Participant Characteristics

Between March and June 2021, 19 telephone interviews were conducted with patients (n = 8) and caregivers (n = 11). All patients except one were enrolled in the long-term extension study of setmelanotide at the time of their interview. Baseline weight and hunger were previously reported for all patients included in the phase 2 and 3 trial primary analyses [30, 33]. The average age of patient participants was 36 years, and the average age of patients whose caregivers were interviewed was 16 years. Most patient participants were female (n = 6; 75.0%) and all caregiver participants were female parents (i.e., the mother). The mean time since the first approximately 1-year clinical trial of setmelanotide was 29 (range 12–48) months for patient participants and 24 (range 8–40) months for patients whose caregivers were interviewed (Table 1). Exemplar quotes are from individual patients with BBS and caregivers of patients with BBS.

Table 1 Baseline patient characteristicsSymptoms and Behaviors Associated with HyperphagiaFeelings of Hunger and Pursuit/Consumption of Food

While all 19 participants described experiences of uncontrollable hunger that were consistent with hyperphagia, none spontaneously used the term “hyperphagia” (Table 2). All participants characterized hyperphagia as all-consuming and extreme, which caused an obsessive focus on and a relentless pursuit and consumption of food. Hyperphagia was continuous, with nearly half of participants (n = 9) reporting hunger that was intense throughout the day; the remaining participants reported hunger that varied in relation to the time of day. Caregivers indicated that hyperphagia prompted incessant food-seeking behaviors from patients including queries about the next meal or constantly wanting more food.

“I was always hungry. And if I didn’t eat when I needed to, I would be very unhappy. Couldn’t wait to eat.” —Patient

“She was hungry all the time, and it was a relentless hunger. She would eat everything on her plate and everything on my plate, and anything she could find.” —Caregiver

Table 2 Patient- and caregiver-reported experiences of hunger, eating habits, and effect of hyperphagia before treatment with setmelanotide in clinical trials

Patients were also asked to recall the highest level of hunger they experienced before starting the clinical trial using a numerical rating scale where 0 = “not hungry at all” and 10 = “the hungriest possible.” Pretreatment peak hunger ratings ranged from 8 to 10, and peak hunger was associated with physical and emotional manifestations including fatigue, pain, frustration, irritability, and a hyperfocus on obtaining food. When caregivers were asked what behaviors signified their child was experiencing the most intense level of hunger, they reported severe tantrums, irritability, and hyperfocus on obtaining food.

“If she didn’t get food, she was just a terror…. She’d have a fit, everything except for self-harming. That’s the only thing she didn’t do.” —Caregiver

While patients consistently reported some level of satisfaction after eating, many noted the sensation was short-lived, only achieved with a large meal, and resembled fullness or satiation rather than a feeling of positive emotional valence. Conversely, most caregivers (n = 9; 81.8%) reported that their child never seemed to be full or satisfied after eating.

Eating Habits and Engagement in Food-Seeking Behaviors

All participants reported that hyperphagia influenced what and/or how much was consumed (Table 2), with carbohydrates and/or sugary foods being the most sought during periods of extreme hunger. Further, most participants (15 of 19 overall [78.9%]; 5 of 8 patients [62.5%] and 10 of 11 caregivers [90.9%]) described a lack of control with eating, and caregivers frequently remarked that their child would not stop eating without outside influence (Table 2). Food-seeking behaviors were reported by most caregivers and included begging, bargaining, and/or attempting to bribe others for food. Although hiding and stealing food is considered a hyperphagic behavior [6, 21], only 25.0% of patients reported doing this, but more than half of caregivers (n = 6; 54.5%) reported observing these behaviors.

“I was eating pretty much whatever, whenever and wasn’t able to stop myself from eating or sneaking food in the middle of the night.” —Patient

“He would eat until he was physically hurting. And then in the same breath, tell us that he was hurting and asked for a snack or something to eat. He’d sneak food…. It seemed like he was just hungry all the time.” —Caregiver

Multifactorial Consequences of Hyperphagia on Patients and CaregiversEmotional Consequences of Hyperphagia

Participants were asked about the effects of hyperphagia experienced before beginning setmelanotide treatment. Overall, most patients (n = 7; 87.5%) and caregivers (n = 10; 90.9%) experienced negative effects directly related to hyperphagia; one patient and one caregiver attributed negative effects to increased weight instead. The most commonly reported effect pertained to patients’ emotional states (Table 2). Both patients and caregivers reported emotional effects of hyperphagia including sadness, frustration, irritability, anxiety, and guilt. These feelings often centered around food and were related to either the desire to eat (e.g., irritability, anxiety) or the patients’ inability to control their hunger or eating habits (e.g., frustration, guilt).

