Muscular Atrophy, Spinal, Type II

The intrathecal version data comes as Zolgensma sales have stalled at Novartis. More than three years after Novartis’ plan for a speedy approval for intrathecal Zolgensma was thwarted by an FDA requirement for a pivotal phase 3 trial, the company is back with a positive readout from that study, which could give the gene therapy a much-needed boost.The one-time therapy, coded OAV-101 IT, helped Type 2 spinal muscular atrophy (SMA) patients aged 2 to less than 18 years achieve a significantly better motor function than a sham treatment did after one year, Novartis said Monday.The findings mean the randomized phase 3 trial, dubbed Steer, met its primary endpoint, which is measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE) score, an industry scale that assesses the motor ability of patients with SMA. Trial participants hadn't received any prior SMA treatments and were able to sit but couldn’t walk independently when entering the study.Zolgensma as an intravenous infusion has been approved in the U.S. for children under 2 years with SMA since 2019. The intrathecal version injects the gene therapy directly into the spinal cord, thereby allowing for a smaller dose needed to have enough therapeutic payload reaching the motor neurons, Daniel Grant, VP & global program head of some of Novartis’ gene therapy projects, explained in an interview with Fierce Pharma.The goal is to get Zolgensma into a larger, older patient population. As the IV version is dosed based on a patient’s weight, toxicity doesn’t allow it to be given in older individuals.Liver toxicity is a known side effect that appears as a boxed warning on Zolgensma’s U.S. label. The intrathecal route of administration could reduce liver exposure to the adeno-associated virus capsid that’s used to deliver the gene therapy, Grant said, citing biodistribution studies in monkeys.In its Monday release, Novartis described the safety profile of OAV101 IT as “favorable,” citing "similar" overall adverse events and serious adverse events between the trial arms. Because of Zolgensma’s age—or weight in Europe—limitation, more than 70% of patients living with SMA have never had a shot at the gene therapy, Grant observed.“The meaningfulness of this study for me is that it allows us to take an AAV and make gene replacement an option for patients all the way across the spectrum of one specific disease,” he said. “That’s kind of a landmark from the AAV front.”Novartis said it plans to share the Steer results with regulators, including the FDA, to seek approvals for OAV-101 IT. Grant said a submission is expected in the first half of 2025.Novartis had originally aimed to file intrathecal Zolgensma for FDA approval in 2021 based on data from a phase 1/2 trial in patients aged 2 to less than 5 years old. But a temporary partial clinical hold caused by toxicology findings from a preclinical study and a following FDA requirement to run a phase 3 trial delayed Novartis’ regulatory plan.By Novartis’ estimate, OAV-101 IT represents a multibillion-dollar opportunity in peak sales, CEO Vas Narasimhan said during an investor event in November.The intrathecal version comes at a time when Zolgensma sales have become stagnant, relying mainly on new geographic expansions. In the first nine months of 2024, sales from the one-time gene therapy reached $952 million, up 3% year over year.Besides the 125 subject-strong Steer trial in treatment-naïve patients, Novartis also anticipates an upcoming readout from another study called Strength, which includes about 30 treatment-experienced patients. The open-label study is meant to show how patients do after switching from existing chronic treatment to a one-time therapy, and therefore is not expected to prompt any major changes in motor function scores, Grant explained.The approval of OAV-101 IT will be solely dependent on the phase 3 Steer trial, Grant said. Outside of Zolgensma, Novartis has recently made several investments in gene therapies for neuromuscular diseases, including a $100 million-upfront deal with Voyager Therapeutics and a pending $1.1 billion acquisition of Kate Therapeutics.Novartis is “at a place where we think our gene therapy capabilities […] we brought in-house with the various vectors from Regenxbio and other partners will allow us to solve the biology that we did solve with Zolgensma but then struggled to solve for other monogenic or polygenic neuromuscular diseases,” CEO Narasimhan said at the November event.

