Rationale and Design of ASCEND: a Phase 3b Study Evaluating Higher Dose Nusinersen in Risdiplam-Treated Participants with Spinal Muscular Atrophy


Clinical Trials

Poster Number: 83


Nancy Kuntz, MD, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA., Tim Hagenacker, MD, Universitätsklinikum Essen, Essen, Germany, Basil Darras, MD, Department of Neurology, Boston Children’s Hospital, Richard Finkel, MD, St. Jude Children’s Research Hospital, Memphis, TN, USA., Eugenio Mercuri, Paediatric Neurology and Centro Clinico Nemo, Catholic University and Policlinico Gemelli, Fondazion, Jacqueline Montes, PT, EdD, Columbia University Medical Center, Michelle A. Farrar, MD, PhD, Sydney Children’s Hospital Network and UNSW Medicine, UNSW Sydney, Valeria A. Sansone, MD, PhD, Neuromuscular Omniservice Clinical Center, Neurorehabilitation Unit, Univ. of Milan, Milan, Italy, Zdenek Berger, PhD, Biogen, Cambridge, MA, USA, Drew MacCannell, PhD, Biogen, Cambridge, MA, USA, Changyu Shen, PhD, Biogen, Cambridge, MA, USA, Angela D. Paradis, ScD, Biogen, Cambridge, MA, USA, Justin Bohn, ScD, Biogen, Cambridge, MA, USA, Kathleen Somera-Molina, PhD, MSci, Biogen, Cambridge, MA, USA

Background: Nusinersen 12 mg (approved dose) has demonstrated a positive benefit–risk profile in infants, children, teenagers, and adults with SMA. Pharmacokinetic/pharmacodynamic modeling indicates higher dose nusinersen (2 loading doses of 50 mg 2 weeks apart followed by 28 mg maintenance doses every 4 months) may achieve higher cerebrospinal fluid (CSF) exposure, potentially providing greater benefit than 12 mg nusinersen. Pharmacokinetic population modeling shows steady-state CSF nusinersen exposure is similar across wide ranges of body weights. Risdiplam is an RNA splicing modifier approved for SMA patients ?2 months old. Subgroup analysis from SUNFISH showed improved scores on the 32-item Motor Function Measure with risdiplam in younger participants with Type II/III SMA (age 2–5 years); however, efficacy was lower in participants aged 6–25 years. While this may be due to disease progression, and motor neuron loss over time, lower risdiplam exposure may also be an important contributor. We hypothesize that due to the 5 mg risdiplam dosing cap, lower risdiplam exposure in patients >20 kg may limit the potential for optimal benefit among these patients.
Objectives: Describe the design of ASCEND (NCT05067790), an open-label, single-arm study of higher dose nusinersen in participants with SMA previously treated with risdiplam.
Results: ASCEND will enroll later-onset, non-ambulatory participants with SMA (symptom onset age >6 months) who were previously on risdiplam (stopped treatment pre-enrollment) and are either nusinersen-naïve or nusinersen-experienced. Nusinersen-naïve participants must be age 5–39 years and have received risdiplam for ?6 months and ?12 months pre-enrollment. Nusinersen-experienced participants must be age 18–39 years, stopped nusinersen ?16 months pre-enrollment, and received risdiplam for ?12 months and ?18 months pre-enrollment. ~135 participants at 40 sites globally will receive higher dose nusinersen for ~2 years with a visit 4 months after the last nusinersen dose. Endpoints include the Revised Upper Limb Module, safety, and other clinical assessments.
Conclusions: ASCEND will evaluate the benefit-risk of higher dose nusinersen in participants with SMA previously treated with risdiplam.
Study Support: Biogen