“I felt very agitated and very sad a lot of the time…. I just really didn’t have many friends, really even many friends to hang out with and…I don’t know. I just kind of felt alone in a sense.” —Patient

“I’d feel crappy and crabby because maybe I ate sweets and stuff I really shouldn’t have had but I wanted…. It made me mad after I ate it because I know I did want it, but then I thought, ‘Should I have really eaten that even though I really wanted it?’” —Patient

Impacts of Hyperphagia on Family Dynamics

Hyperphagia had broad negative impacts on family dynamics including impaired relationships with siblings and tensions between caregivers and patients (Table 2). For example, one caregiver described decreased interactions between siblings because the siblings “didn’t know how to handle” the consistent emotional distress of the patient. Caregivers also experienced strains on spousal and familial relationships due to regulation of food intake.

“It affected my relationship with my husband…he is a lot better at saying no than I am. And sometimes it would be so hard for me because he was just so black-and-white about it and would just say, ‘No, get out of the kitchen,’ and then I would feel bad and cry and be mad at him. I would think he was being mean to her when really, he was doing what was best for her.” —Caregiver

Caregivers experienced diminished emotional and psychological well-being due to their child’s hyperphagia, reporting feeling burdened by the need to constantly monitor eating behaviors, guilt related to their child’s health, and fear of judgment from others. For more than half of caregivers (n = 6; 54.5%), hyperphagia negatively impacted social participation because of required hypervigilance in situations involving food and reluctance to leave their child in the care of another individual.

“Yeah, we didn’t like to go places. And if you go to somebody’s house, trying to keep them away from the chips and dip is so hard, it’s easier to just not go.” —Caregiver

Productivity at Work and School

Participants reported impaired concentration and focus as a consequence of hyperphagia (2 of 8 patients [25.0%]; 8 of 11 caregivers [72.7%]). For children, this translated into challenges at school because of an obsessive focus on food.

“Looking back at it now, I think it affected his concentration a lot, especially at school. Before the trial, at school, he’d spend a lot of time out of the classroom. He’d be crying, he’d be upset about something. Most times, he wouldn’t be able to tell them why he was upset. And I just always think that it was because he was hungry. But of course, we didn’t know that at the time.” —Caregiver

A subset of caregivers (n = 2; 18.2%) also experienced reduced productivity and ability to complete tasks as a result of their child’s hyperphagic behaviors and the attendant need to plan and prepare meals.

Changes with Setmelanotide TreatmentImprovements in Hyperphagia, Food-Seeking Behaviors, and Weight with Setmelanotide Treatment

Table 3 shows the proportion of participants who reported improvements in hyperphagia and associated outcomes with setmelanotide treatment. All participants (N = 19) reported substantial improvements in hyperphagia and satiety within 2 months of initiating setmelanotide treatment. Decreases in peak hunger scores ranged from 2 to 6 points. Notably, a previous psychometric evaluation estimated that within-patient decreases in hunger score of 1–2 points are sufficient to yield improvements in clinical status and perceived meaningfulness of hunger reduction [30]. Similarly, caregivers consistently observed changes in food-seeking and eating behaviors.

“I feel great. I feel satisfied. I feel full when I’m done eating. Sometimes, I won’t eat everything that’s on my plate.” —Patient

“After we started this setmelanotide trial, she told me for the first time that she had no idea what it was not to be hungry. So that was really sad. So before the trial, I guess, according to her, she had never experienced not being hungry before….” —Caregiver

Table 3 Proportion of participants who reported improvements in hyperphagia and associated consequences with setmelanotide treatment

Consistent with improved hunger, all participants reported a large reduction in food consumption, greater control over how much food was consumed, and consumption of or requests for healthier foods (Table 4).

“I feel like I’ve had a lot more willpower since I’ve been on the medication, and I feel like I haven’t really been tempted to grab really anything during meals, which has felt good.” —Patient

Table 4 Patient- and caregiver-reported experiences of hunger, eating habits, and effect of hyperphagia during and after treatment with setmelanotide in clinical trials

Patients and caregivers also reported fewer hyperphagic behaviors (e.g., eating in secrecy, eating foods that others would find undesirable) after treatment initiation. None of the participants who reported these behaviors before setmelanotide (2 of 8 patients [25.0%] and 6 of 11 caregivers [54.5%]) experienced or observed them after initiating setmelanotide treatment. Additionally, all 11 caregivers noted the ability to give their child greater autonomy around food choices and consumption and a reduced need to monitor their child’s food intake.

