SMN1

Researchers from the University of Liverpool have identified and characterised antibody fragments that target free light chain (LC) to help treat patients living with AL amyloidosis. The new research, published in The FEBS Journal , could help to stabilise and prevent their LC antibody aggregation and could also be applied to other forms of the condition, including Alzheimer’s disease. Estimated to affect five to 12 people per million worldwide every year, amyloidosis is a group of rare, serious conditions caused by the abnormal folding of amyloid proteins that build up in tissue throughout the body. Currently the most common but rare and severe form of the condition, AL amyloidosis occurs when abnormal LC proteins in the body mutate and gather on the tissues and organs, including the heart, kidneys, liver, spleen, nervous system and digestive tract. The current treatment can be difficult to tolerate “and diagnosed patients often have a poor prognosis, with the estimated survival time being between six months and three  years,” explained Dr Jill Madine, senior lecturer, biochemistry, cell and systems biology, University of Bristol. Using phage-display screening methods – a form of high-throughput screening that allows large numbers of peptide segments to be screened for binding to a target – researchers identified a variable-heavy (VH) domain called VH1, targeted towards FLCs SMA, LEN and REC. Each LC is composed of two tandem immunoglobulin domains: one constant (CL) domain and one variable domain (VL), which is important for binding antigen. Results showed that VH1 was able to bind and kinetically stabilise LCs, which improved the stability of the inhibition of fibril formation of SMA by reducing aggregation to baseline levels and mimicking the dimeric antigen binding site of the native Ig molecule and SMA homodimeric structure. After testing in three participating AL amyloidosis patients, the FLC concentration was found to be significantly raised, while only SMA and REC were found to be amyloidogenic in vevo. The findings suggest that VH1 has the potential to therapeutically target AL amyloidosis by stabilising native LCs, improving its stability and preventing the aggregation of VH1 alone. Madine commented: “We are excited by this finding, which has potential to provide a much-needed treatment for people diagnosed with the condition.”

27th Annual Meeting of the American Society of Gene and Cell Therapy in Baltimore, MD on May 8, 2024 PHILADELPHIA--(BUSINESS WIRE)-- Exegenesis Bio, a rapidly growing global genetic medicines company, is pleased to announce the presentation of clinical efficacy and safety data from its EXG001-307 Phase 1/2 clinical trial in Spinal Muscular Atrophy (SMA) Type I at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting in Baltimore, Maryland on May 8, 2024 (poster #627). EXG001-307 is a next generation recombinant adeno-associated virus (rAAV) gene therapy in development for Spinal Muscular Atrophy (SMA) Type 1. Data from nine patients demonstrate improved head control and sitting without external assistance as early as three months following dosing. EXG001-307 has a unique AAV design, including a novel pro-NS promoter, leading to high expression in target spinal cord tissue and reduced off target expression in liver and heart tissue versus currently available gene therapy. Data Highlights: EXG001-307 has a unique engineered AAV design that includes a novel pro-NS promoter, which is believed to contribute to improved efficacy and safety in SMA Type 1. EXG001-307 has demonstrated high expression in target spinal cord tissue and reduced off target expression in liver and heart tissue than AAV9.CBA.SMN1. Patients in the EXG001-307 low-dose group (1.1 E 14 vg/kg) achieved head control 3 to 6 months after dosing and sitting without external assistance 11 months following dosing. The first patient in the mid-dose group (1.5 E 14 vg/kg) achieved sitting with assistance 3 months following dosing. EXG001-307 demonstrated high tolerability and no dose-limiting toxicity, no >Grade 2 test article related serious adverse events, and no >Grade 1 elevation of transaminases or cardiac enzymes. “Spinal Muscular Atrophy is a debilitating and fatal genetic disease that impacts the lives of thousands of babies and young children and their families. I