unique mode of action developed specifically to deplete CD19+ B-cells and prevent attacks.5,6,7 "NMOSD has historically been misdiagnosed for multiple sclerosis (MS), which can delay proper treatment and worsen outcomes, especially if treated with MS drugs," said Mark Freedman, director, Multiple Sclerosis Research Unit, Professor of Neurology, University of Ottawa, Dept of Medicine, Senior Scientist, the Ottawa Hospital Research Institute. "We can now accurately diagnose NMOSD, which is distinctly different from MS and warrants specific treatment. UPLIZNA is an important new treatment option that provides physicians and patients living with NMOSD a therapy with proven efficacy, a favorable safety pro a twice-yearly maintenance dosing schedule." "We at The Sumaira Foundation are excited to see new, clinically proven therapies becoming available to NMOSD patients in Canada that give them additional options for treatment and management of this rare but serious condition," said Sumaira Ahmed, an NMOSD patient, founder and Executive Director of The Sumaira Foundation. "Many patients have benefitted from access to these therapies in the US, Europe and around the world. As a patient living with this rare disease for ten years, I know first-hand how important it is to have multiple treatment options available. As a patient advocacy leader, I have seen how they can transform the lives of fellow patients." UPLIZNA was approved by the U.S. Food and Drug Administration (FDA) in June 2020, by the Japanese Ministry of Health, Labor and Welfare in March 2021, by the European Commission (EC) in April 2022 and by the Brazilian Health Regulatory Agency (ANVISA) in December 2022. For additional information about UPLIZNA, please see the product monograph. About Neuromyelitis Optica Spectrum Disorder (NMOSD) NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.9,10 Approximately 80% of all patients with NMOSD test positive for anti-AQP4 antibodies.11 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.12 Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.13 Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.12-14 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.15 Each NMOSD attack can lead to further cumulative damage and disability.16,17 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.18,19 About Horizon Horizon, now part of Amgen, is a global biotechnology company focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: We apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. References: Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103. Marrie RA, Gryba C. The Incidence and Prevalence of Neuromyelitis Optica. International Journal of MS Care. 2013;15(3):113-118. doi:10.7224/1537-2073.2012-048 Etemadifar M, Nasr Z, Khalili B, Taherioun M, Vosoughi R. Epidemiology of Neuromyelitis Optica in the World: A Systematic Review and Meta-Analysis. Multiple Sclerosis International. 2015;2015:1-8. doi:10.1155/2015/174720 Canada S. Table 17-10-0005-01 Population estimates on July 1st, by age and sex. Updated December 21, 2022. Accessed June 14, 2023, Cree BA, Bennett JL et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-Momentum): a double-blind, randomised placebo-controlled phase 2/3 trial. The Lancet. 2019;394:1352-63. Rensel M, Zabeti A, Mealy M et al. Long-term efficacy and safety of inebilizumab in neuromyelitis optica spectrum disorder: Analysis of aquaporin-4–immunoglobulin G–seropositive participants taking inebilizumab for ⩾4 years in the N-MOmentum trial. Multiple Sclerosis Journal. 2021:135245852110472. Wingerchuk DM, Hogancamp WF, O'Brien PC et al. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology. 1999;53(5):1107-1114. doi:10.1212/ wnl.53.5.1107. Contetti EC, Correale J. Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies. Journal of Neuroinflammation. 2021;18:208. Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018; 384:96-103. What is NMO? Guthyjacksonfoundation.org. Accessed March 15, 2022. Illés Z. Treatment and new evidences in neuromyelitis optica spectrum disorder. Ideggyogy Sz. 2021;74(9-10):309-321. Liu Y, et al. A tract-based diffusion study of cerebral white matter in neuromyelitis optica reveals widespread pathological alterations. Mult Scler. 2011;18(7):1013-1021. Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706. Duan T, Smith AJ, Verkamn AS. Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody dependent cellular cytotoxicity. Acta Neuropathologica Comm. 2019;7(112). Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580. Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187. Baranello RJ, Avasarala, JR. Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances. J Neuro Ther. 2015;1(1):9-14. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci. 2009;286(1-2):18-23. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783. SOURCE Horizon Therapeutics

