Risdiplam in Patients With Spinal Muscular Atrophy Previously Treated With Nusinersen (RISE)

Risdiplam Exchange in Patients With Spinal Muscular Atrophy (SMA) Previously and Exclusively Treated With Nusinersen

Risdiplam Exchange (RISE) is a study of spinal muscular atrophy (SMA) patients who crossover to 36 months of open-label risdiplam monotherapy following a comparable period of nusinersen treatment. The schedule of assessments (SOAs) carry over seamlessly for the cohort from studies done while treated with nusinersen and continue to track the most informative outcomes from that trial (e.g. nine hole peg test and grip strength), while adding the Box and Block Test (BBT) as an additional measure of upper limb endurance and function.

Risdiplam is an orally bioavailable small molecule that distributes into the central nervous system (CNS) and peripheral tissues where it modifies SMN2 pre-mRNA splicing and increases tissue SMN protein levels. It was approved by the U.S. Food and Drug Administration for all SMA patients older than 2 months of age in August 2020. Clinical trial data prompted us to consider risdiplam a reasonable alternative to nusinersen administered intrathecally or by subcutaneous intrathecal catheter (SIC) for patients with more advanced SMA. Considered within this clinical context, risdiplam presents a significant advantage by eliminating the risks of mechanical failure, intrathecal bleeding, and CNS infection associated with the SIC device. The schedule of assessments (SOAs) used in this cohort during the previous three-year period as part of a nusinersen study provide us with an established framework for data collection. Thus, the overall clinical experience with risdiplam as compared to nusinersen can be assessed using a prospective, crossover design in a real-world setting.

Participants crossover to 36 months of open-label risdiplam mono therapy following a comparable period of nusinersen treatment.

Time in seconds to place and subsequently remove nine one inch pegs in holes assessed in dominant and non dominant hands

Revised Hammersmith Scale (RHS) of 33 items with grades of 0 (unable),1 (attempted, not completed) and 2 (achieves task); the greater the sum total, the higher overall motor function.

box and block test (BBT): number of 1 inch wood blocks moved from one compartment to an adjacent one over a wall within 5 minutes, with more blocks moved corresponding to higher upper limb motor function

maximal inspiratory pressure (MIP) and mean expiratory pressure (MEP), measured in centimeters of water displaced

Inclusion Criteria: Biallelic SMN1 deletions 3 or 4 copies of SMN2 Prior treatment with nusinersen for a minimum of 22 months Exclusion Criteria: Prior treatment with SMN gene replacement therapy Prior exposure to another investigational agent. Confounding neuromuscular disorder other than SMA

Strauss KA, Carson VJ, Brigatti KW, Young M, Robinson DL, Hendrickson C, Fox MD, Reed RM, Puffenberger EG, Mackenzie W, Miller F. Preliminary Safety and Tolerability of a Novel Subcutaneous Intrathecal Catheter System for Repeated Outpatient Dosing of Nusinersen to Children and Adults With Spinal Muscular Atrophy. J Pediatr Orthop. 2018 Nov/Dec;38(10):e610-e617. doi: 10.1097/BPO.0000000000001247.

Carson VJ, Young M, Brigatti KW, Robinson DL, Reed RM, Sohn J, Petrillo M, Farwell W, Miller F, Strauss KA. Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy. Muscle Nerve. 2022 Jan;65(1):51-59. doi: 10.1002/mus.27425. Epub 2021 Oct 19.

Ribero VA, Daigl M, Marti Y, Gorni K, Evans R, Scott DA, Mahajan A, Abrams KR, Hawkins N. How does risdiplam compare with other treatments for Types 1-3 spinal muscular atrophy: a systematic literature review and indirect treatment comparison. J Comp Eff Res. 2022 Apr;11(5):347-370. doi: 10.2217/cer-2021-0216. Epub 2022 Jan 18.