am excited that our team is making rapid progress in our mission to bring this much-needed treatment option to SMA patients worldwide. We are excited about the clinical efficacy and safety data emerging from our Phase 1/2 SMA clinical trial in China. This is leading us to accelerate development in the US. We expect to US IND for SMA Type 1 in 4Q 2024. We are also exploring an accelerated development path in the slightly older SMA Type 2/3 patient population. We look forward to sharing further details during our poster session at ASGCT in Baltimore on May 8, 2024. I would like to congratulate our team for embracing our mission to bring innovative and life-changing genetic medicines to patients globally and for driving our ambitious clinical development timelines,” stated Dr. Zhenhua Wu, CEO of Exegenesis Bio. About EXG001-307 EXG001-307 is a recombinant adeno-associated virus (rAAV)-based gene therapy in clinical development for Spinal Muscular Atrophy (SMA) Type 1. EXG001-307 has demonstrated significantly improved efficacy in SMA Type 1 patients (CHOP Intend score) and lower off target effects in liver and cardiac tissue. Patients in both low and mid-dose cohorts demonstrated improved head control and sitting ability within the 3 to 11 months of dosing. Exegenesis Bio will share additional clinical and non-clinical efficacy and safety data during a poster session at ASGCT on Wednesday May 8, 2024. Poster # 627. About Spinal Muscular Atrophy Spinal Muscular Atrophy (SMA) is an autosomal recessive inherited neuromuscular disease, characterized by motor neuron degeneration, skeletal muscle atrophy, muscle weakness, and ultimately death. SMA is the most common fatal disease in infants, with incidence in newborns ranging from one in six thousand to one in ten thousand. SMA is classified into five subtypes, based on the age of onset, severity of symptoms, and motor milestones. SMA Type 0 manifests prenatally, Type 1 appears during the first six months of age, Type 2 appears between 6 and 18 months of age, Type 3 begins as early as 18 months of age, while Type 4 has late onset and symptoms develop in adulthood1. Data suggest that infants with SMA type 1, the most common type, have a median survival of 10.5 months, and 8% survival rate to 20 months without permanent respiratory support2. SMA is caused by a homozygous loss of SMN1 genes on chromosome 5q13 due to mutations or deletions, leading to a decreased level of survival motor neuron (SMN) protein, which triggers motor neuron overexcitation and degeneration, synaptic dysfunction, and reduced muscle fiber volume. Current SMA therapies work by increasing levels of SMN protein in the body3. About Exegenesis Bio Exegenesis Bio is a clinical stage global gene therapy company with operations in USA and China. The company’s innovative gene therapy pipeline is based on proprietary capsids, promoters and unique protein engineering designs. The company has received IND clearances from US FDA and China CDE and is currently conducting Phase 1/2 clinical trials in USA and China. EXG001-307 is a recombinant AAV (rAAV) gene therapy in Phase 1/2 clinical development for Spinal Muscular Atrophy Type 1 in China. The company plans to US IND for EXG001-307 in 2024. EXG102-031 is a recombinant AAV (rAAV) based gene therapy in clinical development for neovascular Age Related Macular Degeneration (nAMD) in USA and China. The EXG102-031 clinical study is being conducted at two clinical sites in the USA and eight additional sites in China. Exegenesis Bio has built full end-to-end capabilities that include discovery, translational, non-clinical and clinical development, quality and manufacturing. The company operates state-of-the-art cGMP manufacturing facilities that include 500 Liter and 2,000 Liter disposable bioreactors for viral vectors and 30 Liter disposable fermenters for plasmids. The company has raised over $200 Million since inception in 2019 and currently employs over 200 scientific and operations staff worldwide. Please contact us to discuss US and Global licensing and collaboration opportunities. References: Annoussamy et al., Ann Clin Transl Neurol. 2021 8(2):359-373 Finkel et al., Neurology 2014;83;810-817 Kirwin et al., Mol Genet Genomic Med. 2013; 1(2): 113–117

