SUNFISH Parts 1 and 2: 4-year efficacy and safety data of risdiplam in Types 2 and 3 SMA

Introduction: Spinal muscular atrophy (SMA) affects individuals with a broad age range and spectrum of disease severity. Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in over 90 countries worldwide. SUNFISH (NCT02908685) is a multicenter, two-part, randomized, placebo-controlled, double-blind study in patients with types 2 and 3 SMA (inclusion criteria: aged 2–25 years at enrollment). Part 1 (n = 51) assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels in patients with types 2 and 3 SMA (ambulant and non-ambulant). Part 2 (n = 180) assessed the efficacy and safety of the Part 1-selected dose of risdiplam versus placebo in type 2 and non-ambulant type 3 SMA. In Part 2, participants were treated with risdiplam or placebo for 12 months; participants then received risdiplam in a blinded manner until Month 24. At Month 24, patients were offered the opportunity to enter the open-label extension phase. Objectives: To determine the efficacy and safety of risdiplam in patients with Types 2 and 3 SMA after 4 years (48 months) of treatment. Results: The primary endpoint (Part 2) of change from baseline in the 32- item Motor Function Measure (MFM32) total score in patients treated with risdiplam (n=120) versus placebo (n = 60) was met at Month 12. These increases in motor function were sustained in the second and third year after risdiplam treatment, as measured by changes in the MFM32, Hammersmith Functional Motor Scale — Expanded, and Revised Upper Limb Module. At Month 36 (data-cut: 6 September 2021), there were no treatment-related safety findings leading to withdrawal from either SUNFISH Part 1 or 2. Here we present 4-year efficacy and safety data from SUNFISH. Conclusion: SUNFISH is ongoing and will provide further long-term efficacy and safety data of risdiplam in a broad population of children, teenagers and adults with SMA.

 AKP is a PI of SMA studies for F. Hoffmann-La Roche; she has attended advisory boards of Biogen, PTC Therapeutics and AveXis, received speaker honoraria from Biogen and PTC Therapeutics and grant support from Biogen  JWD reports grants from: AMO Pharmaceuticals, aTyr, AveXis, Biogen, Bristol Meyers Squibb, Cytokinetics, Ionis Pharmaceuticals, Roche Pharmaceuticals, Sanofi-Genzyme and Sarepta Therapeutics; he has served as a consultant for: AMO Pharmaceuticals, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Roche Pharmaceuticals, Pfizer, Sarepta Therapeutics and Santhera Pharmaceuticals; he has patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy Type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931)  ND is a PI of SMA studies for F. Hoffmann-La Roche, Novartis, Biogen and AveXis.He has received consultancy fees from F. Hoffmann-La Roche, Biogen and AveXis  ESM is a master trainer for SMA studies and receives consultancy fees from AveXis, Biogen, F. Hoffmann-La Roche and Scholar Rock  AN is a PI of SMA studies for F. Hoffmann-La Roche, Biogen and Scholar Rock; he has received consultancy fees from F. Hoffmann-La Roche, Biogen, Scholar Rock and AveXis  MO is a PI of SMA studies for F. Hoffmann-La Roche and Biogen  KS has attended advisory boards for Biogen, Novartis Pharma and Roche/Chugai; she is a consultant for AveXis and has received research funding from AveXis/Novartis, Biogen and Roche/Chugai for research consultation for execution of clinical trial projects and from Ionis Pharmaceuticals for execution of clinical trial projects  CV is a PI of SMA studies for F. Hoffmann-La Roche; she has attended SAB of Roche, Biogen and AveXis and received consultancy fees from F. Hoffmann-La Roche  GB has received speaker and consultancy honoraria from AveXis, Inc., Roche, PTC and Sarepta Therapeutics  OBT is a PI of studies for F. Hoffmann-La Roche, AveXis, Santhera, Italfarmaco, Ultragenyx and Metfora; she is a DSMB member for Inventiva and Minoryx Therapeutics  NG is a PI of SMA studies for F. Hoffmann-La Roche; she has received consultancy fees from F. Hoffmann-La Roche, Biogen and AveXis  JK has received honoraria for clinical research and/or consultancy activities from Biogen, Novartis Gene Therapies, Roche and Scholar Rock  9,10 Giovanni Baranello,11,12 Odile Boespflug-Tanguy, 13,14 Nathalie Goemans, 15 Janbernd Kirschner, 16 Laurent Servais, 13,17,18   Age at onset of symptoms, months, mean (SD) 16 ( 11) 16 ( 14) Gender, female/male, n (%) 27 ( 53    Many thanks to all the patients who participate in these studies, their families, healthcare professionals and the support of patient groups throughout the world Please scan using your QR reader application to access the graphs and data presented in this presentation.NB: There may be associated costs for downloading data.These costs may be high if you are using your smartphone abroad.Please check your mobile data tariff or contact your service provider for more details.Alternatively this can be accessed at: https://bit.ly/43QeN4w SUNFISH (NCT02908685) is a two-part clinical trial of risdiplam in a broad, heterogeneous patient population with Types 2 and 3 SMA 2 • Here we present efficacy and safety data from patients who have received long-term risdiplam treatment for 4 years (48 months) *Risdiplam has been approved for the treatment of pediatric and adult patients with SMA by the FDA and for patients aged 2 months and older with a clinical diagnosis of Type 1, 2 or 3 SMA or with one to four copies of SMN2 by the EC. 1,3,4 Patients in SUNFISH Part 2 were randomised 2:1 to receive either risdiplam or placebo.Patients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 36 months.Four patients withdrew to start another treatment (nusinersen [SPINRAZA ® ], n=3; unspecified, n=1), four patients were withdrawn by patient/caregiver; n=1 patient withdrew due to COVID-19 measures (please see supplementary data).‡ n=44; adjusted baseline prior to first dose of risdiplam following placebo period, Part 1 only.14% of patients in Part 1 were ambulant.§ n=174.|| n=177.¶ Based on enrolment criteria, at least 56% of patients in SUNFISH Part 2 would have been ineligible for the CHERISH trial (CHERISH inclusion criteria included: aged 2-12 years, baseline HFMSE score ≥10; and exclusion criteria included: severe scoliosis [>40°curvature]).This percentage does not take into consideration patients with severe contractures (CHERISH exclusion criteria included any contracture that, according to the investigator, could interfere with HFMSE). 5Data cut-off: 30 Sep 2020.EC, European Commission; FDA, US Food and Drug Administration; HFMSE, Hammersmith Functional Motor Scale -Expanded; MFM, Motor Function Measure; MFM20, 20-item MFM; MFM32, 32-item MFM; PD, pharmacodynamics; PK, pharmacokinetics; RULM, Revised Upper Limb Module; SD, standard deviation; SMA, spinal muscular atrophy; SMN, survival of motor neuron.1. F. Hoffmann-La Roche.March 2023 press release: https://www.roche.com/media/releases/med-cor-2023-03-20(Accessed June 2023); 2. ClinicalTrials.gov.NCT02908685 (Accessed June 2023); 3. EVRYSDI ® prescribing information: https://www.gene.com/download/pdf/evrysdi_prescribing.pdf(Accessed June 2023); 4. EVRYSDI ® summary of product characteristics: https://www.ema.europa.eu/en/documents/product-information/evrysdi-epar-product-information_en.pdf(Accessed June 2023); 5. Mercuri E, et al.N Engl J Med. 2018; 378:625-635.

