FormalPara Key Summary Points

Pro-opiomelanocortin (POMC) and leptin receptor (LEPR) deficiencies are rare genetic diseases of obesity that are associated with insatiable hunger, which places tremendous burdens on both patients and caretakers; these burdens are not well characterized.

We conducted in-depth interviews in a cohort of patients with POMC and LEPR deficiencies who received treatment with setmelanotide and found a decrease in the daily burdens of insatiable hunger that had meaningful impacts on the patients’ health-related quality of life.

Results from this qualitative study are consistent with those reported in phase 3 trials of setmelanotide and suggest that the impacts of setmelanotide treatment also include patients’ health-related quality of life improvements.

Introduction

Obesity is a multifactorial disease with detrimental impacts on long-term health, given its associations with increased mortality and morbidity, distress related to social stigma, and subsequent impact on health-related quality of life (HRQOL) [1,2,3,4,5,6,7]. Individuals classified as having severe obesity (body mass index ≥ 35 kg/m2) and those with or without chronic comorbidities (e.g., diabetes mellitus, hypertension, and coronary heart disease) have reported decreased HRQOL associated with obesity [2, 5,6,7]. In adults and children, obesity is commonly related to psychological complications that can impact daily living such as anxiety, depression, and low self-esteem [3, 8, 9].

Genetics can play a role in the development of obesity, as exemplified by rare genetic diseases of obesity [10,11,12]. Many of these diseases present with mutations in genes that function in the melanocortin receptor 4 (MC4R) pathway, a hypothalamic pathway regulating hunger and energy balance [11,12,13]. Deficiencies in key genes in the MC4R pathway, including pro-opiomelanocortin (POMC) and leptin receptor (LEPR), can disrupt MC4R signaling, which often results in insatiable hunger, known as hyperphagia, and early-onset severe obesity [11,12,13].

In two open-label phase 3 clinical trials (NCT02896192 and NCT03287960), the MC4R agonist setmelanotide demonstrated significant reductions in body weight and hunger scores, along with general improvements in cardiometabolic parameters [14]. Patients with obesity due to POMC (n = 9) or LEPR (n = 11) deficiency received setmelanotide treatment for 52 weeks (including 4 weeks of placebo); 80% of patients in the POMC trial and 45% in the LEPR trial had at least 10% weight loss after approximately 1 year [14]. Additionally, 43% of patients in the POMC trial and 86% in the LEPR trial achieved at least 25% reduction in peak hunger score [14]. From the results of these clinical trials, setmelanotide was approved by the US Food and Drug Administration in November 2020 for the treatment of patients at least 6 years of age with POMC, LEPR, or proprotein convertase subtilisin/kexin type 1 deficiency [15].

While significant changes in weight and hunger were observed, the clinical trial data may not fully provide information on the potential impact of setmelanotide, especially the patient experience of hyperphagia and beneficial effects on HRQOL. In patients with POMC or LEPR deficiency, managing hyperphagia can be a daily struggle, placing extreme psychological burden on the patients, their family members, and their caretakers [16]. Because POMC and LEPR deficiencies are rare diseases, this burden and the impact on HRQOL are under-recognized and not well characterized in the literature [16].

Here, we conducted in-depth qualitative interviews with patients with POMC and LEPR deficiencies who participated in phase 3 clinical trials of setmelanotide and enrolled in the ongoing open-label extension of these trials (NCT03651765). This qualitative research was conducted as a substudy of this open-label extension in collaboration with two clinical sites in Germany; the primary objectives were to understand the hyperphagia and eating patterns among patients with POMC and LEPR deficiencies and characterize changes experienced by these patients following treatment with setmelanotide as they relate to HRQOL.

Methods

Patients who were enrolled in phase 3 clinical trials of setmelanotide treatment for POMC or LEPR deficiencies at two clinical sites in Germany were eligible to undergo in-depth qualitative interviews conducted using (Zoom Video Communications, Inc.) from January 29 to February 16, 2021. Additional patient eligibility criteria included age 15 years or older, previous diagnosis of POMC or LEPR deficiencies, participation in the open-label extension study (NCT03651765), and informed consent (i.e., willingness and ability to participate in a 1-h, audio-recorded interview) being given. Patients were contacted via email to schedule the interviews. Interviews were conducted in German. Interviews followed a semistructured interview guide; while there was no separate pilot testing, the guide was modified following the first few interviews to improve flow (see Appendix A and Appendix B in the electronic supplementary material). During the interview, patients were asked to describe their experience of hunger, as well as the impacts of hunger on their lives prior to setmelanotide treatment. Subsequently, patients were also asked to describe changes in hunger, weight, and functioning after initiating setmelanotide treatment, including the perceived meaningfulness of the changes. Last, patients described their satisfaction with setmelanotide and how they would feel if they had to discontinue therapy. Each interview was audio recorded, transcribed, and translated into English for analysis. Conventional conceptual content analysis methods were used to analyze the translated transcripts. Given the small sample size and goals of the interviews, data saturation was not discussed.

