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SAT-100 Trial-in-Progress: ZEPHYR, a Pivotal Phase 2b/3 Randomized, Placebo-Controlled Study of Livoletide, a Novel Unacylated Ghrelin Analog, for the Treatment of Hyperphagia and Food-Related Behaviors in Patients with Prader-Willi Syndrome

ABSTRACT: Abstract Background: Prader-Willi syndrome (PWS) is a rare and complex endocrine disease characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity and early mortality and to a significant burden on patients and caregivers. There is no approved treatment for hyperphagia in PWS. Patients with PWS have increased circulating levels of the orexigenic hormone acylated ghrelin (AG) with a relative deficit of unacylated ghrelin (UAG). Livoletide (AZP-531) is a first-in-class UAG analog that was previously shown in a Phase 2 randomized placebo-controlled study in a 47-patient PWS cohort to significantly improve hyperphagia, food related behaviors, and metabolic parameters and to be well-tolerated with no serious adverse events or treatment discontinuations over a 14-day period. [Allas S et al. (2018) PLoS ONE 13(1): e0190849] Objective: ZEPHYR (EudraCT 2018-003062-13) is a pivotal Phase 2b/3 study that is designed to evaluate the long-term safety and efficacy of livoletide in patients with PWS. Methods: The ZEPHYR study will be conducted in centers in North America and Europe. In its Phase 2b portion, approximately 150 patients with PWS will be randomized in a 1:1:1 ratio to receive livoletide low exposure (8 mg/mL), livoletide high exposure (16 mg/mL), or placebo, once a day by sc injection for a three-month core period. Then, patients who received placebo will cross over to livoletide low or high exposure and be treated for 9 months. Patients who received livoletide will continue at their original dose for an additional 9 months. The Phase 3 portion will be initiated following results of the Phase 2b core period with patients randomized 1:1 to livoletide at a dose based on Phase 2b core data or to placebo for a six-month duration. Subsequently, patients who received placebo will be crossed over to livoletide for six months, while patients on livoletide initially will continue for six more months. Main entry criteria for ZEPHYR include genetic diagnosis of PWS, age 8-65 years, single primary caregiver available for the duration of the study, BMI ?65 kg/m2 for adult patients. Patients with type 2 diabetes with HbA1C ?10% and stable therapy may be enrolled. Use of human growth hormone will be allowed if dosage is stable. Patients enrolled in Phase 2b will not be eligible for Phase 3. The primary outcome measure is the Hyperphagia Questionnaire-Clinical Trials (HQ-CT) score. The HQ-CT has been validated and is considered by regulatory authorities as a valid primary endpoint. Secondary outcome measures include fat mass as assessed by DEXA, BMI, and body weight in overweight/obese patients. Results: The study is ongoing: enrollment began in early 2019 and an updated status will be reported. Conclusion: ZEPHYR is a pivotal study that will provide data on the long-term safety and efficacy on hyperphagia and food-related behaviors of the novel UAG analog livoletide in patients with PWS.

SUBMITTER: Allas S

PROVIDER: S-EPMC6552513 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS:Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS:Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ? 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION:I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Project description:ObjectivesPrader-Willi syndrome (PWS) is a rare genetic disorder characterized by maladaptive behaviors, amongst which hyperphagia is a life-long concern for individuals with PWS and their caregivers. The current study examined the contribution of hyperphagia and other factors to caregiver burden across lifespan, in 204 caregivers of individuals with PWS living in the US, using the Zarit Burden Interview (ZBI) and the hyperphagia questionnaire (HQ-CT).ResultsWe found a strong relationship between ZBI and HQ-CT especially in individuals with PWS older than 4 y and showed that HQ-CT scores of individuals with PWS is positively correlated with ZBI scores of their caregivers. The weight status of individuals with PWS was not associated with HQ-CT and ZBI scores, except for obese individuals who had significantly higher HQ-CT scores when compared to normal weight PWS individuals. We looked at PWS symptoms and care-related issues that impacted individuals and caregivers the most. We found that care-related tasks had the biggest negative impact on caregivers of children aged 0-4 y, whereas anxiety, temper tantrums, and oppositional behaviors of older individuals with PWS had the biggest impact on their caregivers concomitant with their high caregiver burden. Finally, we assessed the variability of HQ-CT and ZBI over 6 months in a subgroup of 83 participants. Overall, neither measure differed between 6 months and baseline. Most individual's absolute HQ-CT score changes were between 0-2 units, whereas absolute ZBI score changes were between 0-6 points. Changes in the caregiver's or individual's life had little or no effect on HQ-CT and ZBI scores.ConclusionsThis study demonstrates a relationship between hyperphagia and caregiver burden and sheds light on predominant symptoms in children and adolescents that likely underly PWS caregiver burden. The stability and relationship between HQ-CT and ZBI support ZBI as an additional outcome measure in PWS clinical trials.

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SAT-100 Trial-in-Progress: ZEPHYR, a Pivotal Phase 2b/3 Randomized, Placebo-Controlled Study of Livoletide, a Novel Unacylated Ghrelin Analog, for the Treatment of Hyperphagia and Food-Related Behaviors in Patients with Prader-Willi Syndrome

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