Nephrotic Syndrome, Idiopathic, Steroid-Resistant

All html pdf doc xls ppt match recent 10 20 30 none small medium large Home About Chugai News Anti-CD20 Monoclonal Antibody Rituxan® Approved for Treatment of Refractory Steroid-Resistant Nephrotic Syndrome Zenyaku Kogyo Co., Ltd. Chugai Pharmaceutical Co., Ltd. TOKYO, September 24, 2024 -- Zenyaku Kogyo Co., Ltd. (Japanese-only website) and Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) announced today that Zenyaku obtained regulatory approval from the Ministry of Health, Labour and Welfare (MHLW), for an anti-CD20 monoclonal antibody Rituxan® intravenous injection 100 mg and 500 mg [generic name: rituximab (genetical recombination)] (hereafter, “Rituxan”) for “refractory steroid-resistant nephrotic syndrome*1.” Nephrotic syndrome is a general term for a condition in which damage to the glomerular slit membrane in the nephrons that make up the kidneys results in severe proteinuria and hypoalbuminemia, leading to generalized edema1). Nephrotic syndrome that develops in childhood is the most common chronic kidney disease in children2) and is a designated intractable disease of unknown cause. Approximately 10% to 20% are classified as “steroid-resistant nephrotic syndrome,” in which complete remission cannot be achieved with steroid treatment, which is the first-choice drug3). Steroid pulse therapy or remission induction therapy using immunosuppressants are recommended for “steroid-resistant nephrotic syndrome,” but in cases of “refractory steroid-resistant nephrotic syndrome” where remission cannot be achieved even with these treatments, there is a high risk of developing end-stage renal failure and the prognosis is poor3). Rituxan is an anti-CD20 monoclonal antibody that specifically binds to CD20, a protein expressed on B cells, excluding hematopoietic stem cells and plasma cells. It attacks target B cells using the immune system equipped with the human body, and damages cells. It has been suggested that B cells may be involved in the pathogenesis and disease activity of nephrotic syndrome4) 5) 6), and it is expected that removing B cells with Rituxan will have a therapeutic effect on nephrotic syndrome. Rituxan was approved in August 2014 for the treatment of childhood-onset “refractory nephrotic syndrome (frequently relapsing or steroid-dependent).” In the development of Rituxan for “refractory steroid-resistant nephrotic syndrome,” the primary endpoint (reduction rate from baseline in urinary protein creatinine ratio at 169 days) was achieved7) 8) in an investigator-initiated clinical trial*2 targeting patients with childhood-onset refractory steroid-resistant nephrotic syndrome. Zenyaku filed an application for partial changes to the manufacturing and sales approval items on December 22, 2023, which led to the current approval. Zenyaku and Chugai will continue working closely together so that Rituxan can further contribute to the treatment of refractory nephrotic syndrome. Trademarks used or mentioned in this release are protected by law. *1 Approved indication or effect Refractory nephrotic syndrome (frequently relapsing, steroid-dependent or steroid-resistant) Rituxan was approved for the treatment of refractory nephrotic syndrome (frequently relapsing or steroid-dependent) in August 2014, and obtained additional approval for the treatment of refractory steroid-resistant nephrotic syndrome. *2 Multicenter single-armed clinical trial of combination therapy with IDEC-C2B8 and steroid pulse therapy for childhood-onset refractory steroid-resistant nephrotic syndrome (JSKDC11) Sources Chapter I “Introduction.” 1. Disease concept and etiology. Supervision by The Japanese Society of Pediatric Nephrology and edited by refractory disease policy research project refractory “Establishment of clinical and research system for rare / intractable diseases in pediatric kidney” (MHLW Science Research Grant). Pediatric Nephrotic Syndrome Guidelines 2020, SHINDAN TO CHIRYO SHA Inc., 2020, pp2-4 Iijima K, Sako M, Nozu K. VII. Idiopathic nephrotic syndrome in children. Journal of the Japanese Society of Internal Medicine. 