Biogen Inc. today announced plans to initiate a global Phase 3b clinical study, ASCEND. The ASCEND study is designed to evaluate the clinical outcomes and assess the safety of a higher dose of nusinersen* in children, teens and adults with later-onset spinal muscular atrophy (SMA) following treatment with Evrysdi (risdiplam).
People with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the ongoing maintenance of motor neurons that support sitting, standing and movement. Over time, people with SMA may lose their ability to perform everyday activities, including brushing their teeth, turning on a light switch or drinking from a cup The goal of treatment in SMA is to sufficiently protect motor neurons and help preserve function.
“We believe that lower drug exposure may be contributing to less-than-optimal treatment outcomes for some patients treated with Evrysdi. The ASCEND study seeks to understand if nusinersen may address that unmet medical need and will help inform the future of SMA treatment, with the hope of improving patients’ outcomes for the long term,” said Maha Radhakrishnan, M.D., Chief Medical Officer at Biogen.
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Available data suggest that exposure to Evrysdi diminishes with increased age and weight, with an approximately 40 percent reduction in drug concentration in adults compared to infants. Evrysdi’s dosing is capped at 5 milligrams (mg) once patients reach 20 kilograms (kg).
At the approved 12-mg dose, motor neuron exposure to nusinersen remains similar as patients age and grow. Further, nusinersen has demonstrated proven, sustained efficacy and a well-characterized safety profile, with long-term data in patients treated for more than 7 years across ages and SMA types. Taken together, these data support further exploration of whether a higher dose can deliver even greater efficacy to patients. The ASCEND study will assess if nusinersen at a higher dose may address outstanding clinical needs among later-onset SMA patients treated with Evrysdi who want to make a change in their treatment regimen. The same investigational higher dose of nusinersen is also being evaluated in the ongoing DEVOTE study.
“There have been significant advances in SMA treatment; however, there is still no cure and unmet medical needs remain,” said Professor Tim Hagenacker, Head of Neuromuscular Diseases Unit, Essen University in Germany, and a member of the ASCEND study steering committee. “As part of my clinical practice, we’ve observed an opportunity to potentially further improve patient outcomes. With a higher dose of nusinersen, we are positioned to explore what may be possible.”
The ASCEND protocol has been submitted to the U.S. Food and Drug Administration and is planned to be an approximately 2.5-year study projected to enroll up to 135 later-onset, non-ambulatory individuals with SMA (aged 5 to 39). All participants must have been previously treated with Evrysdi at the maximum recommended dose of 5 mg and be willing and able to change their treatment regimen to a higher dose of nusinersen. Participants must also fall within a particular Revised Upper Limb Module (RULM) measurement range to enter the study. Individuals enrolled in ASCEND will receive two loading doses of nusinersen 50 mg two weeks apart, followed by a maintenance dose of 28 mg every four months during the study period. Efficacy is planned to be assessed by RULM. Additional clinical outcomes include safety, Hammersmith Functional Motor Scale Expanded (HFMSE) and caregiver burden. The study will also evaluate upper limb fine motor function in participants aged 13 and older using the mobile application Konectom™, and neurofilament levels as a marker of biological disease activity, both exploratory endpoints.
The study aims to include children, teens and adults naïve to treatment with nusinersen, as well as adults who were previously treated with nusinersen prior to Evrysdi. The company aims for the first eligible patients to be enrolled in 2021.
In addition to ASCEND, as a leader in SMA Biogen supports over 15 SMA disease registries with more than 4,000 patients across the globe, which will help support treatment decisions within the context of currently approved therapies, including the 12-mg dose of nusinersen.
*Nusinersen is currently commercialized under the brand name SPINRAZA, and the U.S. Food and Drug Administration-approved dose is 12 mg.
About SPINRAZA (nusinersen)
The SPINRAZA clinical development program encompasses clinical studies, which have included more than 300 individuals across a broad spectrum of patient populations, including two randomized controlled studies (ENDEAR and CHERISH). The ongoing SHINE and NURTURE open-label extension studies are evaluating the long-term impact of SPINRAZA. The most common adverse events observed in clinical studies were respiratory infection, fever, constipation, headache, vomiting and back pain. Laboratory tests can monitor for renal toxicity and coagulation abnormalities, including acute severe low platelet counts, which have been observed after administration of some ASOs.
Biogen licensed the global rights to develop, manufacture and commercialize SPINRAZA from Ionis Pharmaceuticals, Inc. (Nasdaq: IONS), the leader in antisense therapeutics. Please click here for Important Safety Information and full Prescribing Information for SPINRAZA in the U.S., or visit your respective country’s product website.
About Spinal Muscular Atrophy (SMA)
SMA is a rare, genetic, neuromuscular disease that affects individuals of all ages. It is characterized by a loss of motor neurons in the spinal cord and lower brain stem, resulting in progressive muscle atrophy and weakness.11 SMA is caused by a deficiency in the production of survival motor neuron (SMN) protein due to a damaged or missing SMN1 gene, with a spectrum of disease severity. Some individuals with SMA may never sit; some sit but never walk; and some walk but may lose that ability over time. In the absence of treatment, children with the most severe form of SMA would not be expected to reach their second birthday.
SMA impacts approximately 1 in 11,000 live births, is a leading cause of genetic death among infants and causes a range of disability in teenagers and adults.
Date: Sep 15, 2021
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