Search

Background: The GM1 and GM2 gangliosidoses and type 2 Gaucher disease (GD2) are inherited lysosomal storage disorders with most cases having symptom onset in infancy and reduced life expectancy. The conditions are rare, and there is therefore a need for accurate and up to date information concerning the disease course and survival to assist in the design of clinical trials. RETRIEVE is a natural history study aiming to: (1) collect data on the survival of patients with early-onset (onset of first neurological manifestation before 24 months of age) GM1, GM2, or GD2; (2) collect data that could constitute a historical control group for future clinical trials; and (3) evaluate whether the conditions can be assessed together in a single interventional clinical trial. Group A included patients who were deceased or with unknown survival status at enrollment and was thus limited to retrospective data. Group B included patients who were alive at enrollment, who were followed prospectively with additional retrospective data collection., Results: Group A included 185 patients (60 with GM1, 78 with GM2, and 47 with GD2), and Group B included 40 patients (18 with GM1, 16 with GM2, and 6 with GD2). Mean and median age at diagnosis and age at onset of first neurological manifestation were youngest in patients with GD2 and oldest in patients with GM2 in both groups. In Group A, median (95% CI) survival was 19.0 (18.0, 22.0), 44.0 (37.0, 51.9) and 14.0 (10.0, 16.0) months in patients with GM1, GM2 and GD2, respectively. In Group B, hypotonia was experienced by most patients with GM1 (17/18, 94.4%), and was less common in patients with GM2 (12/16, 75.0%) and GD2 (4/6, 66.7%). Strabismus and splenomegaly were reported in all six patients with GD2., Conclusions: RETRIEVE is one of the largest natural history studies of GM1, GM2, and GD2. Results were generally consistent with the published literature, with differences potentially due to variation in inclusion criteria. The difference in median survival between patients with early-onset GM1, GM2, and GD2 reported in this study suggests that the three diseases should not be pooled for study in clinical trials., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in compliance with Good Epidemiology Practice guidelines, the ethical principles arising from the Declaration of Helsinki revised in 2013, and all current local regulations. Ethics Committee/Institutional Review Board approval was obtained as required by applicable site policies, national privacy regulations and other state and local laws relating to medical information. Informed consent of the parent or legal guardian was obtained as required by local law. Consent for publication: Not applicable. Competing interests: BH: Is an Investigator in the RETRIEVE study and in P1-GM101 Lysogene clinical trial and in other clinical studies supported by Orphazyme/KemPharm, Azafaros, Sanofi Genzyme, Chiesi, JR Pharmaceuticals, Mallinckrodt. SB: Nothing to disclose. EM: Has received research grants and consultation fees and speakers’ honoraria from Sanofi Genzyme, Amicus, Takeda, Orphazyme, Prevail, Idorsia, Cyclo Therapeutics, Sio and Taysha. RG: Has received research grants, investigator fee, speaker honorarium, support for travel to scientific meetings, or consultation fee from Abeona, Allievex, Amicus, Avrobio, Azafaros, BioMarin, Chiesi, Cyclo, Denali, Idorsia, Inventiva, Janssen, JCR, Novartis, Paradigm, PassageBio, Pfizer, PTC, RegenxBio, Sanofi, Sigilon, Sobi, Takeda, and Ultragenyx. MP: Is an investigator in trials supported by Amicus, Glycomine, Idorsia, Maggie’s Pearl, Orphazyme/KemPharm and Shire/Takeda; receives honoraria as Editor-in-Chief of the Journal of Child Neurology (Sage), Editor of JIMD and JIMD Reports (SSIEM), and royalties as a contributor to, and section editor for, UpToDate (Wolters-Kluwer); owns stock in IntraBio. MG: Has received consulting fees from Sanofi Genzyme, and is an investigator for industrial trials from Horizon, Idorsia, Kaleido, Mallinckrodt, and Orphazyme A/S. PC: Employee of Idorsia Pharmaceuticals Ltd. LT: Employee of Idorsia Pharmaceuticals Ltd. at the time the work was performed. BS: Employee of Idorsia Pharmaceuticals Ltd. MR: Has received consulting fees from Sanofi Genzyme, and travel expenses and congress fees from Amicus., (© 2024. The Author(s).)