2020; 109(5): 926-932. Chapter II “Treatment.” Supervision by The Japanese Society of Pediatric Nephrology and edited by refractory disease policy research project refractory “Establishment of clinical and research system for rare / intractable diseases in pediatric kidney” (MHLW Science Research Grant). Pediatric Nephrotic Syndrome Guidelines 2020, SHINDAN TO CHIRYO SHA Inc., 2020, pp26-34 Tani Y, Kida H, Abe T, et al. B lymphocyte subset patterns and their significance in idiopathic glomerulonephritis. Clin Exp Immunol. 1982; 48(1): 201-204. Yokoyama H, Kida H, Tani Y, et al. Immunodynamics of minimal change nephrotic syndrome in adults T and B lymphocyte subsets and serum immunoglobulin levels. Clin Exp Immunol. 1985; 61(3): 601-607. Garin EH, Diaz LN, Mu W, et al. Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol. 2009; 20(2): 260-266. Nozu K, Sako M, Tanaka S, et al. Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial). Clin Exp Nephrol. 2024; 28(4): 337-348. Japan Registry of Clinical Trials (jRCT) [Internet; cited September 2024]. Available at: https://jrct.niph.go.jp/en-latest-detail/jRCT2051190019 [PDF 256KB] Contact Zenyaku Holdings Co., Ltd. General Affairs Department, Public Relations Section Tel: +81-3-3946-1123 Chugai Pharmaceutical Co., Ltd., Corporate Communications Dept., Media Relations Group Tel: +81-3-3273-0881 E-mail: pr@chugai-pharm.co.jp Investor Relations Group Tel: +81-3-3273-0554 E-mail: ir@chugai-pharm.co.jp Back Home About Chugai News Anti-CD20 Monoclonal Antibody Rituxan® Approved for Treatment of Refractory Steroid-Resistant Nephrotic Syndrome About Chugai Message from the CEO Chugai’s Five Strengths Company Outline Our Vision Our Strategy History of Chugai Pharmaceutical Chugai Group R&D Digital Transformation "CHUGAI DIGITAL" Videos & Advertisements Press Room News Media Conference Partnering To our suppliers Investor Relations Management Policy Financial Results Reports & Downloads Shareholder Information Corporate Governance ESG at Chugai Main Products / Development Pipeline See how Chugai compares to other companies Strategic Alliance with Roche Chugai’s Five Strengths Events & Presentations Contacts & Information FAQs Recruitment Chugai Recruiting Site Sustainability Basic Policy (Creation of Shared Value) Sustainability and Business Strategy Sustainable Patient-Centric Healthcare Global Health Human Resources and Diversity & Inclusion Ethics and Compliance Supply Chain Management Human Rights Social Contribution Global Environment Health and Productivity Management Governance External Evaluations Activity Reports Data Chugai's Transparency Guidelines You are now moving to an external website. 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Purespring Therapeutics presents preclinical data at the 61st ERA Congress Data establishes the potential of AAV gene therapy to deliver transgenes to the podocyte to replace defective genes or to modulate protein production Data underpin the potential of AAV as an important novel modality to treat a broad range of kidney disease London— 24 May 2024— Purespring Therapeutics, a pioneering gene therapy company focused on transforming the treatment of kidney diseases, is presenting preclinical data at the 61st European Renal Association (ERA) Congress, showing that transgenes can be efficiently targeted to podocytes to replace defective genes or to use the podocyte as a protein factory to modulate kidney biology. The presentation: “A novel podocyte gene therapy enables pathway to clinical translation for the treatment of glomerular diseases” is being presented today at the ERA Congress, taking place in Stockholm, Sweden from 23-26 May. Adeno associated vector (AAV) gene therapy has the potential to treat a wide range of kidney disease via the targeted delivery of genes to kidney cells, but historically, kidney AAV gene therapy has been challenging due to technical and physiological hurdles limiting effective delivery. The presentation, by Sam