SMN1

The Rainbowfish trial enrolled babies aged from birth to six weeks who had not yet shown symptoms of SMA. Credit: Studio Romantic via Shutterstock. Roche’s spinal muscular atrophy (SMA) drug Evrysdi (risdiplam) has helped pre-symptomatic babies reach rare milestones after two years of treatment in a Phase II trial. The Rainbowfish trial (NCT03779334), run by the Roche subsidiary Genentech, enrolled babies aged from birth to six weeks who had not yet shown symptoms of SMA. After two years, all 26 children were able to swallow and feed orally, and none required permanent ventilation. This is a significant contrast to untreated Type 1 SMA, where children would typically not reach these milestones and rarely survive past two years old, according to natural history studies. The cognitive development of the children was also comparable to babies without SMA, as measured by the Bayley Scales of Infant and Toddler Development, third edition (BSID-III). According to Genentech, this is the first clinical trial in SMA to evaluate cognitive skills as an exploratory endpoint using a standardised scale. The data was presented at the World Muscle Society (WMS) Congress 2024, in Prague, Czech Republic, from 8 to 12 October. This builds on previously announced one-year data, where the trial met its primary endpoint with 80% of patients sitting without support for at least five seconds after one year of Evrysdi treatment, measured by BSID-III. Of the 26 babies, 81% could sit independently for 30 seconds. Adverse events (AEs) for the drug included teething, Covid-19, fever, eczema, and constipation. See Also: CPHI Europe: Gummies as a drug delivery system could improve compliance Sterilisation Solutions, Equipment and Services for the Pharmaceutical Industry SMA is a genetic disorder characterised by the loss of motor neurons, leading to muscle weakness and progressive physical disability. It is caused by mutations in the SMN1 gene, resulting in a deficiency of SMN protein, which is critical for muscle function. Evrysdi is an oral survival motor neuron 2 (SMN2) splicing modifier that targets mutations in chromosome 5q, which is implicated in survival motor neuron (SMN) protein deficiency. It was approved by the US Food and Drug Administration (FDA) in 2022 to treat SMA in patients of all ages, including infants under two months with Type 1, Type 2, or Type 3 SMA, or those with one to four SMN2 copies. Genentech’s chief medical officer Levi Garraway highlighted the potential of Evrysdi in combination with newborn screening programmes : “These two-year findings confirm the potential of early intervention with Evrysdi to meaningfully improve the lives of children with SMA. Working in tandem with newborn screening programs, Evrysdi is the only non-invasive SMA treatment that can be administered during a child’s first hours of life.” Evrysdi generated CHF 1.4bn ($1.64bn) in 2023 for Genentech, as per the company’s annual report, with projections from GlobalData estimating $2.8bn in revenue by 2030. Evrysdi’s main competitor, Biogen ’s Spinraza (nusinersen) won FDA approval in 2016 for infants, children, and adults with SMA. Spinraza is projected to generate less than Evrysdi in 2030, at $1.13bn, mainly due to the favourable oral delivery of Evrysdi compared to the intrathecal route (via a lumbar puncture) for Spinraza. GlobalData is the parent company of Pharmaceutical Technology. In addition to SMN-targeting treatments like Evrysdi and Spinraza, Novartis’ gene therapy Zolgensma (onasemnogene abeparvovec) can also be administered to infants with SMA. Zolgensma delivers a new, working copy of a human SMN gene which is administered in a one-time infusion to children under two years of age. Despite its effectiveness, some infants may be unable to access the gene therapy due to its invasive nature, cost, and accessibility. Evrysdi is also being evaluated in other clinical trials, including the Phase II Jewelfish trial (NCT03032172) in people with SMA aged six months to 60 years who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi.

