A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome

Autoři: Virginia Kimonis aff001;  Abhilasha Surampalli aff001;  Marie Wencel aff001;  June-Anne Gold aff001;  Neil M. Cowen aff003
Působiště autorů: Division of Genetics and Genomic Medicine, Department of Pediatrics, Univ. of California-Irvine School of Medicine, Orange, California, United States of America aff001;  Department of Pediatrics, Loma Linda University Medical School, Loma Linda, California, United States of America aff002;  Soleno Therapeutics, Redwood City, California, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221615



Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS.


This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period.


Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide.


DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.

Klíčová slova:

Adipose tissue – Adverse events – Drug therapy – Cholesterol – Neurons – Prader-Willi syndrome – Diazo compounds


1. McCandless SE, and the Committee on Genetics American Academy of Pediatrics. Clinical Report-Health supervision for children with Prader-Willi syndrome. Pediatrics 2011; 127:195–204. doi: 10.1542/peds.2010-2820 21187304

2. Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, et al Nutritional Phases in Prader–Willi Syndrome. Am J Med Genet A. 2011; 155A(5):1040–1049. doi: 10.1002/ajmg.a.33951 21465655

3. Hedgeman E, Ulrichsen SP, Carter S, Kreher NC, Malobisky KP, Braun MM, et al. Long-term health outcomes in patients with Prader-Willi Syndrome: a nationwide cohort study in Denmark. Int J Obes 2017; 41(10):1531–1538.

4. Strong T. PWS Patient Voices. Foundation for Prader-Willi Research 2014. https://www.fpwr.org/wpcontent/uploads/2014/04/PatientVoices_presentationWebinarFinal.pdf

5. Baver SB, Hope K, Lindsley SR, Kirigiti MA, Smith MS, Cowley MA, et al. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J Neurosci 2014;34(6):5486–5496.

6. Baquero AF, de Solis AJ, Lindsley SR, Kirigiti MA, Smith MS, Cowley MA, et al. 2014. Developmental switch of leptin signaling in arcuate nucleus neurons. J Neurosci 2014;34(30): 9982–9994. doi: 10.1523/JNEUROSCI.0933-14.2014 25057200

7. Spanswick D, Smith MA. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 1997; 390: 521–525. doi: 10.1038/37379 9394003

8. Van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 2004; 7(5): 493–494. doi: 10.1038/nn1226 15097991

9. Kishore P, Boucal L, Boucal L. Zhang K, Li W, Koppaka S, et al. Activation of KATP channels suppresses glucose production in humans. J Clin Invest 2011; 121(12): 4916–4920. doi: 10.1172/JCI58035 22056385

10. Ruud J, Steculorum SM, Brȕning JC. Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nature Commun 2017; 8: 15259.

11. Bruinstroop E, Pei L, Ackermans MT, Foppen E, Borgers AJ, Kwakkel J, et al. Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL-triglyceride secretion in rats via the sympathetic nervous system. Diabetes 2012; 61: 1043–1050. doi: 10.2337/db11-1142 22461566

12. Taher J, Farr S, Adeli K. Central nervous system regulation of hepatic lipid and lipoprotein metabolism. Curr Opin Lipidol 2017; 28(1): 32–38 27906714

13. Dykens EM., Maxwell MA, Pantino E, Kossler R, Roof E. Assessment of hyperphagia in Prader-Willi syndrome. Obesity. 2007; 15: 1816–1826. doi: 10.1038/oby.2007.216 17636101

14. Butler MG, Kimonis V, Dykens E, Gold JA, Miller JA, Tamura R, Driscoll DJ. Prader-Willi syndrome and early-onset morbid obesity NIH rare disease consortium: A review of natural history study. Am J Med Genet A 2018; 176(2):368–375. doi: 10.1002/ajmg.a.38582 29271568

15. Mtaweh H, Tuira L, Floh AA, Parshuram CS. Indirect calorimetry: History, technology and application. Front Pediatr 2018; 6:257. doi: 10.3389/fped.2018.00257 30283765

16. Touati G, Poggi-Travert F, Ogier de Baulny H, Rahier J, Brunelle F, Nihoul-Fekete C, et al. Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr 1998; 157(8): 628–633. doi: 10.1007/s004310050900 9727845

17. Gill GV, Rauf O, MacFarlane IA. Diazoxide treatment for insulinoma: a national UK survey. Postgrad Med J 1997; 73: 640–641. doi: 10.1136/pgmj.73.864.640 9497974

18. Welters A, Lerch C, Kummer S, Marquard J, Salgin B, Mayatepek E, et al. Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers. Orphanet J Rare Dis 2015; 10: 150. doi: 10.1186/s13023-015-0367-x 26608306

19. Mariot P, Gilon P, Nenquin M, Henquin JC. Tolbutamide and diazoxide influence insulin secretion by changing the concentration but not the action of cytoplasmic Ca2+ in beta-cells. Diabetes 1998; 47(3): 365–373. doi: 10.2337/diabetes.47.3.365 9519741

20. Lucignani G, Panzacchi A, Bosio L, Moresco RM, Ravasi L, Coppa I, et al. GABAA receptor abnormalities in Prader-Willi syndrome assessed with positron emission tomography and [11C] flumazenil. Neuroimage 2004; 22(1): 22–28. doi: 10.1016/j.neuroimage.2003.10.050 15109994

21. Rice LJ, Lagapoulos J, Brammer M, Einfeld SL. Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome. Am J Med Genet Part B 2016; 171(8): 1041–1048. doi: 10.1002/ajmg.b.32472 27338833

22. Watts AE, Hicks GA, Henderson G. Putative pre- and postsynaptic ATP-sensitive potassium channels in the rat substantia nigra in vitro. J Neurosci 1995; 15(4):3065–3074. 7722645

23. Tricarico D, Mele A, Camerino GM, Bottinelli R, Brocca L, Frigeri A, et al. The KATP channel is a molecular sensor of atrophy in skeletal muscle. J Physiol 2010; 588(5): 773–784.

24. Farahini H, Habibey R, Ajami M, Davoodi SH, Azad N, Soleimani M, et al. Late anti-apoptotic effect of KATP channel opening in skeletal muscle. Clin Exp Pharmacol Physiol 2012; 39(11): 909–916. doi: 10.1111/1440-1681.12015 23046319

25. McCandless SE, Yanovski JA, Miller J, Fu C, Bird LM, Salehi P, et al. Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2017; 19(12): 1751–1761. doi: 10.1111/dom.13021 28556449

26. Allas S, Caixàs A, Poitou C, Coupaye M, Thuilleaux D, Lorenzini F, et al. AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized, placebo-controlled trial. PlosONE 2018; 13(1): e0190849.

27. Rice LJ, Einfeld SL, Hu N, Carter CS. A review of clinical trials of oxytocin in Prader-Willi syndrome. Curr Opin Psychiatry 2018; 31(2): 123–127. doi: 10.1097/YCO.0000000000000391 29206687

28. Dykens EM, Miller J, Angulo M, Roof E, Reidy M, Hatoum HT, et al. Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome. JCI Insight 2018; 3(12) pii: 98333. doi: 10.1172/jci.insight.98333 29925684

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