Quality of life outcomes in two phase 3 trials of setmelanotide in patients with obesity due to LEPR or POMC deficiency

Abstract

Introduction Individuals with proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency are young and experience severe obesity, hyperphagia, and comorbidities, which can impair quality of life (QOL). Methods Two pivotal Phase 3 trials explored the effect of setmelanotide on body weight and hunger in individuals with obesity due to POMC (NCT02896192) or LEPR (NCT03287960) deficiency. QOL and depression were investigated in parallel using the disease-specific, age-appropriate Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Pediatric Quality of Life Inventory (PedsQL), and Patient Health Questionnaire-9 (PHQ-9). Results In total, the POMC and LEPR trials enrolled 21 patients. Adults (≥ 18 years old; n = 7) had moderate-to-severe impairment in QOL at baseline, with mean (standard deviation [SD]) IWQOL-Lite total score 60.3 (13.2; maximum IWQOL-Lite total score = 100). The effect of setmelanotide on IWQOL-Lite total score was observed as soon as Week 5. Among those with scores at Week 52, 5 of 6 adults experienced a clinically meaningful improvement, with mean (SD) total scores increased from baseline by 24.2 (12.1) points. Children (6–12 years old; n = 2) and adolescents (13–17 years old; n = 4) had impaired QOL at baseline, with mean (SD) self-reported PedsQL total scores 53.3 (6.2) and 63.3 (29.1), respectively (maximum PedsQL total score = 100). Three of 5 patients experienced clinically meaningful improvement in PedsQL, with 2 children whose PedsQL total score increased by 28.3 and 3.3 points and 3 adolescents whose mean (SD) total score increased from baseline by 5.8 (18.3) points. Baseline mean (SD) PHQ-9 score (in those ≥ 12 years old) was 5.3 (3.8) and was generally maintained through Week 52. Conclusions Patients with POMC or LEPR deficiency had impaired, and in some cases severely impaired, QOL before setmelanotide treatment. Setmelanotide improved QOL in patients as early as Week 5, with some patients no longer experiencing impaired QOL at Week 52. Improvements in QOL may be related to a reduction in hunger and body weight associated with setmelanotide. Because of the highly complex psychological consequences of rare genetic diseases of obesity, some patients may require a long period of treatment to improve QOL and benefit from interdisciplinary care.

Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet–Biedl syndrome: phase 3 trial results

“…In this population, 60% of patients reported clinical impairment in HRQOL at baseline. The HRQOL deficits reported at baseline in patients with BBS were similar to those reported by patients with POMC, PCSK1, or LEPR deficiency [31]. Compared with HRQOL reported in clinical trials of the glucagon-like peptide 1 receptor agonist semaglutide in patients with general obesity, patients with BBS reported comparable or worse baseline HRQOL than those with general obesity [42].…”

“…Similar impacts of setmelanotide treatment on HRQOL and hyperphagia burden have also been reported in pediatric and adult patients with other rare genetic diseases of obesity, including POMC and LEPR deficiency, highlighting the clinical utility of setmelanotide for HRQOL in patients with rare genetic diseases of obesity. [31,33] 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.…”

“…Similar impacts of setmelanotide treatment on HRQOL and hyperphagia burden have also been reported in pediatric and adult patients with other rare genetic diseases of obesity, including POMC and LEPR deficiency, highlighting the clinical utility of setmelanotide for HRQOL in patients with rare genetic diseases of obesity. [ 31 , 33 ]…”

“…One study in caregivers of patients with BBS found that obesity stigmatization is common in this population, similar to stigmatization experienced by patients with general obesity [ 22 , 30 ]. In patients with other rare genetic diseases of obesity, such as POMC, proprotein convertase subtilisin/kexin type 1 (PCSK1), or LEPR deficiency, notable impairments in quality of life have been reported [ 31 ]. Hyperphagia can also contribute to impaired quality of life.…”

Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity

“…Three out of five participants reported improvements in PedsQL scores at week 52 that were considered clinically meaningful. Of these 5 children and adolescents, 3 also reported improvements in physical functioning scores and 4 reported improvements in psychosocial health scores, which are secondary analyses of the PedsQL [ 20 ].…”