HMN (Hereditary Motor Neuropathy) Proximal Type I

Positive data confirm Evrysdi efficacy and safety in children first treated pre-symptomatically before six weeks of age, with most achieving motor milestones similar to children without SMA All children were able to swallow and feed orally, with none requiring permanent ventilation Evrysdi is the only non-invasive SMA therapy and is approved in over 100 countries, with more than 16,000 people with SMA treated globally 14 October 2024 - Roche (SIX: RO, ROG; OTCQX: RHHBY) presented positive two-year data from the ongoing RAINBOWFISH study at the 29th World Muscle Society (WMS) Congress, 8-12 October, 2024, assessing the efficacy and safety of Evrysdi® (risdiplam) in children with SMA who were treated pre-symptomatically as infants before six 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 Organisation (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 two years of treatment. After two 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 two. After two 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 standardised scale. “These two-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., Roche’s Chief Medical Officer and Head of Global Product Development. “Working in tandem with newborn screening programmes, 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 six weeks of age (median age of first dose was 25 days). The study analysed 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, diarrhoea, eczema and pyrexia. The AEs observed in the year-two 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. Roche leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics. 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. 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 multicentre 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 five 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 six 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, multicentre study, investigating the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in babies (n=26), from birth to six 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 two-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 two 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. 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. Neuroscience is a major focus of research and development at Roche. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases. Roche is 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. 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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.

Last year, the U.S. Food and Drug Administration approved 55 new drugs. Choosing the right clinical outcome assessments (COAs) is an important part of successfully advancing drug development and securing regulatory approval.COAs are critical to all phases of drug development, from collecting patient data to submission for regulatory approval. Their use throughout these phases ensures that the outcomes being measured are meaningful to patients and capture the therapeutic impact of a drug. Successful COA selection mattersSelecting the appropriate COA for use in a clinical trial is essential for evaluating the benefits and risks of a treatment and influences how treatment claims are labeled. The information gathered from COAs isnt critical for individual trials only; it can also be used to compare results across different trials. It's not surprising, then, that COAs have a growing role in establishing the clinical benefit of novel therapies and in regulatory decision-making.Choosing the right COA for a clinical trial is a complex and critical process. COAs should: Be relevant to the patients experience.Capture outcomes that are meaningful to patients. Align with patients health concerns and treatment goals. An effective COA is psychometrically sound, with established reliability, validity and sensitivity to detect meaningful changes in the condition being treated. Additionally, COAs must meet standards set forth by regulatory agencies, be consistent with trial objectives, and consider patient burden.Selecting an inappropriate COA carries significant risks, says J. Lynsey Psimas PhD, director of business development at Pearson Assessments US. It can produce misleading results regarding the efficacy or safety of a treatment, potentially leading to incorrect conclusions about its clinical benefits and increasing the risk of regulatory delays or rejection. Psimas adds that a poorly chosen COA may also impose an undue burden on patients, which could negatively impact their participation in clinical trials and lead to higher dropout rates. From scale selection to drug developmentThe selection of the right COA is fundamental to demonstrating the efficacy and safety of a treatment and ensuring that clinical outcomes reflect real patient experiences. Pearson assessments are backed by over 80 years of test development. These well-validated scales have been widely used in research and clinical trials across various therapeutic areas. They are particularly well-suited for central nervous system (CNS) conditions such as Alzheimer's disease, schizophrenia, rare genetic diseases and neurodevelopmental disorders. Recent examples of Pearson assessments use in successful drug development include: Chronic schizophrenia: An international pharmaceutical company, Newron Pharmaceuticals, used the Positive and Negative Syndrome Scale (PANSS) as a primary endpoint in a clinical trial evaluating the safety, tolerability and efficacy of a novel drug for chronic schizophrenia. The PANSS is widely recognized for use in clinical trials and has long been the gold standard for schizophrenia trials. The four-week, international, randomized, double-blind and placebo-controlled add-on Phase II/III study was conducted in 45 centers in 11 countries across Europe, Asia and Latin America. The results substantiate the role of glutamate as a new therapeutic option for treatment resistant schizophrenia (TRS) patients.Pediatric spinal muscular atrophy: Researchers from Novartis are using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), in a pivotal Phase 3 study. This open-label, single arm, multicenter clinical trial evaluates the safety, tolerability and efficacyof an intravenous drug for pediatric patients with spinal muscular atrophy (SMA).The Bayley was used to measure key developmental motor milestones and their change from baseline at 6 and 12 months post-dose in participants with SMA.Hunter Syndrome (MPS II): REGENXBIO announced positive long-term results from its pivotal trial of RGX-121 for MPS II (Hunter syndrome). Data showed an 85 percent median reduction in cerebrospinal fluid (CSF) levels of heparan sulfate, a key biomarker, sustained for up to two years. Additionally, 80 percent of patients discontinued enzyme replacement therapy. This Phase 2/3 multicenter, open-label study used the Bayley-III as a primary endpoint and the Vineland-II as a secondary endpoint. The selection of a well-validated COA plays an integral role in advancing drug development and securing regulatory approval. Choosing the right COA enhances the impact of trial findings, facilitates cross-study comparisons, and streamlines the process of bringing new therapies to market. Appropriate COAs not only minimize the need for trial redesign but also keep timelines and budgets on track, contributing to the success of clinical trials and the development of innovative treatments. '