BASEL, Switzerland I December 30, 2024 I Novartis today announced positive topline results from the Phase III STEER study. This pivotal study assessed the efficacy and safety of investigational intrathecal onasemnogene abeparvovec (OAV101 IT) in treatment-naïve patients with spinal muscular atrophy (SMA) Type 2, aged two to less than 18 years who are able to sit but have never walked independently. 1 Efficacy and safety results for OAV101 IT were compared against a sham control, a procedure designed to mimic the administration of an investigational drug, without delivering any active treatment. The STEER study met its primary endpoint showing an increase from baseline across the study population in total Hammersmith Functional Motor Scale – Expanded (HFMSE) scores. HFMSE is a gold standard for SMA-specific assessment of motor ability and disease progression. 2,3,4,5,6 The increase was observed in patients treated with OAV101 IT compared to sham controls indicating better motor function in patients with SMA. The safety profile of OAV101 IT was favorable. The overall adverse events and serious adverse events were similar between arms. The most common adverse events were upper respiratory tract infection, pyrexia and vomiting. Novartis plans to share results with regulatory agencies in 2025, including the US Food and Drug Administration (FDA), with the aim to make OAV101 IT available to help patients with SMA in need. Data will be presented at an upcoming medical meeting in 2025. “Many patients with SMA currently rely on chronic treatments to manage their disease. These positive topline results from the STEER trial underscore the efficacy, safety and tolerability of OAV101 IT in patients with SMA aged two and above,” said Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis. “The totality of evidence clearly supports a positive risk benefit profile of OAV101 which is expected to support registration covering a broad range of SMA patients. We remain committed to leading innovation in SMA treatment through our one-time gene therapies, uniquely designed to replace the function of the missing or defective SMN1 gene.” “Maintaining motor function is a key goal for many older patients with SMA. This may allow them the capacity to continue to propel their electric wheelchair, feed themselves with intact hand to mouth function, and perform other activities of daily living as independently as possible” said Crystal Proud, M.D., Pediatric Neurologist and a Principal Investigator at Children’s Hospital of the King’s Daughters.OAV101 IT administration has not only been demonstrated to maintain motor function, but also increased it in indicating the impact a one-time therapy could have.” Results from STEER build on the Phase I/II open-label STRONG study which showed that treatment with OAV101 IT led to a clinically meaningful increase in HFMSE scores in one year, 7 and a clinically meaningful response in patients aged two to five years with SMA Type 2, who were able to sit but had never walked independently. 7 The results from the Phase III STEER study add to the clinical data and emerging real-world evidence for the use of one-time gene therapy to treat SMA. STEER Study STEER is a Phase III randomized, double-blind, sham-controlled study to evaluate the clinical efficacy, safety, and tolerability of a one-time dose of intrathecal onasemnogene abeparvovec (OAV101 IT) in treatment naïve patients with SMA Type 2, aged two to less than 18 years who were able to sit, but had never walked independently. 1 The therapeutic effect of OAV101 IT was evaluated using the Hammersmith Functional Motor Scale – Expanded (HFMSE) scores. 1 This is a validated assessment tool specifically designed to evaluate motor abilities and disease progression in patients with SMA. Secondary objectives included evaluating safety and efficacy of OAV101 IT using the Revised Upper Limb Module (RULM) scale. 1 More than 100 patients were randomized to receive OAV101 by IT injection or to receive a sham procedure. 1 At the end of the 52-week period, all eligible patients who received the sham procedure received OAV101 IT and all eligible patients who received OAV101 IT received the sham procedure. 1 About OAV101 IT Intrathecal onasemnogene abeparvovec (OAV101 IT) is an investigational, one-time gene therapy for patients with spinal muscular atrophy (SMA). OAV101 IT was evaluated in three clinical studies, including the Phase III STEER study, Phase I/II STRONG study and the Phase IIIb STRENGTH study. 1,7,8, 9 The STEER study was a randomized, double-blind, sham-controlled study to evaluate the clinical efficacy, safety, and tolerability of OAV101 IT in treatment naïve patients with SMA Type 2, aged two to less than 18 years who were able to sit, but had never walked independently. 1 The STRENGTH study was an open-label, single arm, multi-center study evaluating the safety, tolerability and efficacy of OAV101 IT in patients with SMA who had discontinued treatment with nusinersen or risdiplam. 