In compliance with the International Council on Harmonisation for Good Clinical Practice, all patients provided informed consent for data to be presented in aggregate and anonymously. Given that POMC and LEPR deficiencies are rare genetic diseases, the qualitative data are presented here with limited identifying information to preserve patient confidentiality. Accordingly, we present categorical data focusing on three main topics: the patient experience of hunger prior to setmelanotide use, changes in hunger and hunger-related impacts noted by patients with setmelanotide treatment, and overall patient satisfaction with treatment. These three main research themes were identified in advance of the interviews.

This study was conducted in accordance with ethical principles founded in the Declaration of Helsinki. The institutional review board (IRB)/independent ethics committee (IEC) reviewed and approved all appropriate study documentation. Interview guides were reviewed by MW and PK and approved by the Ethics Commission Berlin (LAGeSo EK Berlin).

Results

Patient Characteristics

In the open-label extension of the phase 3 setmelanotide clinical trials (NCT03651765), there were a total of 10 patients with POMC (n = 7) or LEPR (n = 3) deficiency enrolled at two clinical sites in Germany. This substudy cohort consisted of five of these patients with POMC (n = 3) or LEPR (n = 2) deficiency who met eligibility criteria and gave informed consent to participate in these interviews. The average age was 23.8 years (range, 15–33 years), and four of the five patients were male. One patient was hearing impaired, and the interview was facilitated by the mother, who responded to interview questions on behalf of the patient.

Patient Experience Prior to Setmelanotide Treatment

Feelings of Hunger

Patients were asked to describe their hunger before participating in their first clinical trial of setmelanotide, which was typically 3–4 years prior to the interview. Given the elapsed time since initiating treatment, it was difficult for some patients to remember details such as the magnitude of variations in their hunger; however, all five patients were able to characterize the general nature of their hunger. All five patients described abnormal sensations of hunger; two patients described the sensation as a strong psychological desire, much like addiction (Table 1 and Fig. 1). Despite clearly describing hyperphagia when relaying their experiences with hunger, none of the patients were familiar with the term.

Table 1 Patient-reported experiences of hunger, eating habits, and impact of hyperphagia prior to clinical trials with setmelanotide
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Fig. 1
figure 1

Number of patients with POMC (n = 3) or LEPR (n = 2) deficiency who experienced hyperphagia and related impacts on health-related quality of life (a) before and (b) after treatment with setmelanotide. LEPR leptin receptor, POMC pro-opiomelanocortin

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While most patients described hunger as always or nearly always present, one patient with LEPR deficiency described extended periods with no hunger or desire for food. Another patient with POMC deficiency reported variations in hunger related to environment and activities, indicating that hunger was less noticeable while being out of the house and “distracted.” Two patients indicated that the absence of hunger was relatively unusual and short lived, and one patient with POMC deficiency indicated they were never without a feeling of hunger before starting treatment. All five patients described strong feelings of hunger in relation to their preferred foods, which generally included sweets and highly processed carbohydrates.

Patients easily reported the nature of their hunger before starting treatment; however, two patients expressed difficulty in precisely recalling and rating the average intensity. When asked to score their average pretreatment hunger on a numerical rating scale ranging from 0 to 10, all five patients reported scores ranging from 7 to 9. Four patients scored their maximum hunger as a 10 on the scale, while the remaining patient with POMC deficiency had difficulty recalling maximum hunger and did not provide a score.

Eating Habits

The primary focus of the interview was on hunger experienced by patients; however, each described their eating habits. Common habits among patients were eating in secrecy, eating quickly, eating large amounts of food, and feeling a lack of control, particularly in relation to desired foods (Table 1). When asked if they felt full or satisfied after eating, no patients described a clear, unequivocal feeling of satiety (Fig. 1). Instead, patients either assumed they felt full, given they stopped eating at some point, or reported no recollection of feelings of fullness. When patients reported some level of satisfaction after eating, this feeling was generally short-lived.