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LS is a PI of SMA studies for F. Hoffmann-La Roche Ltd, Biogen, and AveXis; he has attended SAB of F. Hoffmann-La Roche Ltd, Biogen and AveXis and received consultancy fees from Biogen; he serves on the board for Cytokinetics; he is co-inventor in the patent 20190029605 (Method for estimating physical activity of the upper limb) from which he has not perceived any financial interest  JB, MG, KG, CM, WYY and RSS are employees of, and hold shares in, F. Hoffmann-La Roche Ltd  EM receives fees from AveXis, Biogen and F. Hoffmann-La Roche  This study was sponsored by F. Hoffmann La Roche Ltd, Basel, Switzerland.Writing and editorial assistance was provided by Kiran Verma, of Nucleus Global, in accordance with Good Publication Practice (GPP2022) guidelines (http://www.ismpp.org/gpp-2022)Conflicts
1* Presenter *±95% CI. † Baseline is the last measurement prior to the first dose of risdiplam or placebo.‡ Data cut-off: 6 Sep 2022.§ Data cut-off: 6 Sep 2019.Patients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 36 months.Risdiplam period not shown in this graph.|| Number of patients with valid results = number of patients with an available total score (result) at respective time points.Intent-to-treat patients.AIM, Association Institut de Myology; CI, confidence interval; MFM32, 32-item Motor Function Measure; NatHis, natural history; RULM, Revised Upper Limb Module; SMA, spinal muscular atrophy; SMAIS-ULM, SMA Independence Scale-Upper Limb Module. 1. Roche data on file; courtesy of AIM, first presented at MDA 2021.
The SUNFISH and PNCR populations were not concurrent, and PNCR includes US sites while SUNFISH recruited patients from US, Europe, China, Japan and the rest of the world.1*PresenterMost

frequent AEs are reflective of underlying disease or the known adverse reaction profile of risdiplam Overall rate of AEs and SAEs per 100PY
*Includes 120 patients in the risdiplam arm who have been treated with risdiplam for 48 months and 58 patients from the placebo arm who were switched to the risdiplam arm after 12 months and have been treated with risdiplam for 36 months.One patient randomised to placebo was withdrawn prior to receiving any risdiplam dose.† Includes 51 patients from Part 1 and 179 patients from the risdiplam and placebo/risdiplam arms in Part 2 (one patient randomised to placebo was withdrawn prior to receiving any risdiplam dose).‡ ± 95% CI.Data cut-off: 6 Sep 2022.§ Includes 51 patients from Part 1 and 179 patients from the risdiplam and placebo/risdiplam arms in Part 2 (one patient randomized to placebo was withdrawn prior to receiving any risdiplam dose).AE, adverse event; CI, confidence interval; PY, patient-years; SAE, serious AE.

Additional results are available in the supplementary data (accessible via QR code)
AE, adverse event; SMA, spinal muscular atrophy.
* Presenter *±95% CI. † Baseline is the last measurement prior to the first dose of risdiplam or placebo.‡ Data cut-off: 6 Sep 2019.§ Data cut-off: 6 Sep 2022.Patients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 36 months.|| Number of patients with valid results = number of patients with an available total score (result) at respective time points.Intent-to-treat patients.The percentage of patients is calculated by using the number of valid total scores at corresponding visits as a denominator.A score of ≥3 shows a marked improvement and a score of ≥0 shows stabilization or improvement.CI, confidence interval; MFM32, 32-item Motor Function Measure.