X-Linked Combined Immunodeficiency Diseases

18 October 2024 – Novo Nordisk today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending approval of Alhemo® (concizumab) as the first once-daily subcutaneous prophylactic treatment for people aged 12 years or older living with haemophilia A or B with inhibitors. Haemophilia is a rare bleeding disorder that impairs the body’s ability to make blood clots, a process needed to stop bleeding. Haemophilia is often treated by replacing the missing clotting factor via intravenous infusions, also known as replacement therapy. However, sometimes the body can produce inhibitors as an immune response to the clotting factors in the therapy, which means replacement therapy does not work and limits treatment options overall. Currently, it is estimated that up to 30% of people living with severe haemophilia A develop inhibitors,1 and 5-10% of those with severe haemophilia B develop inhibitors.2,3 Alhemo® is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody that, if approved by the European Commission, will offer the first once-daily subcutaneous prophylactic treatment to people with haemophilia A or B with inhibitors.4 Alhemo® is designed to block a protein called TFPI in the body that stops blood from clotting. By blocking TFPI, Alhemo® ensures the production of thrombin, which helps to clot the blood and prevent bleeding, even when the other clotting factors are missing or deficient. Importantly, this means Alhemo® allows blood clots to happen, even in the presence of inhibitors.5 “The positive opinion from the CHMP for Alhemo® is a major milestone for patients,” said Stephanie Seremetis, chief medical officer for haemophilia at Novo Nordisk. “If approved, Alhemo® would be an important addition to our growing haemophilia portfolio as it offers the potential of everyday prophylaxis to prevent bleeds for people living with haemophilia who have developed the complication of inhibitors. It could alleviate the physical, emotional, and overall treatment burden for people living with haemophilia, as it is delivered in a pre-filled, multi-use, portable pen that can be stored at room temperature for up to four weeks. This could enable patients to have greater confidence in the pursuit of daily activities, which is especially important for people living with haemophilia B with inhibitors, who currently have very limited treatment options.” The CHMP positive opinion is based on data from the phase 3 explorer7 study, which was designed to evaluate the efficacy and safety profile of Alhemo® for people living with haemophilia A or B with inhibitors.6 If approved, Alhemo® will be provided in a portable, pre-mixed and prefilled pen, enabling quick and easy subcutaneous administration with the aim of easing the treatment burden of regular intravenous infusions.7 Novo Nordisk expects a final approval by the European Commission within approximately two months. Alhemo® (concizumab) is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody designed to block a protein in the body that stops blood from clotting. By blocking TFPI, Alhemo® ensures the production of thrombin, which helps to clot the blood and prevent bleeding.5 Alhemo® is currently approved in Australia8 and Switzerland9 for the treatment of adolescents and adults (12 years or older) with haemophilia A or B with inhibitors. In Japan,10 Alhemo® is currently approved for the treatment of adolescents and adults (12 years or older) with haemophilia A or B with and without inhibitors and is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. In explorer7, 133 males (aged 12 years or older) were randomised 1:2 to either no prophylaxis (arm one; ≥24 weeks) or concizumab prophylaxis (arm two; ≥32 weeks) or assigned to concizumab prophylaxis (arm three and four).11 The primary analysis compared the number of treated spontaneous and traumatic bleeding episodes, measured as annualised bleeding rate (ABR), between arms one and two. The results showed an 86% reduction in treated spontaneous and traumatic bleeds when on concizumab prophylaxis, with an estimated mean ABR of 1.7 compared to 11.8 with no prophylaxis.12 The overall median ABR of concizumab was zero, compared to 9.8 for no