Impacts of Hyperphagia on HRQOL

Beyond the impact of hyperphagia on weight, all five patients reported additional psychological, social, and health-related consequences impacting their HRQOL. Every patient reported negative emotions stemming from their inability to control their desire for food, including guilt, frustration, sadness, and even feelings of failure (Table 1). Additionally, when asked to share what bothered them the most about their hunger before starting treatment, patients commonly cited the emotional struggle with hunger and the inability to control the urge to eat.

Social and health-related consequences of hyperphagia influenced both family dynamics and work/school performance. While most of the patients in this cohort are now adults living independently, all five reported impacts on their families, particularly their mothers. Arguments and strains in these relationships often stemmed from the need for parents to monitor and limit food intake. One patient with LEPR deficiency reported a particularly traumatic experience of being removed from their childhood home at age 4; health care professionals believed the problem was due to the mother purposefully overfeeding the patient rather than a condition the patient had.

Four of the five patients reported difficulties with work and/or school. While some issues related specifically to hunger (i.e., attempts to control hunger or obtain food), others pertained directly to being overweight and associated health problems. In describing difficulties at school, one patient with LEPR deficiency mentioned difficulty walking at their heaviest weight and how severe joint pain prevented them from standing or attending recess. This same patient also described how continual hospital visits prevented them from maintaining employment later in life (Table 1).

Changes with Setmelanotide Treatment Noted by Patients

Reduction and Maintenance of Weight

All five patients experienced considerable weight loss following treatment with setmelanotide (average, 47.4 kg; range, 25–97 kg). Four of the five patients indicated it was very easy to maintain their weight loss with setmelanotide. The remaining patient with LEPR deficiency had initially maintained weight loss, but during the COVID-19 pandemic regained between approximately 10 and 13 kg.

Feelings of Hunger

All five patients reported notable changes in their hunger following treatment with setmelanotide, including a decrease in the intensity as well as the frequency and duration of their hunger (Table 2). Despite the approximately 3–4 years that elapsed since patients were first treated with setmelanotide, four of five patients said they noticed changes very quickly; the remaining patient with POMC deficiency reported that it took several months of raising the dose before noticing a reduction in hunger.

Table 2 Patient-reported experiences of hunger, eating habits, and impact of hyperphagia during and after clinical trials with setmelanotide
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Additionally, all five patients reported a decrease in average hunger scores after setmelanotide treatment. Specifically, scores of average hunger ranged from 2 to 7 after treatment, whereas pretreatment average scores ranged from 7 to 9. Similarly, scores of peak hunger ranged from 5 to 9 after treatment, down from 10 before treatment. While two of five patients had difficulty recalling the exact intensity of their peak pretreatment or posttreatment hunger and did not provide a score, their qualitative descriptions of hunger after treatment were consistent with the decreased numerical rating scale scores of hunger reported.

Eating Habits

Consistent with the reductions in their hunger, all five patients reported eating far less than before starting treatment with setmelanotide, both in terms of eating frequency and food quantity (Table 2). All five patients also reported feeling satiated after eating something substantial (e.g., a meal) on most occasions (Fig. 1). Last, all five patients said they are now more likely to desire healthier foods, a meaningful improvement compared with their incessant cravings for sweets and other processed carbohydrates before setmelanotide treatment. Patients who still enjoyed their favored pretreatment foods were able to do so in moderation.

Impacts of Reduced Hyperphagia on HRQOL

All five patients reported considerable improvements in each area of functioning they had previously reported as impaired because of their hunger (Table 2; Fig. 1). With reductions in their hunger and consequently their weight, all five patients also reported emotional improvements. In addition to improvements in their mood, patients described feeling more confident and self-assured, as well as feeling relieved that they no longer struggled to control their hunger-related impulses. Additionally, all five patients stated they are more physically active than they were prior to setmelanotide treatment and the subsequent weight loss, commonly noting enjoyment of exercise and/or increased energy.

Reduction of hyperphagia with setmelanotide treatment improved both family dynamics and work/school performance (Table 2 and Fig. 1). As mentioned previously, all five patients reported pretreatment negative impacts of their hunger on family members, mostly stemming from the need for parents to monitor and limit their food intake. While the essential nature of these relationships had not changed, four of five patients reported improvements pertinent to their family members. The remaining patient with LEPR deficiency had been living alone for some time, but described the relationship and interactions with their parents as consistently positive between the time before treatment and the time of the interview.