Sunday, Oct 13, 2024 Positive data confirm Evrysdi efficacy and safety in children first treated pre-symptomatically before 6 weeks of age, with most achieving motor milestones similar to children without SMAAll children were able to swallow and feed orally, with none requiring permanent ventilationEvrysdi is the only non-invasive SMA therapy and is approved in over 100 countries, with more than 16,000 people with SMA treated globally South San Francisco, CA -- October 13, 2024 -- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), presented positive 2-year data from the ongoing RAINBOWFISH study at the 29th World Muscle Society (WMS) Congress, October 8-12, 2024, assessing the efficacy and safety of Evrysdi® (risdiplam) in children with SMA who were treated pre-symptomatically as infants before 6 weeks of age (n=23). The study found the majority of children achieved key motor milestones, were able to swallow and feed orally, and demonstrated cognitive skills typical of children without SMA, with none requiring permanent ventilation. “In children with SMA, motor neuron degeneration starts before the onset of symptoms, so time is of the essence if we hope to preserve muscle function,” said Laurent Servais, M.D., Ph.D., Professor of Paediatric Neuromuscular Diseases at the MDUK Oxford Neuromuscular Centre. “It’s heartening to see that through early intervention with Evrysdi these children have achieved important milestones like sitting, standing and walking that would typically be unattainable without treatment.” All of the children treated with Evrysdi who had three or more SMN2 copies (n=18), achieved standing and walking (100%) milestones as assessed by Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and Hammersmith Infant Neurological Examination, Module 2 (HINE-2), with most achieving these milestones within World Health Organization (WHO) windows of typical child development. Among the children with two SMN2 copies (n=5), all could sit (100%) and most could stand and walk (60%) independently after 2 years of treatment. After 2 years of treatment, all children were able to swallow and feed orally and none required permanent ventilation. Natural history studies indicate that without disease-modifying treatment, children with Type 1 SMA would not be able to reach such milestones, nor typically live past the age of 2. After 2 years of Evrysdi treatment, children in the study showed cognitive skills typical of children without SMA, as assessed by the BSID-III Cognitive Scale. This study was the first clinical trial in SMA to assess cognition as an exploratory endpoint using a standardized scale. “These 2-year findings confirm the potential of early intervention with Evrysdi to meaningfully improve the lives of children with SMA,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “Working in tandem with newborn screening programs, Evrysdi is the only non-invasive SMA treatment that can be administered during a child’s first hours of life.” To assess outcomes of early treatment initiation before the onset of symptoms, children in the study started treatment with Evrysdi before 6 weeks of age (median age of first dose was 25 days). The study analyzed outcomes against the number of copies of the SMN2 gene each child had. Generally, fewer SMN2 copy numbers are associated with more severe SMA. There were no deaths or adverse events (AEs) leading to withdrawal or treatment discontinuation. The most common AEs were teething, gastroenteritis, diarrhea, eczema and pyrexia. The AEs observed in the year-2 analysis are generally consistent with those AEs seen in other Evrysdi trials in SMA. AEs were more reflective of age than underlying SMA. The majority of AEs were not considered treatment-related and resolved over time. Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics. About Evrysdi® (risdiplam) Evrysdi is a survival motor neuron 2 (SMN2) splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency. Evrysdi is administered daily at home in liquid form either by feeding tube or by mouth. Evrysdi is designed to treat SMA by increasing and sustaining the production of SMN protein in the central nervous system (CNS) and peripheral tissues, as demonstrated in animal models. SMN protein is found throughout the body and is critical for maintaining healthy motor neurons and core motor functions, such as swallowing, speaking and breathing. Evrysdi was granted PRIME designation by the European Medicines Agency (EMA) in 2018 and Orphan Drug Designation by the U.S. Food and Drug Administration in 2017. In 2021, Evrysdi was awarded Drug Discovery of the Year by the British Pharmacological Society as well as the Society for Medicines Research Award for Drug Discovery. Evrysdi is currently approved in more than 100 countries, and the dossier is under review in a further 12 countries. A new risdiplam room-temperature stable tablet is currently under review by regulators. Evrysdi is currently being, or has been, evaluated in numerous global multicenter trials in people with SMA: FIREFISH (NCT02913482) – an open-label, two-part pivotal clinical trial in infants with Type 1 SMA. Infants were approximately 5.5 months of age (median) at the time of enrollment and of the 58 infants that completed the first year of treatment, 52 entered the open-label extension study. The study met its primary endpoint and has concluded after 5 years of follow up. SUNFISH (NCT02908685) – a two-part, double-blind, placebo-controlled