Illingworth, Purespring’s Head of Translational Research, demonstrates the development of Purespring’s novel AAV gene therapy which can efficiently deliver transgenes to podocytes, a specialised kidney cell implicated in the majority of glomerular kidney disease. Exemplified through the development of PS-001, both murine model and large animal data show this approach can effectively target transgenes to podocytes to replace defective genes and rescue kidney function, providing an important novel modality for treating a broad range of kidney diseases. Alice Brown, Purespring’s Chief Scientific Officer, commented: “These data show that an AAV gene therapy can be used to deliver transgenes effectively, specifically, and safely to podocytes and establish this approach as a modality to treat many glomerular diseases. This sets us on a clear pathway towards clinical development for PS-001 and other kidney indications in our pipeline, and we’re excited to be able to present this to the international nephrology community.” Julian Hanak, Purespring’s Chief Executive Officer, added: “This highlights the potential of our podocyte-targeting approach to stop, reverse and potentially cure chronic kidney diseases. Affecting over 840 million people worldwide, chronic kidney disease places an innumerable burden both on patients and their families, as well as on global health systems.” Methods to translate Purespring’s approach to a clinical setting were also established, with additional toxicological assessments of renal and other organ function showing no pre-clinical treatment-related safety concerns. PS-001 is being developed as a novel approach to treat steroid resistant nephrotic syndrome caused by mutated NPHS2 and may become the first podocyte targeted gene therapy to enter clinical development. Results Using our AAV gene therapy platform, which includes a capsid that is highly effective at transducing human podocytes and promoter that drives gene expression specifically in the podocyte, the gene therapy product PS-001 encoding NPHS2 has been generated. Using a murine analogue of PS-001, in vivo proof of concept studies in a translationally relevant murine disease model (Nphs2R140Q/-) showed NPHS2 delivery and podocin expression in glomeruli and efficacy in terms of renal function rescue. This was demonstrated by resolution of severe proteinuria improved serum albumin and reduction in glomerulosclerosis. The methods to translate the approach to the clinical setting were established in pigs. Administration of PS-001 resulted in transgene mRNA expression across 89% ± 11% of kidney glomeruli as assessed by RNAScope, and transgene derived podocin protein could be specifically detected in podocytes. Using qPCR, RT-PCR and ELISA it was shown that using local administration, podocin gene expression was restricted exclusively to the kidney glomerulus, with gene expression undetectable in off-target organs including the liver. Additional toxicological assessments of renal and other organ function from urine and blood, and post-study histopathological assessments revealed no pre-clinical treatment-related safety concerns. For further information, contact: Purespring: Julian Hanak, CEOcontact@purespringtx.com+44 (0)20 3855 6324LinkedIn ICR Consilium Amber Fennell, Jessica Hodgsonpurespring@consilium-comms.com Notes to Editors About Purespring Purespring is the first and leading company to treat kidney diseases by targeting the podocyte, a specialised cell implicated in many renal diseases, through AAV gene therapy administered directly to the kidney. Purespring was founded on the work of Professor Moin Saleem, Professor of Paediatric Renal Medicine at the University of Bristol, where he heads a world leading multidisciplinary group researching glomerular diseases. Purespring seeks to advance gene therapies for the treatment of both monogenic and non-monogenic chronic renal diseases that are currently poorly addressed with existing treatments. For more information please visit: purespringtx.com and follow us on LinkedIn.