Background: Sphingosine-1-phosphate (S1P) is a signalling molecule that has an inhibitory role in atherosclerosis, inflammation, cell proliferation, and immunity. Cenerimod is a selective S1P 1 receptor modulator under investigation for the treatment of systemic lupus erythematosus (SLE). We aimed to determine the efficacy, safety, and tolerability of four doses of cenerimod in adults with moderate-to-severe SLE receiving standard of care background therapy., Methods: CARE was a double-blind, randomised, placebo-controlled, phase 2 trial, in adults (aged 18-75 years) with moderate-to-severe SLE (a score of at least 6 out of 105 on the SLE disease activity index-2000, modified to exclude leukopenia [mSLEDAI-2K] score). Participants were recruited from 189 hospitals, specialist centres, and outpatient clinics in 22 countries in Asia Pacific, Latin America, Europe, and the USA. Participants were randomly assigned (1:1:1:1:1), using an interactive response technology via balanced block randomisation (block size of 5) and stratified by oral glucocorticoid dose at randomisation and disease activity at screening, to once-daily oral cenerimod at 0·5 mg, 1·0 mg, 2·0 mg, or 4·0 mg or placebo, in addition to stable background SLE therapy, and followed up for 12 months. After 6 months, participants assigned to cenerimod 4·0 mg were randomly assigned again (1:1) to either cenerimod 2.0 mg or placebo for a further 6 months. The primary endpoint was change from baseline to month 6 in mSLEDAI-2K score, assessed in all participants randomly assigned to treatment (full analysis set). To meet the primary endpoint, the doses had to show a significant improvement over placebo, when adjusting for multiplicity, considering the hierarchical testing strategy, per a prespecified plan. Safety analyses included all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03742037, and is complete., Findings: Between Dec 21, 2018, and Aug 25, 2022, 810 patients were screened and 427 were randomly assigned to 0·5 mg (n=85), 1·0 mg (n=85), 2·0 mg (n=86), and 4·0 mg (n=85) cenerimod or placebo (n=86). Median age was 42 years (IQR 33-51), 406 (95%) of 427 participants were women, 21 (5%) were men, and 337 (79%) were White. At month 6, the least squares mean change from baseline in mSLEDAI-2K score was -2·85 (95% CI -3·60 to -2·10) for the placebo group and -3·24 (-3·98 to -2·49; difference vs placebo -0·39 [95% CI -1·45 to 0·68]; p=0·47) for the cenerimod 0·5 mg group, -3·41 (-4·16 to -2·67; difference vs placebo -0·57 [-1·62 to 0·49]; p=0·29) for the 1·0 mg group, -2·84 (-3·58 to -2·09; difference vs placebo 0·01 [-1·05 to 1·08]; p=0·98) for the 2·0 mg group, and -4·04 (-4·79 to -3·28; difference vs placebo -1·19 [-2·25 to -0·12]; p=0·029) for the 4·0 mg group; hence, the primary endpoint was not met. Treatment-emergent adverse events up to 12 months had no clear treatment-related or dose-related pattern across the groups. At month 6, treatment-emergent lymphopenia was reported in one (1%) of 85 patients who received cenerimod 0·5 mg, five (6%) of 85 patients who received 1·0 mg, nine (10%) of 86 patients who received 2·0 mg, 12 (14%) of 84 patients who received 4·0 mg, and no patients who received placebo. Two deaths due to adverse events occurred (both in the cenerimod 1·0 mg group; one due to acute coronary syndrome and the other due to upper gastrointestinal haemorrhage), and were determined to be unrelated to study treatment., Interpretation: The primary endpoint was not met. Cenerimod was well tolerated over 12 months. Cenerimod 4·0 mg is being investigated for the treatment of SLE in two ongoing phase 3 trials (NCT05648500, NCT05672576)., Funding: Idorsia Pharmaceuticals., Competing Interests: Declaration of interests ADA is a consultant for Amgen, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb, Cabaletta, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Sana, Sanofi, and UCB; has received grants from AstraZeneca, Biogen, BMS, Cabaletta, Idorsia, Genentech, NKARTA, Pfizer, Sana, Sanofi, and UCB; and has been a participant on advisory boards for Amgen and BMS. DD is a consultant advisor for GSK, UCB, and CSL Vifor; has received speaker fees from GSK and UCB; and has received support from CSL Vifor for attending European Alliance of Associations for Rheumatology 2023. CC was an employee of Idorsia Pharmaceuticals at the time the work was performed. KK is a consultant for BMS, GSK, Genentech/Roche, Equillium, AstraZeneca, Biogen, Eli Lilly, Amgen, Aurinia, Cabaletta, Shoreline, Ventyx, and Mirador; has been a participant on an advisory board for Genentech/Roche; holds a leadership or fiduciary role in Lupus Therapeutics and Lupus Foundation of America; and hold stocks in Artiva Bio and Bento Bio. JTM is a consultant for AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, BMS, EMD Serono, Genentech, Gilead, GSK, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas; has received grants from BMS, GSK, and AstraZeneca; has received speaker fees from AbbVie, BMS, Merck, and Remegen; and is Chief Advisor for Clinical Development for Lupus Foundation of America. SVN is aconsultant for Biogen, Idorsia, and AstraZeneca; has received speaker fees from Astellas, AstraZeneca, Aurinia, Pfizer, GSK, and Roche; has participated on advisory boards and data safety monitoring boards for Roche; and is President and Chief Executive Officer of Rheumatology Educational Trust Foundation. PC, MJM, DSS and OB are employees of Idorsia Pharmaceuticals and shareholders in the company. LT was an employee of Idorsia Pharmaceuticals and a shareholder in the company at the time the work was performed., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)