ESPE2024 Free Communications Fat, Metabolism and Obesity 2 (6 abstracts)
Long-term Efficacy Results of Diazoxide Choline Extended-Release (DCCR) Tablets in Participants with Prader-Willi Syndrome from the Completed C601 (DESTINY PWS) and C602 Open Label Extension (OLE) Studies
Evelien Gevers 1,2 , Nicola Bridges 3 , Jack Yanovski 4 , Eric Felner 5 , Parisa Salehi 6 , Ashley Hall Shoemaker 7 , Amy Fleischman 8 , Anthony Goldstone 9 , Moris Angulo 10 , David Stevenson 11 , Kathryn Obrynba 12 , M Guftar Shaikh 13 , Anthony Holland 14 , Verghese Mathew 15 , David Viskochil 16 , Shawn E. McCandless 17 , Lynne Bird 18,19 , Melissa Lah 20 , Virginia Kimonis 21 , Jennifer Abuzzahab 22 , Laura Konczal 23 , Elizabeth Littlejohn 24 , Heidi Shea 25 , Poonam Dharmaraj 26 , Urmi Das 26 , Jorge Mejia-Corletto 27 , John Wilding 28 , Katerina Harwood 29 , Kristen Yen 30 , Raj Gandhi 30 , Jing Gong 30 , Patricia Hirano 30 , Neil Cowen 30 , Anish Bhatnagar 30 , Michael Huang 30 , Merlin Butler 31 & Jennifer Miller 32
1Queen Mary University of London, Barts and The London Medical School, Wiliam Harvey Research Institute, Centre for Endocrinology, London, United Kingdom. 2Barts Health NHS Trust, Royal London Hospital, London, United Kingdom. 3Chelsea and Westminster Hospital NHS Trust, London, United Kingdom. 4National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. 5Emory University School of Medicine, Atlanta, GA, USA. 6Seattle Children's, Seattle, WA, USA. 7Vanderbilt University Medical Center, Nashville, TN, USA. 8Boston Children's Hospital, Boston, MA, USA. 9Imperial College London Healthcare NHS Trust, London, United Kingdom. 10Good Samaritan Hospital Pediatrics, Babylon, NY, USA. 11Stanford University, Stanford, CA, USA. 12Nationwide Children’s Hospital, Columbus, OH, USA. 13Royal Hospital for Children, Glasgow, United Kingdom. 14University of Cambridge, Cambridge, United Kingdom. 15Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom. 16University of Utah, Salt Lake City, UT, USA. 17University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA. 18University of California San Diego, San Diego, CA, USA. 19Rady Children’s Hospital, San Diego, CA, USA. 20Indiana University School of Medicine, Indianapolis, IN, USA. 21University of California, Irvine Medical Center, Irvine, CA, USA. 22Children's Minnesota, St. Paul, MN, USA. 23University Hospitals of Cleveland, Cleveland, OH, USA. 24University of Michigan Health-Sparrow, Lansing, MI, USA. 25Endocrine Associates of Dallas, Plano, TX, USA. 26Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom. 27New York University Langone Hospital, Garden City, NY, USA. 28Aintree University Hospital, Liverpool, United Kingdom. 29St. Joseph's Children’s Hospital, Paterson, NJ, USA. 30Soleno Therapeutics, Inc., Redwood City, CA, USA. 31Kansas University Medical Center, Kansas City, KS, USA. 32University of Florida, Gainesville, FL, USA
Background: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disorder characterized by hyperphagia and behavioral/psychological complications. No approved therapies exist for treating hyperphagia in patients with PWS. DCCR is an oral, once-daily medication currently under development for the treatment of PWS.
Objective: The objective was to determine the efficacy of investigational DCCR on hyperphagia, behavior, and metabolic problems in PWS after long-term exposure to DCCR. The long-term safety of DCCR was presented previously.
Methods: 125 participants with genetically-confirmed PWS ≥4 years of age received daily oral DCCR in Study C601 (Phase 3, 13-week, double-blind, placebo-controlled study conducted at 29 sites in the US and UK) and/or its open-label extension, Study C602. The primary efficacy analysis was change in hyperphagia based on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score (0-36). Other efficacy analyses included the PWS Profile (PWSP) questionnaire, Clinical Global Impression of Severity (CGI-S), Caregiver Global Impression of Severity (Caregiver GI-S), body composition by DXA, and metabolic markers. Efficacy endpoints were analyzed through 3 years of exposure. Metabolic markers were analyzed through 1.5 years.
Results: At Baseline, mean (SD) participant age was 13.4 (7.0) years, 55.2% were female, and mean (SD) HQ-CT Total Score was 21.5 (6.7). Median exposure was 3.0 years (maximum: 4.5 years). Mean improvements in HQ-CT Total Scores were statistically significant versus Baseline at all timepoints through 3 years (Weeks 13, 26, 39, 52, 78, 104, 130, and 156) (P <0.0001). The extent of change increased progressively over the first 52 weeks (-6.4 to -9.9 points), was clinically meaningful beginning at Week 26, and was maintained thereafter (-10.7 to -11.6 points). Long-term DCCR administration was associated with significant improvements (P <0.001) in all PWSP domains (aggression, anxiety, compulsivity, depression, disordered thinking, rigidity/irritability) at all timepoints through 3 years. Disease severity per CGI-S and Caregiver GI-S were significantly reduced (P ≤0.0004) at all timepoints through 3 years. Lean body mass was significantly improved at all timepoints (P <0.0001) and increased progressively (LS mean change [SE] at 3 years: 7.3 kg [0.46]; 40.3% increase from Baseline; P <0.0001). Improvements in metabolic markers (insulin, insulin resistance [HOMA-IR], leptin, and adiponectin) through Week 78 were significant (P <0.05) at all but 1 timepoint (HOMA-IR at Week 39; P = 0.0617).
Conclusions: Long-term administration of DCCR in participants with PWS was associated with statistically significant, clinically meaningful, and durable changes in hyperphagia, behavior measures, clinician/caregiver assessments, lean body mass, and metabolic markers.
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