Genetic mutations which cause a debilitating hereditary kidney disease affecting children and young adults have been fixed in patient-derived kidney cells using a potentially game-changing DNA repair-kit. Genetic mutations which cause a debilitating hereditary kidney disease affecting children and young adults have been fixed in patient-derived kidney cellsusing a potentially game-changing DNA repair-kit. The advance, developed by University of Bristol scientists, is published in Nucleic Acids Research. In this new study, the international team describe how they created a DNA repair vehicle to genetically fix faulty podocin, a common genetic cause of inheritable Steroid Resistant Nephrotic Syndrome (SRNS).* Podocin is a protein normally located on the surface of specialised kidney cells and is essential for kidney function. Faulty podocin, however, remains stuck inside the cell and never makes it to the surface, terminally damaging the podocytes. Since the disease cannot be cured with medications, gene therapy which repairs the genetic mutations causing the faulty podocin offers hope for patients. Typically, human viruses have been utilised in gene therapy applications to carry out genetic repairs. These are used as a 'Trojan Horse' to enter cells carrying the errors. Currently dominating systems include lentivirus (LV), adenovirus (AV) and adeno-associated virus (AAV), which are all relatively harmless viruses that readily infect humans. However, these viruses all share the same limitation in that they are restricted in space within their viral shells. This in turn constrains the amount of cargo they can deliver, namely the DNA kit required for efficient genetic repair, which significantly limits the scope of their application in gene therapy. By applying synthetic biology techniques, the team led by Dr Francesco Aulicino and Professor Imre Berger from Bristol's School of Biochemistry, re-engineered baculovirus, a for humans harmless insect virus which is no longer constrained by limited cargo capacity. "What sets apart baculovirus from LV, AV, and AAV is the lack of a rigid shell encapsulating the cargo space." said Dr Francesco Aulicino, who led the study. The shell of baculovirus resembles a hollow stick -- it simply becomes longer when the cargo increases. This means a lot more sophisticated tool-kit to repair a genetic defect can be delivered by the baculovirus, making it much more versatile than commonly-used systems. First, baculovirus had to be equipped to penetrate human cells which it normally would not do. "We decorated the baculovirus with proteins that enabled it to enter human cells very efficiently." explained Dr Aulicino. This modified baculovirus is considered safe, as it could only multiply in the insect, but not in human cells. The scientists then used their engineered baculovirus to deliver much larger DNA pieces than was previously possible, and build these into the genomes of a whole range of human cells. The DNA in the human genome comprises 3 billion base-pairs making up ~25,000 genes, which encode for the proteins that are essential for cellular functions. If faulty base-pairs occur in our genes, faulty proteins are made which can make us ill, resulting in hereditary disease. Gene therapy promises repair of hereditary disease at its very root, by rectifying such errors in our genomes. Gene editing approaches, in particular CRISPR/Cas-based methods, have greatly advanced the field by enabling genetic repair with base-pair precision. The team used patient-derived podocytes carrying the disease-causing error in the genome to demonstrate the aptitude of their technology. By creating a DNA repair kit, comprising protein-based scissors and the nucleic acid molecules that guide them -- and the DNA sequences to replace the faulty gene, the team delivered with a single engineered baculovirus a healthy copy of the podocin gene concomitant with the CRISPR/Cas machinery to insert it with base-pair precision into the genome. This was able to reverse the disease-causing phenotype and restore podocin to the cell surface. Professor Imre Berger explains: "We had previously used baculovirus to infect cultured insect cells to produce recombinant proteins for studying their structure and function." This method, called MultiBac, developed by the Berger laboratory, has been highly successful to make very large multiprotein complexes with many subunits, in laboratories world-wide. "MultiBac already exploited the flexibility of the baculovirus shell to deliver large pieces of DNA into the cultured insect cells, instructing them to assemble the proteins we were interested in." When the scientists realised that the same property could potentially transform gene therapy in human cells, they went to work to create their new system described in their publication. Dr Aulicino added: "There are many avenues to utilise our system. In addition to podocin repair, we could show that we can simultaneously correct many errors in very different places in the genome efficiently, by using our single baculovirus delivery system and the most recent editing techniques available." "SRNS is one of the more common genetic diseases affecting the kidney" said Professor Moin Saleem, a leading expert in the gene therapy of hereditary kidney disease at Bristol Renal. "SRNS is characterised by kidney failure at an early age, leading to severe loss in quality of life for those affected." Professor Gavin Welsh, Professor of Renal Cell Biology at Bristol Renal, concluded: "These results are very encouraging. This new approach pioneered by the Berger team holds promise not only for SRNS, but also for a range of other genetic diseases of the kidney, where efficient genetic repair is not feasible with current technology. It is a long road ahead to implement a new vector system for clinical applications, but we believe the advantages offered make this a very worthwhile undertaking." This research received funding from the European Research Councial (ERC), Kidney Research UK (KRUK), and the EPSRC/BBSRC Bristol Research Centre for Synthetic Biology BrisSynBio. *About Steroid Resistant Nephrotic Syndrome (SRNS) Hereditary SRNS is a devastating kidney disease affecting children and young adults. It is caused by mutations in genes that are important in the function of the specialised filtration cell of the kidney, called the podocyte. These disorders currently have no available therapy, and result in rapid onset of kidney failure, requiring dialysis and transplantation.