9 The STRONG study was an open-label, dose ranging study evaluating the safety and efficacy of OAV101 IT in patients with SMA with 3 copies of SMN2 aged 6 months to less than 60 months. The OAV101 IT clinical development program was studied in a broad population of approximately 170 patients with SMA and follow-up was conducted for up to 6.4 years. 10 Novartis has an exclusive, worldwide license with Nationwide Children’s Hospital to both the intravenous and intrathecal delivery of adeno-associated virus 9 (AAV9) gene therapy for the treatment of all types of SMA; 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; an exclusive, worldwide licensing agreement with Généthon for in vivo delivery of AAV9 vector into the central nervous system for the treatment of SMA. About Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease caused by a lack of a functional SMN1 gene, resulting in the irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement. 11-14 The severity of SMA varies across a spectrum of types that each correspond to the copy number of the SMN2 gene, which produces a small fraction (~10%) of functional SMN protein compared with SMN1. 12 Loss of motor neurons cannot be reversed, so patients with SMA with symptoms at the time of treatment will likely require some supportive respiratory, nutritional and/or musculoskeletal care to maximize functional abilities. 13 About Novartis 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 SOURCE: Novartis

Grand Warszawski / Shutterstock Genentech shared new data from its SUNFISH study evaluating the use of Evrysdi for SMA people ages 2 to 25 years diagnosed with Type 2 or Type 3 spinal muscular atrophy. Grand Warszawski/Shutterstock Genentech , part of the Roche Group, shared new data from its SUNFISH study evaluating the use of Evrysdi (risdiplam) in people ages 2 to 25 years diagnosed with Type 2 or Type 3 spinal muscular atrophy (SMA). SMA is a severe and progressive neuromuscular disorder that can be fatal. A leading genetic cause of infant mortality, it affects one in 10,000 babies. The disease is characterized by nerve dysfunction leading to muscle weakness and decline of motor function. Researchers observed that Evrysdi was able to increase the Motor Function Measure 32 (MFM-32) score from baseline in the first year and maintained this through the third year. Total scores for the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Lim Module (RULM) were also maintained from the first to the third year. Evrysdi was well-tolerated throughout the observation period, and the overall rate of adverse events declined. Evrysdi is a survival motor neuron 2 (SMN2) splicing modifier designed to treat mutations in chromosome 5q, which leads to SMN protein deficiency and then later to SMA. Evrysdi comes in liquid form and is given daily at home orally or via a feeding tube. Treatment is done throughout the patient’s lifetime. “The positive long-term efficacy and safety results for Evrysdi in this broad SMA population are important for physicians as they consider Evrysdi as a treatment option for their patients. In treating people with SMA, our aim is to enable or preserve their independence and patients in the SUNFISH study reported continuous improvement or stabilization in the level of help needed for daily living,” commented Laurent Servais, M.D., Ph.D., professor of pediatric neuromuscular diseases at the MDUK Oxford Neuromuscular Center. In the same announcement, Genentech shared positive interim data on the drug’s effect on newborns. Partial results from the RAINBOWFISH trial demonstrated safety and efficacy in pre-symptomatic babies with SMA who are under two months old. For this reason, the U.S. Food and Drug Administration granted the drug priority review status in January 2022 for that said indication. SUNFISH and RAINBOWFISH are just two of five multi-center trials that Genentech is conducting on SMA. FIREFISH, an open-label, two-part clinical study, is evaluating Evrysdia in infants with Type 1 SMA while JEWELFISH, an open-label exploratory trial, assesses the tolerability, safety and pharmacokinetics of the drug in ages 6 months to 60 years. Another study, MANATEE, a global Phase II/III trial, is looking into the safety and efficacy of using an anti-myostatin molecule called GYM329 plus Evrysdi in treating patients ages 2 to 10 years who have SMA. Recruitment for MANATEE is ongoing. Genentech rounds out a week of data revelations in the SMA space. Biogen is also conducting a Phase II open-label trial (NURTURE) on the use of Spinraza (nusinersen) for pre-symptomatic patients with the disease. The participants were diagnosed via a genetic test that placed them as highly likely to develop Type 1 or Type 2 SMA. Researchers are observing the patients from six weeks of age to eight years. Spinraza is dosed every four months for the patient’s lifetime. Meanwhile, Novartis is testing Zolgensma (onasemnogene abeparvovec) as a one-time treatment. Data from its Phase III SPR1NT trial found the drug to be promising in children who were treated presymptomatically as they achieved age-appropriate development milestones like walking and standing, with few or no signs of neuromuscular disease. However, many industry observers have criticized Zolgensma because the price for a single treatment is around $2.1 million.