-- Presentations will feature data from the pivotal Phase 3 study of UPLIZNA, including new biomarker analyses -- DUBLIN--(BUSINESS WIRE)--Horizon Therapeutics plc (Nasdaq: HZNP) today announced that new UPLIZNA analyses will be presented at the 39th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2023, Oct. 11-13. UPLIZNA is the first and only targeted CD19+ B-cell-depleting therapy approved by the U.S. Food and Drug Administration, the European Commission and the Brazilian Health Regulatory Agency (ANVISA) for the treatment of NMOSD in adults who are anti-aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+). Presentation Details: P015: Association of Cytokine Proteins with Disease Activity in NMOSD Participants Receiving Inebilizumab Treatment (S. Pittock) Poster Session: Clinical aspects of MS - NMOSD Date: Oct. 11, 2023, 8-8:30 a.m. CEST P409: Long-Term Comparative Efficacy of Inebilizumab in the AQP4+ Subpopulation from the N-MOmentum Open-Label Extension Versus Azathioprine and Immunosuppressive Therapies and Versus Placebo in Patients with NMOSD (B. Cree) Poster Session: Clinical aspects of MS - NMOSD Date: Oct. 11, 2023, 8-8:30 a.m. CEST P011: Matching-Adjusted Indirect Comparison of Current Treatments for NMOSD and Evaluation of Long-Term Effectiveness (F. Paul) Poster Session: Clinical aspects of MS - NMOSD Date: Oct. 11, 2023, 8-8:30 a.m. CEST Horizon will host a symposium Thursday, Oct. 12 from 8:45 to 9:45 a.m. CEST, “Looking for unrecognized disease activity in NMOSD to optimize treatment choice and prevent disability,” chaired by Massimo Filippi, M.D., Ph.D., featuring presentations from Maria Rocca, M.D., Orhan Aktas, M.D. and Jeffrey Bennett, M.D., Ph.D. About Neuromyelitis Optica Spectrum Disorder (NMOSD) NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.1,2 Approximately 80% of all patients with NMOSD test positive for anti-AQP4 antibodies.3 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.4 Anti-AQP4 autoantibodies are produced by plasmablasts and some plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.5 Depletion of these CD19+ B-cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.4,6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.7 Each NMOSD attack can lead to further cumulative damage and disability.8,9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.10,11 About UPLIZNA INDICATION UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. IMPORTANT SAFETY INFORMATION UPLIZNA is contraindicated in patients with: A history of life-threatening infusion reaction to UPLIZNA Active hepatitis B infection Active or untreated latent tuberculosis WARNINGS AND PRECAUTIONS Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic. Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved. Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy. The risk of Hepatitis B Virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis. Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA. Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion. Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections. Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA. Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia. For additional information on UPLIZNA, please see the Full Prescribing Information at . About Horizon Horizon is a global biotechnology company focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: We apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, visit and follow us on Twitter, LinkedIn, Instagram and Facebook. References Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103. What is NMO? Accessed April 15, 2021. Guthyjacksonfoundation.org. What We Know About NMO. Accessed Aug. 2, 2022. Sumairafoundation.org. Liu Y, et al. A tract-based diffusion study of cerebral white matter in neuromyelitis optica reveals widespread pathological alterations. Mult Scler. 2011;18(7):1013-1021. Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706. Duan T, Smith AJ, Verkamn AS. Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody dependent cellular cytotoxicity. Acta Neuropathologica Comm. 2019;7(112). Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580. Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187. Baranello RJ, Avasarala, JR. Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances. J Neuro Ther. 2015;1(1):9-14. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci. 2009;286(1-2):18-23. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783.