prophylaxis. The safety and tolerability profile of concizumab in this study was within the expected range.12 Haemophilia is a rare inherited bleeding disorder that impairs the body’s ability to make blood clots, a process needed to stop bleeding. It is estimated to affect approximately 1,125,000 people worldwide.12 Due to the nature of haemophilia being an x-linked recessive disorder, it often presents differently in males compared to females, with roughly 88% of people diagnosed with haemophilia worldwide being male.13,14 There are different types of haemophilia, which are characterised by the type of clotting factor protein that is defective or missing. Haemophilia A is caused by a missing or defective clotting Factor VIII (FVIII), and haemophilia B is caused by a missing or defective clotting Factor IX (FIX). Novo Nordisk is a leading global healthcare company, founded in 1923 and headquartered in Denmark. Our purpose is to drive change to defeat serious chronic diseases, built upon our heritage in diabetes. We do so by pioneering scientific breakthroughs, expanding access to our medicines, and working to prevent and ultimately cure disease. Novo Nordisk employs about 69,000 people in 80 countries and markets its products in around 170 countries. For more information, visit novonordisk.com, Facebook, Instagram, X, LinkedIn and YouTube. References 1 Kim JY, You CW. The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A. Blood Res. 2019 Sep;54(3):204-209. doi: 10.5045/br.2019.54.3.204 2 Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;26 Suppl 6:1-158. doi:10.1111/hae.14046 3 Male C et al. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica. 2021 Jan 1;106(1):123-129. doi: 10.3324/haematol.2019.239160. PMID: 31919092; PMCID: PMC7776246 4 Shapiro AD. Concizumab: a novel anti-TFPI therapeutic for hemophilia. Blood Adv. 2021;5(1):279 5 Matsushita T, Shapiro A, Abraham A, et al. Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. N Engl J Med 2023;389:783-794 Available at: https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa2216455 Accessed: October 2024 6 Frei-Jones M, Cepo K, d’Oiron R, et al. Subcutaneous concizumab prophylaxis in patients with hemophilia A or B with inhibitors: efficacy and safety results by hemophilia subtype from the phase 3 explorer7 trial. Abstract presented at the 64th American Society of Hematology (ASH) annual meeting and exposition 2022. 7 Kahr Rasmussen et al. The Concizumab Pen-Injector is Easy to Use and Preferred by Hemophilia Patients and Caregivers: A Usability Study Assessing Pen-Injector Handling and Preference. Patient Preference and Adherence 2024:18 1713–1727 8 Therapeutic Goods Administration (TGA), Product Information. Available at: https://www.tga.gov.au/resources/auspar/auspar-alhemo 9 SwissMedic. Switzerland Product Information. Available at: https://www.swissmedic.ch/swissmedic/en/home/about-us/publications/public-summary-swiss-par/public-summary-swiss-par-alhemo.html 10 Japanese Product Information. Latest revision date: June 2024 11 Jiménez-Yuste V, Angchaisuksiri P, Castaman G, et al. Concizumab prophylaxis in patients with haemophilia A or B with inhibitors: Efficacy and safety results from the 32-week primary analysis of the phase 3 explorer7 trial. Presented at ISTH 2022 12 Iorio A, Stonebraker JS, Chambost H, Makris M, Coffin D, Herr C, Germini F; Data and Demographics Committee of the World Federation of Hemophilia. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med. 2019 Oct 15;171(8):540-546. doi: 10.7326/M19-1208. 13 Centers for Disease Control and Prevention. What is Hemophilia? Available at: https://www-cdc-gov.libproxy1.nus.edu.sg/hemophilia/about/?CDC_AAref_Val=https://www-cdc-gov.libproxy1.nus.edu.sg/ncbddd/hemophilia/facts.html Accessed: October 2024 14 Statista. Distribution of people with bleeding disorders worldwide in 2020, by gender. Available at: https://www-statista-com.libproxy1.nus.edu.sg/statistics/495675/percentager-of-people-with-bleeding-disorders-in-worldwide-bygender/#:~:text=This%20statistic%20displays%20the%20percentage,with%20hemophilia%20A%20were%20males Accessed: October 2024 The content above comes from the network. if any infringement, please contact us to modify.