The SMART study supplements a growing body of evidence on the use of Zolgensma in a patient population older and heavier (1.5 – 9.1 years of age) than the children treated in previous clinical studies 1-6 Nearly all patients treated maintained or improved motor milestones after 52 weeks, with most switching to the one-time gene therapy from another chronically administered disease-modifying therapy 1-6 The SMART study is the first open-label clinical study of Zolgensma to include previously treated patients 1-6 March 4, 2024 – Novartis today presented new data that continue to support the clinical benefits of Zolgensma® (onasemnogene abeparvovec), the only one-time gene therapy for the treatment of spinal muscular atrophy (SMA). Final data from the SMART study highlight the safety and efficacy profile of Zolgensma in children with SMA weighing ≥ 8.5 kg to ≤ 21 kg, with a mean age of 4.69 years, most of whom (21/24, 87.5%) had discontinued use of another disease modifying therapy at the time of treatment. The new clinical results supplement emerging real-world experience and use of this innovative therapy in older and heavier children in countries where authorized use is not restricted by age. These data are among a Zolgensma data set being presented during the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Orlando, Florida, March 3 – 6. “The results from the SMART study provide evidence that Zolgensma is clinically beneficial for older and heavier patients with SMA, many of whom have had prior treatment with another disease-modifying therapy,” said Dr. Hugh McMillan, Pediatric Neurologist. “These data inform the use of Zolgensma in children up to 21 kg, supporting the use of a one-time gene replacement therapy as a therapeutic option for SMA in a broader population.” The primary study objective was to evaluate the safety and tolerability of Zolgensma in older and heavier patients than were treated in previous clinical studies. The majority of patients in the study experienced increases in transaminases and transient thrombocytopenia; all cases were asymptomatic and managed with appropriate monitoring and treatment, as described in the product labeling. No new safety signals were observed in the study. Most patients in the SMART study maintained motor milestones observed at baseline throughout the one-year study. The mean increase in total Revised Upper Limb Module (RULM) score was 2 points and a mean increase in total Hammersmith Functional Motor Scale – Expanded (HFMSE) score was 3.7 points. Four patients demonstrated new development milestones at week 52. "This data – the first Zolgensma open-label clinical study to include older and heavier, as well as previously treated, patients – should build confidence among caregivers and healthcare professionals as they make informed treatment decisions, consistent with their local product label, for the studied patient population,” said Dr. Sandra P. Reyna, Chief Scientific Advisor and Head of Global Medical Engagement for SMA at Novartis. “We remain committed to reimagining possibilities for the SMA community.” SMART was a Phase 3b, open-label, single-arm, multicenter study designed to evaluate the safety, tolerability and efficacy of a one-time IV infusion of Zolgensma in pediatric patients who have symptomatic SMA with bi-allelic mutations in the SMN1 gene, any copy number of the SMN2 gene, and weigh ≥ 8.5 kg and ≤ 21 kg. The study enrolled a total of 24 patients with heterogeneous phenotypes of SMA across three weight brackets (8.5 - 13 kg; >13 – 17 kg; >17 – 21 kg), ranging in age from ~18 months to 9 years (mean age of 4.69 years). Three patients were treatment-naïve to previous SMN-dependent therapies; 21 were treatment-experienced and discontinued risdiplam or nusinersen before enrollment in the study. The SMART study was the first open-label clinical study of Zolgensma to include previously treated patients. 