pivotal study in people aged 2-25 years with Types 2 or 3 SMA. The study met its primary endpoint. JEWELFISH (NCT03032172) – an open-label exploratory trial designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in people with SMA aged 6 months to 60 years who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi. The study has completed recruitment (n=174). RAINBOWFISH (NCT03779334) – an open-label, single-arm, multicenter study, investigating the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in babies (n=26), from birth to 6 weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study met its primary endpoint. MANATEE (NCT05115110) – a Phase II/III clinical study to evaluate the safety and efficacy of GYM329 (RG6237), an anti-myostatin molecule targeting muscle growth, in combination with Evrysdi for the treatment of SMA in patients 2-10 years of age. The FDA Office of Orphan Products Development granted GYM329 Orphan Drug Designation for the treatment of patients with SMA in December 2021. The study is currently recruiting. HINALEA 1 (NCT05861986) and HINALEA 2 (NCT05861999) – Phase IV clinical studies to evaluate the effectiveness and safety of Evrysdi in patients under 2 years of age at enrollment, who received onasemnogene abeparvovec gene therapy either pre-symptomatically or post-symptomatically, following a genetically confirmed diagnosis of 5q–autosomal recessive SMA. The studies are currently recruiting. About SMA SMA is a severe, progressive neuromuscular disease that can be fatal. It affects approximately one in 10,000 babies and is the leading genetic cause of infant mortality. SMA is caused by a mutation of the survival motor neuron 1 (SMN1) gene, which leads to a deficiency of SMN protein. This protein is found throughout the body and is essential to the function of nerves that control muscles and movement. Without it, nerve cells cannot function correctly, leading to muscle weakness over time. Depending on the type of SMA, an individual’s physical strength and their ability to walk, eat or breathe can be significantly diminished or lost. What is Evrysdi? Evrysdi is a prescription medicine used to treat spinal muscular atrophy (SMA) in children and adults. Important Safety Information Before taking Evrysdi, tell your healthcare provider about all of your medical conditions, including if you: are pregnant or plan to become pregnant, as Evrysdi may harm your unborn baby. Ask your healthcare provider for advice before taking this medicine are a woman who can become pregnant: Before you start your treatment with Evrysdi, your healthcare provider may test you for pregnancy Talk to your healthcare provider about birth control methods that may be right for you. Use birth control while on treatment and for at least 1 month after stopping Evrysdi Pregnancy Registry. There is a pregnancy registry for women who take Evrysdi during pregnancy. The purpose of this registry is to collect information about the health of the pregnant woman and her baby. If you are pregnant or become pregnant while receiving Evrysdi, tell your healthcare provider right away. Talk to your healthcare provider about registering with the Evrysdi Pregnancy Registry. Your healthcare provider can enroll you in this registry or you can enroll by calling 1-833-760-1098 or visiting http://www.evrysdipregnancyregistry.com are an adult male. Evrysdi may affect a man’s ability to have children (fertility). Ask a healthcare provider for advice before taking this medicine are breastfeeding or plan to breastfeed. It is not known if Evrysdi passes into breast milk and may harm your baby Tell your healthcare provider about all the medicines you take You should receive Evrysdi from the pharmacy as a liquid. If the medicine in the bottle is a powder, do not use it. Contact your pharmacist for a replacement Avoid getting Evrysdi on your skin or in your eyes. If Evrysdi gets on your skin, wash the area with soap and water. If Evrysdi gets in your eyes, rinse your eyes with water The most common side effects of Evrysdi include: For later-onset SMA: fever diarrhea rash For infantile-onset SMA: fever diarrhea rash runny nose, sneezing, and sore throat (upper respiratory infection) lung infection (lower respiratory infection) constipation vomiting cough These are not all of the possible side effects of Evrysdi. For more information on the risk and benefits profile of Evrysdi, ask your healthcare provider or pharmacist. You may report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. Please see full Prescribing Information for additional Important Safety Information. For more information, go to https://www.evrysdi.com/. About Genentech in Neuroscience Neuroscience is a major focus of research and development at Genentech. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases. Genentech and Roche are investigating more than a dozen medicines for neurological disorders, including multiple sclerosis, spinal muscular atrophy, neuromyelitis optica spectrum disorder, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Duchenne muscular dystrophy. Together with our partners, we are committed to pushing the boundaries of scientific understanding to solve some of the most difficult challenges in neuroscience today. About Genentech Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com. All trademarks used or mentioned in this release are protected by law. # # #

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.”