– Data from pivotal dose level demonstrates long-term, sustained reductions in CSF levels of HS D2S6, a key biomarker of brain disease in MPS II – 80% of patients who received the pivotal dose discontinued intravenous enzyme replacement therapy or remained treatment-naïve – Submission of a rolling BLA using the accelerated approval pathway on track for Q3 2024 ROCKVILLE, MD, USA I September 3, 2024 I REGENXBIO Inc. (Nasdaq: RGNX ) today announced positive results from the Phase I/II/III CAMPSIITE ® trial of RGX-121 for the treatment of patients with Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome. The results were presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024. The totality of evidence from the CAMPSIITE trial continues to support RGX-121 as the potential first gene therapy and one-time treatment for MPS II. In the United States, RGX-121 is also on track to be the first treatment that addresses the neurocognitive decline associated with MPS II, with the potential to be the first-line treatment for patients with neuronopathic disease. “As we quickly approach the BLA filing for RGX-121, we are very pleased with the data presented at SSIEM demonstrating encouraging evidence of systemic activity and long-term reductions of CSF D2S6,” said Steve Pakola, M.D., Chief Medical Officer of REGENXBIO. “The data continue to support that by restoring the gene missing in boys with Hunter syndrome, RGX-121 changes the course of disease and has the potential to significantly improve both vital brain function and the systemic manifestations of this devastating disease.” Data Summary In new, long-term data from the Phase I/II/III CAMPSIITE ® trial, patients receiving RGX-121 at the pivotal dose level demonstrated an 85% median reduction of cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6, a key biomarker of brain disease activity, approaching normal levels and sustained for up to two years. Topline results presented earlier this year from the CAMPSIITE trial demonstrated that the pivotal phase of the trial met its primary endpoint with statistical significance. Pivotal results were consistent with data from the dose-finding phase of CAMPSIITE, in which the majority of patients were shown to be exceeding expectations in neurodevelopmental function compared to natural history data up to four years. In the dose-finding part of the trial, investigators chose to discontinue standard-of-care intravenous enzyme replacement therapy (ERT) or to remain ERT-naïve for a majority of patients. At the pivotal dose level (dose level 3), 80% of patients were ERT-free at last time point, up to more than 18 months post-dosing. At dose level 2, 71% of patients were ERT-free at last time point, up to almost three years. As of January 5, 2024, RGX-121 continues to be well tolerated in 25 patients dosed across all phases of the CAMPSIITE trial. “A potential one-time treatment that can allow these boys to exceed the natural history of this disease in their neurocognitive development, as well as the ability to remain off enzyme replacement therapy for multiple years represents a meaningful option for patients and their families,” said Roberto Giugliani, M.D., Ph.D., Professor, Department of Genetics, UFRGS, Medical Genetics Service, HCPA, Porto Alegre, Brazil. “I continue to be very encouraged by the data supporting RGX-121 and look forward to the seeing this program advance towards potential approval for this community.” REGENXBIO is on track to initiate a rolling Biologics License Application (BLA) submission using the accelerated approval pathway in the third quarter of 2024 using CSF D2S6 as a surrogate endpoint reasonable likely to predict clinical benefit. Approval of the planned BLA could result in receipt of a Priority Review Voucher in 2025. Data presented is available on the “Publications” section of the REGENXBIO website at WWW.REGENXBIO.COM . About the CAMPSIITE ® Trial CAMPSIITE is a Phase I/II/III multicenter, open-label trial for boys aged four months up to five years with neuronopathic MPS II. The primary endpoint of the trial is measurement of CSF GAGs. Accurate and sensitive measurements of CSF GAGs, such as HS D2S6, have the potential to be considered a surrogate endpoint that is reasonably likely to predict clinical benefit in MPS II disease under the accelerated approval pathway, as buildup of GAGs in the CSF of MPS II patients correlates with clinical manifestations including neurodevelopmental deficits. The pivotal program is using commercial-scale cGMP material from REGENXBIO’s proprietary, high-yielding suspension-based manufacturing process, named NAVXpress™. In addition to measuring GAGs in the CSF, the trial will continue to collect neurodevelopmental data and caregiver-reported outcomes. About RGX-121 RGX-121 is a potential one-time AAV therapeutic for the treatment of boys with MPS II. RGX-121 expressed protein is structurally identical to normal I2S. RGX-21 Delivery of the IDS gene within cells in the CNS could provide a permanent source of secreted I2S beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS. RGX-121 has received