Discussion
Obesity, obesity, hyperphagia, cognitive impairment, BBS, weight loss or hunger, weight loss
OBESITY, OBESITY, DISEASE, CHRONIC DISEASE
Obesity itself can impose a substantial physical and psychosocial burden for patients and their families [Variability was also observed in baseline HRQOL across patients, as well as in which patients experienced impairment based on different assessments. It is known that response shifting can occur in patients living with chronic disease, where patient perceptions of health shift to cope with their situation [This is the first Phase 3 trial to evaluate the impact of setmelanotide treatment on HRQOL in patients with BBS. Most patients with impaired HRQOL at active treatment baseline reported clinically meaningful improvements in HRQOL after 52 weeks of setmelanotide treatment. Improvements were seen in total PedsQL and IWQOL-Lite scores, along with domain scores including psychosocial and physical functioning. Among patients without impaired HRQOL at baseline, most either preserved or improved their status. It is challenging to determine a direct connection between weight loss and HRQOL, particularly in pediatric patients where HRQOL is assessed by PedsQL, which is not specific to obesity-related measurements of HRQOL. A potential link is supported by these data and a separate sub-study, which conducted qualitative interviews following this trial, demonstrating dramatic qualitative improvements in hyperphagia and quality of life reported by patients with BBS and caregivers [While the current study did not show significant correlations between quantitative measures of hunger and PedsQL, these qualitative examples of patient experience further support the utility of setmelanotide treatment. Further, ≥ 40% improvement in hunger scores were observed in adult and pediatric patients without cognitive impairment in this study. Results in patients with BBS without cognitive impairment in this study highlight that the benefits of obesity management strategies may extend beyond weight and encompass hunger and HRQOL. A more thorough understanding of the link between HRQOL and weight loss or hunger is needed in this population.A limitation of this study is the small sample sizes across some of the assessments, which may in part be due to the rarity of the disease. Although improvements in IWQOL-Lite were correlated with BMI reductions in adults, the small sample sizes should be considered when interpreting these results. Similarly, while no significant correlations were observed between weight or hunger outcomes and HRQOL in pediatric and adolescent patients, this finding may be attributed to the limited overall sample size. Further investigation is needed to determine potential correlations between weight or hunger outcomes and HRQOL in pediatric and adolescent patients. Another limitation is the subjective nature of hunger scoring; however, there is currently no validated hyperphagia measurement for patients with BBS.