“I’ll let her eat what she wants. I guess that’s the biggest deal is that. Do you want to eat more brussels sprouts? Eat more brussels sprouts because I know you’re not going to eat 10 servings of macaroni and cheese or a whole jar of peanut butter today.” —Caregiver

In addition to improvements in hyperphagia and related behaviors, all participants reported weight loss following setmelanotide treatment initiation. While patients self-reported an average weight loss of 52 pounds (range 25–130 pounds; n = 8), three reported regaining some weight, which they attributed to the coronavirus disease 2019 (COVID-19) pandemic (e.g., constant access to food, lack of physical activity). Caregivers reported that patients lost an average of 36 pounds (range 5–100 pounds; n = 11), which underestimates reductions in body mass index, because many noted that their child’s height had also increased (range 2–12 inches).

Emotional and Physical Impacts of Improved Hyperphagia in Patients and Caregivers

Most patients (n = 7; 87.5%) reported improvements in how they felt physically while receiving setmelanotide (e.g., had more energy, could be more active). Caregivers also observed physical improvements, frequently noting that their child was more readily able to participate in recreational activities and sports. Participants consistently reported significant improvements in patients’ moods or emotions with treatment; improvements in hunger led to decreased anxiety, stress, and irritability, as well as increased happiness, self-esteem, and confidence (Table 4). Caregivers also reported reduced stress, worry, and/or anxiety stemming from the need to monitor and control their child’s food intake after their child initiated setmelanotide treatment.

“It made me more positive and more peppy, my voice and thinking and wanting to be out more with people.” —Patient

Improvements in Family and Social Dynamics with Setmelanotide Treatment

Both patients (n = 4; 50.0%) and caregivers (n = 6; 54.5%) noted that improvements in hunger had benefited family dynamics including better sibling interactions, and some participants (2 of 8 patients [25.0%]; 3 of 11 caregivers [27.3%]) noted their (or their child’s) social life and friendships improved because of improved hunger (Table 3). Further, for some caregivers, reduced stress and worry led to improved family relationships, better sleep, and a more positive outlook.

“And he has friends this year. He’s never really had friends, probably because he was always crying…. So, yeah, he’s got some buddies this year.” —Caregiver

“Well, it’s just a lot easier because I don’t have to be the food police anymore…. It’s like everything in the house is more laid back instead of being on edge about food.” —Caregiver

Improvements in Concentration and Productivity at School and Home with Setmelanotide Treatment

All participants reported improved focus and concentration related to reductions in obsessive behaviors associated with food. A subset of participants (2 of 8 patients [25.0%]; 7 of 11 caregivers [63.6%]) noted that this increased ability to focus resulted in improved task performance at school or home (Table 3).

Perceived Meaningfulness and Overall Satisfaction with Treatment

Participants were asked to identify the most important changes attributable to improvements in their (or their child’s) hunger (open-ended question; Table 5). The most frequently reported changes (5 of 8 patients [62.5%]; 6 of 11 caregivers [54.5%]) were weight loss and associated health benefits (e.g., reduced blood pressure) and reduced obsessive focus on food (3 of 8 patients [37.5%]; 5 of 11 caregivers [45.5%]) and associated life impact. Patients and caregivers commonly described the improvements in hyperphagia as “very meaningful” and “life changing” (Table 6).

“Oh, totally meaningful. This is who he gets to be for the rest of his life. Somebody who’s conscious of what food does to your body and be healthy and not die young. This is everything.” —Caregiver

Table 5 Most important improvement to patients in clinical trials with setmelanotideTable 6 Patient- and caregiver-reported meaningfulness of improvements in hunger, overall satisfaction of treatment, and feelings if treatment were discontinued

All but one participant reported that they were “very satisfied” with setmelanotide (Table 6). Similar to perceived meaningfulness, participant satisfaction was attributed to improvements in hyperphagia and associated behavioral changes, as well as weight loss and associated health benefits. Participants also commonly reported feeling less worry about their (or their child’s) health in the future as a result of treatment. The patient who indicated being less than very satisfied with setmelanotide noted being satisfied with the improvement in hunger, but was disappointed with weight regain during the COVID-19 pandemic.

At the conclusion of each interview, participants were asked to describe how they would feel if patients could no longer take setmelanotide (Table 6). Patients commonly used the terms “very upset,” “disappointed,” and “distraught.” Caregivers used more dramatic language such as “terrifying,” “devastating,” and “a death sentence.”