Two patients described substantial improvements in their ability to work or perform tasks in school following treatment with setmelanotide. One patient with POMC deficiency attributed their success in college to the medication, while the other patient with LEPR deficiency described being able to work a steady job for the first time in their life. Two additional patients described feeling more included and able to do activities similar to their peers at school. The remaining patient with POMC deficiency indicated having some current work-life difficulties; however, these were not attributed to the medication but rather mental fatigue of an unknown origin (Fig. 1).

Perceived Meaningfulness and Overall Patient Satisfaction with Treatment

All five patients consistently and unequivocally indicated that the improvements in their hunger and subsequent weight loss were very meaningful to them (Table 3). Additionally, all five patients indicated that they were very satisfied with setmelanotide treatment, commonly focusing on their weight loss, as well as the prevention of future weight gain and obesity-related diseases (Table 3). Not surprisingly, given the positive changes in their lives and level of satisfaction with treatment, all five patients indicated they would be very upset if they had to discontinue treatment with setmelanotide, using words and phrases such as “terrible,” “end of the world,” “threatening,” and “catastrophe.” One patient with LEPR deficiency even indicated they would contemplate suicide if denied access to setmelanotide (Table 3).

Table 3 Patient-reported meaningfulness of improvements in hunger, overall satisfaction of treatment, and feelings if treatment were discontinued
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Discussion

POMC and LEPR deficiencies are rare genetic diseases characterized by hyperphagia and early-onset obesity that place tremendous burdens on patients and caregivers [11,12,13, 16]. The impacts of these burdens on HRQOL are under-recognized and not well characterized [16]. To provide insight into patient experiences of hyperphagia, we conducted in-depth qualitative interviews in a small cohort of patients with obesity due to POMC and LEPR deficiencies participating in an ongoing open-label extension of the phase 3 trials of setmelanotide.

Before treatment with setmelanotide, patients consistently described experiences of extreme hunger, much like an addiction or compulsion to eat. All patients reported impacts of hunger on their daily functioning, including negative emotions, poor self-esteem, and strained interactions with their families. Patients also reported difficulties with work and/or school related specifically to hunger (attempts to control hunger or obtain food), as well as to being overweight and having other health problems.

Following treatment with setmelanotide, most negative impacts attributed by patients to their hunger and/or weight had resolved, and all five patients reported improved mood that had a positive influence on their HRQOL. Specifically, patients reported feeling more confident and self-assured and feeling relieved that they no longer struggled with controlling hunger-related impulses. Additionally, all five patients described a quick and profound reduction in their hunger, including a decrease in the intensity and the frequency and duration of hunger. Consistent with these reductions in hunger, all participants reported eating far less food and feeling satiated after eating and experiencing substantial weight loss, which they were able to maintain. Beyond these impacts on daily life, the changes experienced by patients after setmelanotide treatment were personally meaningful, and all five patients indicated that they were very satisfied with setmelanotide treatment.

The qualitative results from these interviews complement the primary results from the phase 3 trials of setmelanotide that used an 11-point scale to determine the hunger score [14]. Following treatment with setmelanotide, the mean peak hunger score decreased from 8.1 (standard deviation [SD], 0.8) at baseline to 5.8 (SD, 2.0) after approximately 1 year on a therapeutic dose in patients with POMC deficiency and from 7.0 (SD, 0.8) at baseline to 4.1 (SD, 2.1) after approximately 1 year on a therapeutic dose in patients with LEPR deficiency [14]. Hunger scores decreased quickly and were maintained throughout the duration of the study during setmelanotide treatment [14].

Of note, there are currently no validated patient- or caregiver-reported assessments of hyperphagia in patients with rare genetic diseases of obesity. The assessments used in the phase 3 clinical trials may be useful in patients with varying degrees of hunger in an untreated state, although it is unclear how meaningful these assessments are for evaluating hyperphagia in patients with POMC and LEPR deficiencies who have never experienced “normal” variations in hunger prior to a treatment baseline reference. However, qualitative data from these interviews provide additional context, given that patients could verbally describe the experiences related to changes in hunger.

Conclusion

Overall, by reducing hunger and improving satiety, treatment with setmelanotide facilitated substantial and meaningful changes in the lives of the patients within our interview cohort. The results of this study confirm that the benefits of treatment with setmelanotide in patients with POMC and LEPR deficiencies surpass favorable clinical changes (e.g., weight and hunger) and are also inclusive of HRQOL improvements that are highly meaningful to patients. Furthermore, to our knowledge, we described the first detailed interviews from the perspective of patients with POMC and LEPR deficiencies that provide valuable insights for clinicians and caretakers.