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Novel therapies offer optimism in the treatment of Prader-Willi syndrome
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Prader-Willi syndrome is a complex neurodevelopmental disorder caused by the lack of paternally derived genetic material in the chromosome region 15q11-13. This rare disorder is characterized by many endocrinopathies, as well as intellectual disability and a distinctive behavioral phenotype, all of which present lifelong challenges for affected individuals. The defining feature of Prader-Willi syndrome is hyperphagia, typically presenting in early to middle childhood. The overwhelming drive to eat, coupled with reduced energy expenditure and decreased caloric requirements, leads to morbid obesity unless food intake is strictly controlled.
Need for hyperphagia therapies
Current standard of care for Prader-Willi syndrome (PWS) includes beginning growth hormone therapy as soon as possible after diagnosis, initiating physical, occupational and speech/feeding therapy in early infancy, and proactively pursuing the evaluation and treatment of sleep-related breathing abnormalities. GH therapy, the only FDA-approved treatment specifically for PWS, provides many important benefits for patients, such as normalized linear growth during childhood, improved body composition and increased stamina.
Theresa Strong
Jennifer Miller
However, GH therapy does not ameliorate PWS-associated hyperphagia. Indeed, hyperphagia is the major concern for individuals with PWS and their families, and the inability to control food intake severely restricts the individuals’ opportunities for employment, social engagement and independent living. In addition, the behavioral issues associated with food restriction and the need for constant vigilance are a tremendous stress on parents and caregivers, and a source of frustration for the person with PWS.
To date, no drugs have proved effective in controlling appetite and weight gain in PWS, and the biological mechanisms underlying hyperphagia remain poorly understood. Despite these difficulties, there are reasons to be hopeful. Many antiobesity drugs and devices currently in clinical development, or recently approved, have the potential to offer new therapeutic options for those with PWS.
Research, pipeline drugs
Against this backdrop, the Foundation for Prader-Willi Research (FPWR) held its annual meeting in Garden City, N.Y., in November. The conference highlighted research advances and upcoming clinical trials, and included a discussion of disease impact and unmet medical needs from the family member/caregiver perspective. Notable research advances include newly developed tools, such as induced pluripotent stem (iPS) cells from patients with PWS, which are providing opportunities to dissect the genetics of PWS and identify disruptions in cellular pathways. As work continues to elucidate how loss of the PWS critical region leads to the broad phenotype that characterizes the disorder, clinical studies are moving ahead to evaluate novel therapeutics for PWS.
Several medications will be in clinical trials for PWS in 2015, including beloranib (Zafgen), RM-493 (Rhythm), diazoxide (Essentialis), AZP-531 (Alizé), intranasal oxytocin, and an oxytocin analog (Ferring). Each of these agents has a different target, ranging from affecting fat metabolism to directly targeting the hypothalamic pathways of appetite and satiety. Additionally, several recently approved drugs could potentially improve satiety or help to ameliorate obesity in individuals with PWS, including exenatide (Byetta, AstraZeneca), lorcaserin (Belviq, Eisai), naltrexone/bupropion (Contrave, Takeda) and phentermine/topiramate (Qsymia, Vivus). To date, none of these has been examined in long-term clinical trials for this population. Some devices in testing also may improve appetite and behavior in individuals with PWS, including transcranial direct magnetic stimulation and vagal nerve stimulators.
Study challenges
Clinical trials in PWS present many unique challenges, including population size, cognitive and behavioral issues, concomitant use of medications and study endpoints. PWS is a rare disease with a reported prevalence of approximately 1 in 20,000, and, thus, the number of possible study participants is limited. As well, endocrinologists with expertise in conducting clinical trials in PWS are not common, since very few clinical trials have been conducted in recent years.
Individuals with PWS typically have some degree of intellectual disability and frequently exhibit high levels of anxiety and challenging behaviors. Thus, the travel requirements and disruptions of routine that typify many clinical trials can be overwhelming at times, and successful completion of study protocols requires dedicated caregivers and an experienced study staff. Because adolescents and adults with PWS can be on a number of drugs to control behavior, psychiatric illness and complications of obesity, clinical trials in this population must tolerate concomitant drug use where possible. Finally, defining clinical endpoints that accurately and sensitively assess changes in appetite, food-related behaviors and food intake is a challenge shared across those clinical trials targeting hyperphagia as a study endpoint. However, the many challenges of performing trials in this population are balanced by the tremendous unmet medical need, the complete lack of therapies to control hyperphagia in PWS, and a patient community that is strong, socially connected and highly motivated to learn about and participate in clinical studies.
Benefits beyond PWS
The benefits of clinical trials in PWS will likely extend well beyond the initial study population. Carefully planned trials with correlative studies have the potential to provide insights into the mechanisms driving hyperphagia and obesity in PWS, perhaps providing a new understanding of obesity in the general population. Finally, these therapies have the potential to be life-altering with respect to both improved health and enhanced quality of life for all individuals with PWS and their families.
We welcome the new year with the expectation that 2015 will bring a plethora of data to advance the understanding and treatment of PWS, and the hope that the outcome of these studies will allow those with PWS and their families to lead healthier and happier lives.
For more information:
- Deal CL. J Clin Endocrin Metab. 2013;98:E1072-87.
- Goldstone AP. J Clin Endocrinol Metab. 2008;93:4183-4197.
- McCandless SE. Pediatrics. 2011;127:195-204.
- Theresa Strong, PhD, chair of the Scientific Advisory Board for the Foundation for Prader-Willi Research (FPWR) and professor of medicine at the University of Alabama at Birmingham, can be reached at theresa.strong@fpwr.org.
- Jennifer Miller, MD, associate professor in the Division of Endocrinology, Department of Pediatrics at the University of Florida, can be reached at millejl@ufl.edu.
Disclosures:
- Strong and Miller do not have any relevant financial disclosures.