1-6 Increases in transaminases (ALT or AST >3xULN) were observed in the majority of patients (21/24, 87.5%); transient thrombocytopenia were observed in 17/24 (70.8%) patients; all cases were asymptomatic and managed with appropriate treatment. There were no reported cases of acute liver failure or bilirubin elevations. Increases in RULM from baseline were demonstrated; mean (SD) increase from baseline at Week 52 was 2.0 (4.0) points. Increases in HFMSE from baseline were demonstrated; mean (SD) increase from baseline at Week 52 was 3.7 (4.3) points. Most patients maintained or improved motor milestones from baseline at the time of final analysis. Nearly all (23/24, 95.8%) patients who could sit with slight support still met this milestone at Week 52. Three patients achieved the milestone of newly standing with support and one achieved newly walking with support at Week 52. All patients (6/6, 100%) who could walk at baseline maintained this milestone until end of study. Zolgensma® (onasemnogene abeparvovec) is the only approved gene therapy for the treatment of spinal muscular atrophy (SMA) and the only SMA treatment designed to directly address the genetic root cause of the disease by replacing the function of the missing or non-working SMN1 gene to halt disease progression through sustained SMN protein expression with a single, one-time IV infusion. Zolgensma is now approved in more than 51 countries and more than 3,700 patients have been treated with Zolgensma globally across clinical trials, managed access programs, and in the commercial setting.7 Novartis is unwavering in its commitment to reimagine the possibilities for children living with SMA and continues to evaluate Zolgensma across a robust clinical development program, as well as the investigational intrathecal administration of OAV101 in patients with later-onset forms of SMA. Novartis AG has an exclusive, worldwide license with Nationwide Children's Hospital to both the intravenous and intrathecal delivery of AAV9 gene therapy for the treatment of all types of SMA; has an exclusive, worldwide license from REGENXBIO for any recombinant AAV vector in its intellectual property portfolio for the in vivo gene therapy treatment of SMA in humans; and an exclusive, worldwide licensing agreement with Généthon for in vivo delivery of AAV9 vector into the central nervous system for the treatment of SMA. Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease and a leading genetic cause of infant death.8,9 Caused by the lack of a functional SMN1 gene, the most severe forms of SMA result in the rapid and irreversible loss of motor neurons, affecting muscle functions including breathing, swallowing and basic movement.10 Severity varies across a spectrum of types corresponding to the number of copies of the back-up SMN2 gene.11 The majority (>70%) of patients with two copies of SMN2 develop Type 1, the most common form, accounting for 60% of cases.12,13 Type 1 is severe and, left untreated, leads to death or the need for permanent ventilation by the age of two in more than 90% of cases.8,9 Most patients (>80%) with three copies of SMN2 develop Type 2, accounting for 30% of cases.12 Left untreated, patients with Type 2 are unable to walk and will require a wheelchair, and more than 30% will die by age 25.14 Loss of motor neurons cannot be reversed, so it is imperative to diagnose SMA and begin treatment, including proactive supportive care, as early as possible to halt motor neuron loss and disease progression.15,16 Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitter and Instagram. References 1. Day JW, et al. Lancet Neurol. 2021; 20:284–93. 2. Mendell JR, et al. N Engl J Med. 2017; 377:1713–22. 3. Al-Zaidy SA, et al. J Neuromuscul Dis. 2019; 6:307–17. 4. Mercuri E, et al. Lancet Neurol. 2021; 20:832–41. 5. Strauss K, et al. Nat Med. 2022; 28:1381–9. 6. Strauss K, et al. Nat Med. 2022; 28:1390–7. 7. Data on File. Novartis AG, 2023. 8. Anderton RS and Mastaglia FL. Expert Rev Neurother. 2015;15(8):895–908. 9. Finkel RS, McDermott MP, Kaufmann P. et al. Neurology. 2014;83(9):810–7. 10. Sugarman EA, Nagan N, Zhu H, et al. Eur J Hum Genet. 2012;20(1):27–32. 11. Lorson CL, Rindt H, Shababi M. Hum Mol Genet. 2010;(15):111–8. 12. Verhaart IEC, Robertson A, Wilson IJ, et al. Orphanet J Rare Dis. 2017;4;12(1):124. 13. Feldkötter M, et al. Am J Hum Genet. 2002;70:358–68. 14. Darras BT, Finkel RS. “Natural history of spinal muscular atrophy.” In: Sumner CJ, Paushkin S, Ko CP, eds. Spinal Muscular Atrophy: Disease Mechanisms and Therapy. (2nd ed. London, UK: Academic Press/Elsevier; 2017. Pp. 399‒421. 15. Soler‐Botija C, et al. Brain. 2002;125(7):1624–1634. 16. Glascock J, et al. J Neuromuscul Dis. 2018;5:145–158. The content above comes from the network. if any infringement, please contact us to modify.