Orphan Drug Product, Rare Pediatric Disease, Fast Track and Regenerative Medicine Advanced Therapy designations from the U.S. Food and Drug Administration and advanced therapy medicinal products (ATMP) classification from the European Medicines Agency. About Mucopolysaccharidosis Type II (MPS II) MPS II, or Hunter Syndrome, is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme iduronate-2-sulfatase (I2S) leading to an accumulation of glycosaminoglycans (GAGs), including heparan sulfate (HS) in tissues which ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system (CNS). MPS II is estimated to occur in 1 in 100,000 to 170,000 births. In severe forms of the disease, early developmental milestones may be met, but developmental delay is readily apparent by 18 to 24 months. Specific treatment to address the neurological manifestations of MPS II remains a significant unmet medical need. Key biomarkers of I2S enzymatic activity in MPS II patients include its substrate HS D2S6, which has been shown to correlate with neurocognitive manifestations of the disorder. ABOUT REGENXBIO Inc. REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. Since its founding in 2009, REGENXBIO has pioneered the development of AAV Therapeutics, an innovative class of gene therapy medicines. REGENXBIO is advancing a pipeline of AAV Therapeutics for retinal and rare diseases, including ABBV-RGX-314 for the treatment of wet AMD and diabetic retinopathy, being developed in collaboration with AbbVie, RGX-202 for the treatment of Duchenne and RGX-121 for the treatment of MPS II. Thousands of patients have been treated with REGENXBIO’s AAV Therapeutic platform, including Novartis’ ZOLGENSMA for children with spinal muscular atrophy. Designed to be one-time treatments, AAV Therapeutics have the potential to change the way healthcare is delivered for millions of people. For more information, please visit www.regenxbio.com . SOURCE: REGENXBIO

RGX-121 is a gene therapy designed to deliver a functional copy of the IDS gene to the central nervous system via the NAV AAV9 vector. Credits: Natali _ Mis/Shutterstock.com RegenxBio has announced that the pivotal dose level from its multiphase study of RGX-121 has demonstrated positive long-term data for the treatment of patients with mucopolysaccharidosis type II (MPS II) or Hunter syndrome. As per the 3 September press release, patients who received a pivotal dose of RGX-121, described as dose level 3, had a median reduction of cerebrospinal fluid (CSF) heparan sulfate D2S6 levels of 85%. These levels were found to be approaching normal measures and were reportedly sustained for up to two years. RGX-121 is a gene therapy designed to deliver a functional copy of the IDS gene to the central nervous system via the NAV AAV9 vector. The biotech is on track to submit a rolling biologics license application (BLA) through the accelerated approval pathway in Q3 2024. RegenxBio intends to use CSF D2S6 as a surrogate endpoint to predict clinical benefit. The Phase I/II/III CAMPSIITE study (NCT03566043) is an open label study comprised of two parts. Part 1 marked the Phase I/II single arm dose escalation study evaluating RGX-121 in 16 pediatric participants with neuronopathic MPS II over a period of 24 weeks. Assessing safety was the primary objective during the study period, after which participants continued to be evaluated for safety and efficacy for up to 104 weeks. Part 2 is the single arm pivotal expansion evaluating 30 pediatric patients at various points over 24 months. Primary endpoints of part 2 included CSF GAG biomarker levels, as measured by D2S6, and neurodevelopmental function as determined by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Mullen Scales of Early Learning (MSEL). See Also: Ocaliva approval in Europe withdrawn following data re-assessment UK NHS launches vaccine programme for RSV The Rockville, Maryland-based biotech noted that as of 5 January, RGX-121 was found to be well tolerated in the 25 patients who received treatment across all phases of the study. MPS II is a rare, X-linked recessive disorder characterised by a deficiency in lysosomal enzyme iduronate-2-sulfatase (IDS), which leads to a build-up of large sugar molecules called glycosaminoglycans in body tissues. According to GlobalData’s consensus forecasts, RGX-121 is anticipated to generate global sales of $460m in 2030. GlobalData is the parent company of Pharmaceutical Technology . Presenting data earlier in the year at the 20th Annual WORLDSymposium, RegenxBio shared that CAMPSIITE achieved its primary endpoint , with the findings being consistent with that found in the dose-finding portion of the study. “The data continue to support that by restoring the gene missing in boys with Hunter syndrome, RGX-121 changes the course of disease and has the potential to significantly improve both vital brain function and the systemic manifestations of this devastating disease,” said CMO Dr. Steve Pakola in the press announcement. Cell & Gene Therapy Coverage on Pharmaceutical Technology supported by Cytiva. Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy