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Setmelanotide (Imcivree): CADTH Reimbursement Review: Therapeutic area: Bardet-Biedl syndrome [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Dec.
The Bardet Biedl Syndrome Foundation (https://www.bardetbiedl.org/) is a registered 501(c)3 non-profit agency that connects families and shares information on research, treatment and therapies for Bardet Biedl Syndrome (BBS). It is registered in Delaware.
The information contained in this submission was gathered by the BBS Foundation through a 30-minute online survey and one-on-one interviews conducted by telephone/videoconference. All data were contributed anonymously.
The online survey was disseminated in English and responses were collected between January 30 and February 10, 2023. Survey respondents were recruited by the BBS Foundation through promotion via email and social media, and through the BBS registry maintained by Fighting Blindness Canada. The following populations were invited to take part: people living with BBS (“patients”) and caregivers and/or family members of people living with BBS (“caregivers”).
There was a total of 41 respondents to the online survey. Most (n=34) were caregivers, and the remainder (n=7) were patients. The majority of respondents were from the U.S. (61%) and Canada (29%), with the remainder from Germany, Ireland, Spain and the U.K.
Of the caregivers who completed the survey, 79% reported that their loved one with BBS is 18 years of age or younger, with 41% of all caregiver respondents reporting that their loved one is 3 to 10 years of age. All of the patients who responded to the survey are adults.
In February 2023, the information gathered through the survey was supplemented through telephone/videoconference interviews with one patient and four caregivers, all of whom have experience with setmelanotide.
Given the indication of the drug under review, information gathering focused on understanding patient and caregiver experiences with BBS-related obesity and hunger, and no other symptoms of the disease.
Bardet Biedl Syndrome is a rare genetic disorder. It is associated with the following primary symptoms: visual impairment caused by retinal abnormalities; obesity, typically apparent by age one; polydactyly (extra fingers or toes); hypogonadism; renal anomalies (kidney malformations and/or malfunctions); fewer common symptoms include ASD, learning disabilities, anosmia, Legg-Perthes disease.
While there are more than 20 genes associated with BBS, the underlying cause regardless of gene is malfunction of primary cilia, a key component of cellular communication. BBS is therefore categorized as a ciliopathy, or a disease of the cilia.
BBS is a rare disease affecting approximately 1 in 250,000 people around the world. Based on general population trends, there are likely about 3,000 people in the United States and Canada living with BBS. It is more common in some areas of the world including Newfoundland, where prevalence is estimated to be 1 in 17,500, and in the Middle East (among Bedouin populations).
There is currently no cure for BBS and no available, targeted treatments for BBS either overall, or for BBS-related hunger and obesity, other than setmelanotide which has been approved by the FDA in the United States.
Of patients who responded to the survey, 57% said that as a toddler or young child, doctors or medical professionals had identified that their weight was a concern and 71% said they are currently obese (having a body mass index of 30.0 or higher). Of caregivers who responded to the survey, 71% stated that their loved one is currently obese because of their BBS.
Survey respondents were asked to indicate the degree to which they (or their loved ones, in the case of caregivers) were affected by symptoms related to their hunger.
As shown in Table 1, a large majority of patients (86%) responded that they sometimes, often or always take a longer time to feel full after eating. Thinking about food constantly was reported by 71% of patients to occur sometimes, often or always.
Patient Responses About Hunger-Related Symptoms and Behaviours.
When asked to rank the importance of being able to manage these symptoms of hunger, all but one of the seven patients who responded (86%) ranked “taking a longer time to feel full after eating” as 4/5 or 5/5 on a five-point scale, with 5 ranking as extremely important.
When asked to describe in their own words how hunger affected their behaviour, patients said:
“I was diagnosed with a binge eating disorder at the age of 22. I had done therapy for it, and nothing seemed to help. I often find my hunger to be the worst at night, typically I can ignore it by keeping busy during the day. I was diagnosed about 8 weeks ago with BBS at age 31 and now I am questioning the past 9 years of living with the eating disorder. I don't think anything worked because it's not really a mental health/eating disorder problem.”
“I would get upset with anyone who was withholding food from me.”
“Having negative self-esteem and body image, never feeling like a normal person, and being susceptible to bullying by others, not feeling comfortable in regular chairs, or other public venues.”
“I used to sneak food when no one was watching.”
Similarly, an equally large majority of caregivers (85%) responded that their loved ones sometimes, often or always take a longer time to feel full after eating. As shown in Table 2, 91% of caregivers responded that their loved ones sometimes, often or always seem preoccupied with food or talk about it a lot.
Caregiver Responses About Hunger-Related Symptoms and Behaviours.
When asked to describe in their own words how they observed hunger affecting their loved one’s behaviour, caregivers said:
“He wakes up in the middle of the night to eat or he will not sleep because he says he is hungry. We have started to limit his food as he will eat everything and will beg his siblings for their food, or he brings them so he can have their food.”
“Celebrations are impossible for him.”
“At birthday parties or celebrations, she will take other kids’ food if they leave it on their plate.”
“My son was always focused on food. It took a lot to distract him, and other parents didn’t want to deal with that, so he never was invited to other kids’ parties or for sleepovers.”
“Used to sneak food constantly but not so much anymore. We lock cabinets and fridge so they cannot get to food, so they don’t try.”
“She will get up at night and sneak food.”
“Things were so bad, that I needed to put locks in the pantry and fridge doors. As he got older and cognitively able to understand why we have a feeding schedule, he no longer roots for food, but still asks constantly and watches the clock and is hyper focused on when he can eat again.”
“Does not know when he is full, frequently saying he’s hungry, crying at the end of every meal, and steals brother’s food.”
“Had to lock fridge. Child would be angry if I forgot because she knew she had no self-control.”
From a quality of live perspective, BBS-related hunger has the greatest impact on social life and emotional/psychological well-being. This was reported both by patients and by caregivers when responding about the observed impact on loved ones, as well as impact on their own quality of life, as shown in Table 3. A significant number of patients and caregivers also noted that BBS-related hunger has an impact on work or school life, as well as their relationships with family.
Patient and Caregiver Responses About Quality of Life Impacts.
Patients elaborated on how BBS-related obesity and hunger have affected them:
“When I was in middle school other kids would try to see how much they could feed me and tease me.”
“Not feeling worthy enough of a dating relationship, having to buy expensive clothes to fit my size and feeling different and judged by others.”
Caregivers commented about on how BBS-related obesity and hunger has affected their loved ones:
“The school has called to ask if we have enough food for him as he seems to not get enough at school. He has lied to the district saying we don't feed him so he can get more food. He has no friends because he hounds them for their meals while at school.”
“Food seems to be on his mind very often. He wants to know what and when we'll be eating next. He often takes food when he thinks no one is watching and definitely eats more than he should. Because he is overweight it affects his mobility and self-esteem.”
“She couldn't focus on school, friends, siblings anything all she thought about was eating.”
“Her focus on food would cause worse mood swings which impacted her socially and the preoccupation impacted her attention at school.”
“My son was not usually invited over friends’ houses because other parents didn’t like telling him no.”
“It was very difficult as a child to bring her to birthday parties. I would turn around for 5 min and she had eaten 5 pieces of pizza. Just no control over food. I would also find wrappers hidden everywhere in her room, she would steal food and hide to eat it.”
“My daughter was low energy and was depressed about her body weight and image and dissatisfied with herself. She could not keep up with her friends and was often left out of activities or social outings they planned because of it.”
“Her desire to eat more causes her anxiety.”
Caregivers also shared how their loved one’s BBS-related hunger has affected their own quality of life:
“He bullies his younger siblings until they give him their food, or he will just take it…it has caused major fights and resulted in my younger kids and myself going hungry cause he will steal the food.”
“The whole condition of BBS has been trying. The hunger has been difficult along with weight gain and concerns about the social impacts and health impacts. The worry has for sure caused us increased anxiety and stress.”
“It’s always on my mind - how’s she doing physically, how much she’s eating, how much exercise she’s getting…I think about whether it’s ‘okay’ to give her unhealthy foods because I worry, she won’t eat the healthy food that her body needs. We as a family worry about how this will impact her throughout her life as she gets older. How much freedom will we be able to provide to her when it comes to food choices as she grows and matures?”
“Lack of sleep due to 3 to 6 nightly feedings; trouble weaning from breastfeeding, especially during nighttime; time-consuming food-prepping/cooking; own orthopaedic issues due to heavy weight of BBS-impacted child which has to be carried a lot (cannot walk, yet); social isolation due to child's behaviour (screaming).”
“At parties I would be the one trying to keep control on my son's eating and that was stressful. People would tease me and tempt my son because they thought it was funny.”
“People do not understand. He has a typical brother who eats all day and tons of junk food and stays thin. People see him and immediately think I am over feeding him, or he just eats all day, but he doesn’t. I’ve even had social services called on me to investigate if I am over feeding him. It is so tiring and such a struggle.”
In Canada, there is no approved treatment for BBS either overall, or for BBS-related hunger and obesity. Patients and caregivers were asked about weight management strategies they have employed, and their degree of effectiveness.
As shown in Table 4, when patients were asked what environmental controls, they have tried to help manage their weight, they identified a regular exercise plan as somewhat (43%) or very (43%) effective. Only one other strategy – supervision from others – was identified by more than half of respondents to be somewhat or very effective.
Patient Responses About Environmental Controls.
Caregivers identified that a regular exercise plan was a somewhat (56%) or very (18%) effective way for their loved one to manage their weight. Because all caregivers identified that their loved one with BBS is 18 years of age or younger, other strategies were identified to be effective to varying degrees, including:
Table 5 shows all the response options and the data provided by caregivers.
Caregiver Responses About Environmental Controls.
Even taking these environmental controls into consideration, many caregivers anecdotally shared the challenge of helping their loved one to manage their weight:
“No matter what we did she was always hungry.”
“Food restrictions never worked for us and looking back I think it’s because she was sneaking food. Exercise is still hard because she’s uncoordinated and tires so easily. Keeping food away and schedules helped the most.”
"No diet seems to work. Exercise is hard as he is rapidly out of breath due to excess weight."
“No matter how much exercise and diet restriction my son still gained weight.”
“Did numerous weight loss attempts but my son would always find ways to sneak food.”
“We have tried everything except locking up food, nothing was very effective. I find offering healthier food, and eating regularly, routine has helped with the hunger...but no matter what we did, she still gained weight and fast.”
Patients and caregivers were asked if they or their loved ones had used any of the following weight management medication for weight regulation related to their BBS: orlistat (Xenical, Alli); phentermine-topiramate (Osymia), naltrexone-bupropion (Contrave), liraglutide (Saxenda), semaglutide (Wegovy, Ozempic, Rybelsus), phentermine, benzphetamine, diethylpropion, and/or phendimetrazine.
Of patients who responded to the survey, only two reported that they had tried any of these medications: one reported that semaglutide was very effective while another reported that phentermine was somewhat effective.
Similarly, of the 34 caregivers who responded to the survey, only semaglutide had been tried, and only in two instances. One respondent indicated it was somewhat effective for their loved one, while the other said it was very effective. Of note, in one of these instances, semaglutide was being used at the same time as setmelanotide. Additionally, vyvanase and metrofmin were mentioned by one respondent.
When asked what would be meaningful for them in a treatment that manages the hunger associated with their BBS, all seven patient respondents said being able to effectively manage their weight. Feeling full faster was named by six of the seven patients, and not thinking about food so much, not feeling hungry right after they’ve eaten, and reduced stigma and/or judgment were each identified by five of the respondents. In the words of one patient:
“So much would be easier if my weight was managed. Travel, interactions with my kids, self-esteem, medical care for problems not associated with weight - the bias of medical professionals because of weight is awful - social life and work environment would be better.”
When thinking about what they believed would be meaningful to their loved one in a treatment that manages BBS-related hunger, caregivers’ top answer was not thinking about food so much (80%), followed by not feeling hungry right after they’ve eaten (68%) and reduced stigma and/or judgment (63%). Given that their loved ones with BBS are all 18 years of age or younger, caregivers’ comments overwhelmingly reflected the hope for their loved ones to have an easier life journey especially in their youth:
“She could be happy and so much less stressed. The ability to not worry about food provides the freedom every child deserves.”
“Improved self-esteem and reduced health concerns.”
“Food won’t be the focus most of the time.”
“Better access to healthcare without judgement when he is older.”
“Less screaming and lower stress level, improved motor skills (ability to walk) due to weight loss.”
“Happier individuals. As parents, that's all we want for them.”
“They could start to focus on other things more and stop letting hunger steal their joy and pleasure in other activities. They could have better control over their weight and not feel shame each time they are weighed.”
“He would have more of a social life and be able to travel easier.”
“We would be able to go longer in doing things without stopping constantly fighting him on wanting food. He would be able to stay healthier.”
“He can move more and be more active. He could focus more on just being a teenager and living life and going on vacations and not being so tired all the time or feeling bad about himself because people can be so mean. His family wouldn’t constantly make comments about his weight and what I’m doing about it.”
“She would not be struggling as much to get around. Her sight is already quite affected by BBS, her balance is not the greatest either.... to add obesity to that, is hard. It's for sure affecting her self-confidence. She would be able to move more freely, and to focus on things that matter, instead of thinking about food and eating all the time.”
Caregivers also acknowledged that a treatment to manage their loved one’s BBS-related hunger would have broader benefits for them personally and their family overall:
“Less emphasis on food would limit the stress built around family meals. Family members need to focus on supporting each other and not on food.”
“We would also be less stressed about food. It would feel like a huge weight had been lifted off our family.”
“We would be able to go out and to parties without someone ‘standing guard’ near the food table.”
“The worry and battle of weight management would not be a priority in our relationship.”
“All of my time and energy would not be focused on keeping him healthy and redirected from his obsession with food and eating. We could have cable TV again without worry of what food commercial may come on. We could go to a fair or carnival or out to eat without his having a meltdown because he needs all the food.”
Among all survey respondents, 17 had experience with setmelanotide: four patients reported they are taking it, and 13 caregivers indicated their loved ones are taking it. Clinical trials and private insurance were the most common ways that survey respondents were able to access the drug.
Many patients and caregivers reported positive outcomes as a result of their experience with setmelanotide:
“The benefits were many... after about a month or two of being on setmelanotide... my 12-year-old at the time told me she was not hungry anymore.... for the first time in her life. She herself said, ‘Mom, I am not hungry anymore... and I have never felt this feeling before.’ She said I did not know before what it was to not feel hunger. That broke my heart, but that's when I realized that it was working. She is now cutting down her portion size herself, makes better food choices, not hungry all the time.... she has lost some weight; she feels good about herself.”
“Life changing. He gets full and satisfied. He has lost almost 50 lbs and moves better. He seems excited about not being so obsessed with food and making better food choices, without my constant guidance.”
“It was a game changer in every aspect of our lives, no question about it, and our daughter is healthier and happier overall, and we are happier and feel relieved that there is a medicine out there that can help our child afflicted by something that is not her fault and can make so many wonderful impacts on her life.”
“It is very difficult to reason with someone you know is sick and is also young. If your child has BBS they probably have sight issues or no sight and balance/coordination issues so it is very difficult to get them to try to be active in the usual sense-you have to become creative and when you have so many other extenuating circumstances to a caring for a loved one with BBS it is difficult to only focus on the nutrition aspect of their lives also because you see they derive so much pleasure out of eating. We know that our daughter snuck food, almost always the worst of snacks but we never locked our cabinets or fridge as we didn't want to make her feel bad because of it. We would definitely speak with her about it after the fact and tried to explain to her why it isn't good to do it because of her health, etc. But the brain is definitely wired differently for her and at the end of the day it wasn't her fault - that is why Imcivree is so special because it regulates that for them, and they are not interested in food as irrationally as before - like making sure there are seconds before she even finished the plate in front of her.
“Did well. Lost 50lbs but had to travel to Washington to get the medication and injection was hard for him to manage without help as his vision is very poor.”
“Setmelanotide helped my son lose over 130 pounds and keep it off. He is much happier that he moves around so easily. The first time he didn’t have to use a seatbelt extender on the airplane he was so excited.”
“Slow, steady weight loss, better mental and physical health. Social relationships greatly increased and/or improved.”
“Weight loss, decreased stress, and worry over hunger. Increased focus and attention at school and at home.”
“I lost over 130 pounds during the 5 years that I was in the study for setmelanotide and taking Imcivree now and with regular exercise I am keeping the weight off.”
“For the first time I was able to sustain weight loss due to reduced hunger and cravings.”
“My daughter is currently in the trial for setmelanotide so these answers were our experience prior to that medication. She used to be hyper focused on food. As a 6.5-year-old she does still focus on food in play a lot, but not nearly as much as before the study. She leaves food on her plate now and never did before the study.”
“We are currently in the Setmelanotide study, and it has been life changing! My daughter lost 14 lbs so far from March 2022 to now (as a six-year-old!) and is healthier than she has ever been in her life. We have much less stress and worry and we are so hopeful for more treatments to come with BBS after such a positive experience in this study…. I would recommend [setmelanotide] because the side effects are so minimal, and it is a very easy medicine to take once you are in a routine. The benefits seem to really outweigh the risks in terms of changing the life of the person with BBS as well as their family. The long-term effects of the weight loss cannot be understated. This would decrease risks of weight related health issues in the long run.”
“Setmelanotide has been a life saver; literally.”
When asked about any negative impacts experienced with setmelanotide, the most commonly mentioned ones were the darkening of the skin, and bruises and scars being more noticeable.
Nausea and gastrointestinal upset were mentioned to a lesser extent, as well itchiness and/or pain at the injection site. Several respondents noted the method of administration via daily injection was challenging for patients who were vision-impaired, which is a symptom of BBS, or for younger patients for whom it could limit activities of daily living such as field trips and sleepovers. One respondent reported feeling jittery and limited their caffeine as a result; they have since been able to add it back in. One patient has an allergy to setmelanotide and is unable to take it.
Of the 41 people who responded to the survey, all but one patient and one caregiver would recommend that setmelanotide be made available to people with BBS. Comments about this included:
“Everyone should have the ability to make informed decisions regarding their healthcare. If a medication has shown that it effectively treats a disease, the patient should be able to advocate for themselves and decide if they would like to try a treatment.”
“I think it would provide an option for those with BBS who are struggling with their obesity and the secondary effects of that (diabetes, hypertension, etc.) to be able to manage it more successfully.”
“People with BBS are not lazy and do not overeat [on] purpose. The co-morbidities are so much worse and more expensive than the cost of this life changing treatment. Setmelanotide truly gives a person back their life and health, both physically and mentally. All people with BBS should have access to this medication.”
“Every person with BBS who has a hunger/obesity issue should be able to take this medicine. It is caused by a medical condition, not because they are lazy or at fault - it is the wiring in the brain that causes this - setmelanotide is effective and life altering for anyone afflicted by BBS - it has so many synergies in one's life with health, mental health, school life is easier to focus at school, social aspects are enhanced as one's mood is enhanced - the possibilities exponentially increased once the hunger is addressed.”
“I strongly recommend that this medication be accessible. Prior to starting the trial my husband and I were not sure if we would even notice an impact on our son and were blown away by his immediate progress in not only hunger management but overall development and mood. I have tears in my eyes as I type this. Every person living with BBS should have access to this medication. Observing the changes to all areas of his development are so encouraging and suggest even BBS individuals with controlled weight or hunger may benefit as well. While he is not able to communicate how he feels, I really do think the feeling of being hungry was always there, we just didn't know it. Because of his food aversions he never seemed preoccupied with food until 3 years old (we noticed him asking for crackers more around that age) and he also never seemed to eat more than his older brothers when they were his age. He has always been significantly obese, seemingly regardless of what he ate. Setmelanotide seems to allow him to more fully participate in everything, I'm guessing because his brain doesn't think he is starving. His teachers and therapists have been so impressed with the changes as well. Please make this medication available to every individual with BBS.”
In addition to the survey responses summarized above, one (1) patient and four (4) caregivers were interviewed regarding their experiences with setmelanotide and its impact on their lives. All those who participated in the interviews were from the U.S., and have accessed setmelanotide through clinical trials and private insurance.
Caregiver A says that “Imcivree saved his life” when sharing her experience with her son, Patient A, who was diagnosed with BBS in 2011 when he was a high school senior. The diagnosis was a relief to the family since Patient A’s weight issues were previously attributed to his personal inability to control his hunger and not a medical condition. Caregiver A said, “We just didn't know until he was diagnosed. And then I read everything about it, and I'm like, oh, my God, this totally explains this kid!” Patient A shared how BBS has had a significant impact on his life. As a child, his compulsion to eat “was often made fun of in school” and his mother said that “other parents had misgivings about inviting him over because of his hunger issues.” Because of his weight, Patient A had trouble playing sports and he wasn’t able “to do basic things like learning to ride a bike with training wheels” because the training wheels bent when he sat on the bike, due to his weight. Despite exercise and significant lifestyle changes over many years, Patient A was unable to lose weight until he was able to access setmelanotide through a clinical trial in 2017. At the time he enrolled in the clinical trial, Patient A weighed 325 pounds. Today, he weighs 195 pounds and goes on daily walks with his family and cycles with his father every morning. Caregiver A says that “People can barely recognize my son now”. Patient A says that “I felt I had nothing to lose by trying setmelanotide and my life is so much better for it.”
Caregiver B, a mother of two daughters living with BBS shared the challenges she faced. From birth, this mother noticed that her first-born daughter wanted to nurse constantly, to the point where she wasn’t able to produce enough breast milk. As a first-time mom, she initially thought that this need for constant breast-feeding was a normal part of her baby’s growth cycle. When her daughter became a toddler, she used to “raid the grocery bags” if they were put in the back seat for the drive home. After her second daughter was born, she noticed that both children were “rapidly gaining weight” despite only serving them healthy meals and not allowing her daughters to have dessert “unless it was a special occasion like a birthday or company visiting.” After returning to work full-time, her two daughters would “sneak food” after school, before their mom got home from work, so she began to “hide food in the garage.” Eventually, one of her daughters was diagnosed with diabetes and the other one with kidney disease, as a result of their BBS. Today, Caregiver B credits setmelanotide for helping one of her daughters to “no longer need a kidney transplant” and for dramatically reducing the amount of insulin her diabetic daughter now needs due to improved A1C levels – both thanks to the drug’s effectiveness in addressing their BBS-driven hunger. This caregiver felt it was important to make setmelanotide accessible to all BBS patients who could benefit from it, as it could help “reduce costs to the healthcare system later on” as a result of preventing kidney transplants and the need for diabetes medications.
Caregiver C shared how her daughter was diagnosed with BBS at 2.5 years of age, after one day her eye “turned in and stuck” and she was rushed to the emergency room. Before the diagnosis, her daughter used to have lots of “fits and meltdowns” to the point where she would “beat her head to bleeding” on the wall or the floor during her tantrums. Looking back, this caregiver now believes that her daughter’s tantrums were her way of “just managing feelings and frustrations” of not being able to communicate her insatiable hunger, which “hurts to think about.” The hardest part of her daughter’s BBS diagnosis has been “worrying about what will be in the future and what that [future] looks like for her” considering issues like vision loss, diabetes and kidney failure pose tangible risks to people with BBS. Her daughter was able to receive setmelanotide through a clinical trial and today is doing well at school and is able to be more engaged with friends and family “now that her focus is off food.” She feels that her daughter’s treatment has been “life changing in several areas, we [now] feel like there’s hope.” When it comes to access to setmelanotide, this mother says that “parents need something…with BBS we have so many obstacles and we have so many areas of concern, and not a lot of hope. And [setmelanotide] is what we have right now, and parents need that option.”
Caregiver D’s daughter was born with an extra digit on her hands and was not meeting her development milestones. Her daughter was diagnosed with BBS at one year of age. At the time, Caregiver D had never heard of BBS, but it explained the hunger she observed in her daughter. “It was like a switch was flipped on all the time, she couldn’t focus, she didn’t want to play…everything was about food. It took over our life [as a family]”. When her daughter was nine years old, she started treatment with setmelanotide through a clinical trial and it has been like the “[hunger] switch has been switched off.” Her daughter is losing weight, her Body Mass Index (BMI) is coming down, her energy levels have improved and she’s more focused on school and friends. This mother says that setmelanotide has been “a blessing” and that it “gives her hope” for her daughter’s health in the long-term. Even though her daughter has been on setmelanotide for less than one year, Caregiver D says it’s like a “huge weight has been lifted”. They can finally go out as a family without her daughter having “meltdowns” due to her insatiable hunger. Caregiver D believes that publicly funded access to setmelanotide “should be mandatory. It’s a life-saving medication. Everyone has the right to good health and quality of life.”
Not applicable.
When asked if there was anything else they wanted to share about their experience with BBS or with setmelanotide, this is what patients and caregivers said:
“Apart from curing BBS overall, which is not yet possible, setmelanotide is the game-changing component to someone affected by BBS, specifically if they are enduring the hunger component of the syndrome. For our family it has been a godsend.”
“It has changed our lives completely ... I can't even begin [to describe the impact setmelanotide has had on my life]. I never thought a medicine could change our lives. I cannot say enough wonderful things. Our daughter does not have constant hunger.”
“…Out-of-control hunger and food seeking is the cause of much of the obesity in BBS… that has been successfully treated with setmelanotide. The excess hunger and food seeking not only result in obesity, but they can also cause, or contribute to mental health challenges and relationship issues. Quality of life suffers.”
“Although BBS is rare, those people who are affected by it need to know that Health Canada is willing to approve a drug specifically for them. If it is helping other people in other countries, it needs to be an option for Canadians as well.... The overall results have shown that it is beneficial for people in helping them with their weight. This directly correlates with their risk for other life-threatening diseases.”
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
The BBS Foundation completed the submission independently with external support from EVERSANA.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
The BBS Foundation completed the submission independently with external support from EVERSANA.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for Bardet Biedl Syndrome Foundation.
We are a group of Canadian endocrinologists who treat Bardet-Biedl syndrome (BBS) in pediatric and adult populations. We represent the specialty from across Canada in both academic and community settings and share the goal to improve the health and quality of life of those living with BBS.
An initial draft was written by Dr. Stasia Hadjiyannakis. The resulting final submission was distributed to a group of Canadian physicians who treat BBS. Physicians who wished to support this Clinician Group Input submission signed the submission.
In addition, the following were referenced for background information and supporting evidence.
Clément K, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960-70.
Clinical Trials.gov. Setmelanotide in Pediatric Rare Genetic Diseases of Obesity. Available at: https://clinicaltrials.gov/ct2/show/NCT04966741 (accessed January 3, 2023).
Government of Canada. Meds Entry Watch – New Medicines Approved in 2020. Available at: https://www.canada.ca/en/patented-medicine-prices-review/services/npduis/analytical-studies/meds-entry-watch-6th-edition/new-medicines-approved-2020.html(accessed January 3, 2023).
Haqq AM, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859-68.
Haws RM, et al. The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design. Contemp Clin Trials Comm. 2021;22:100780. https://doi.org/10.1016/j.conctc.2021.100780.
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Pomeroy J, et al. Bardet-Biedl syndrome: Weight patterns and genetics in a rare obesity syndrome Pediatr Obes. 2021;16(2):e12703.
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U.S. Food & Drug Administration. FDA approves treatment for weight management in patients with Bardet-Biedl Syndrome aged 6 or older. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-weight-management-patients-bardet-biedl-syndrome-aged-6-or-older (accessed January 3, 2023).
BBS is a rare multi-system genetic condition that falls under the spectrum of ciliopathy disorder. The estimated incidence of BBS is 1:160,000 in Northern European populations, but as high as 1:13,500 and 1:17,000 in isolated communities in Kuwait and Newfoundland and Labrador, respectively. It is characterized classically by early-onset obesity with hyperphagia, intellectual impairment, renal anomalies, polydactyly, retinal degeneration, hypogonadism and hypogenitalism. People with BBS can also have co-existent musculoskeletal complications, such as scoliosis and hip dysplasia, and often have balance and coordination difficulties. Surveillance includes regular ophthalmologic evaluation, monitoring of renal and liver function, glucose and lipid metabolism, endocrine function, blood pressure, weight/growth, and musculoskeletal function. A multidisciplinary team approach is required to effectively manage and support individuals with BBS. There is currently no targeted therapy for BBS. Complications associated with BBS are treated symptomatically in a similar manner to which they are treated or managed in the general population.
The hyperphagia and obesity in BBS are thought to be related to hypothalamic dysfunction. The consequences of BBS include difficulties trafficking leptin-receptor signaling to proopiomelanocortin (POMC), thereby reducing the activation of the melanocortin 4 receptor (MC4R), which is our main signal of satiety. Lack of MC4R activation leads to insatiable hunger (hyperphagia), decreased metabolism and severe obesity. There is currently no available therapy that directly addresses this consequence of BBS. As a result, 72% to 92% of individuals with BBS have obesity, with most having onset prior to 6 years of age.
Current approaches to weight management in individuals with BBS are similar to those for the general population. Obesity is widely recognized as a complex, chronic, progressive and relapsing condition. The cornerstone of obesity management is lifestyle intervention, which includes counselling and interventions to ensure optimized nutrition, appropriate physical activity, improved sleep patterns, as well as psychosocial/mental health supports. There are also now available pharmacotherapeutic options and bariatric surgery for a subset of people living with obesity. For those living with BBS, engagement in lifestyle interventions is complicated by co-existing biologically driven hyperphagia (deregulation of appetite), as well as low vision, balance and coordination difficulties, intellectual disabilities, and mental health concerns.
While liraglutide is now approved for use in those with obesity aged 12 years and older, and semaglutide and naltrexone HCI/buproprion HCI are approved for those aged 18 years and older, the effectiveness and safety of these agents in those living with BBS has not been studied. Furthermore, these agents do not directly address leptin signaling and MC4R activation at the level at which it is impacted in those living with BBS. The safety, efficacy and durability of bariatric surgery in this population remains largely unknown.
Obesity management goals include prevention of weight-related health complications, including cardiometabolic risk, type 2 diabetes, abnormalities in lipid metabolism, non-alcoholic fatty liver disease (NAFLD), obstructive sleep apnea, musculoskeletal pain/discomfort, and difficulties with activities of daily living. For those living with obesity, a sustained decrease in body mass index (BMI) or body weight of 5% or more can lead to a clinically meaningful decrease in risk for complications related to obesity.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
There is currently no available targeted therapy for BBS. In those living with BBS, obesity is highly prevalent, impacting 72% to 92% of patients, with onset prior to 6 years of age in most. The driver of obesity is hypothalamic dysfunction (interference of leptin signalling and MC4R activation). Weight management is, therefore, complicated by hyperphagia (insatiable appetite). This sustained hyperphagia is distressing and a significant burden to both the individual living with BBS as well as their family or caregivers. Hyperphagia leads to severe obesity that negatively impacts health, quality of life, mobility, mental health (mood, body image, self-confidence), and finances. Patients are also confronted with weight bias and discrimination in school, work, and healthcare environments. Severe obesity can make activities of daily living more difficult and is often exacerbated by co-existent low vision and balance and coordination difficulties. Environmental controls, such as adult/caregiver supervision around food, securing food sources, reducing energy intake and adhering to meal schedules, are essential management strategies for weight regulation for those with BBS. However, these controls are often ineffective, difficult to implement and sustain, and do not address the persistent hyperphagia that can negatively affect quality of life and social dynamics. Things that most people take for granted, such as social gatherings that include food, restaurants, trips to the grocery store or mall, and even school/work cafeterias, can be challenging to manage and navigate. Even for those without BBS, clinically meaningful weight loss is exceptionally difficult to achieve and sustain. In the context of co-existing hypothalamic dysfunction and hyperphagia, it is near impossible.
How would the drug under review fit into the current treatment paradigm?
Hyperphagia is one of the most distressing symptoms associated with BBS and contributes to life-shortening comorbidities, including severe obesity and its consequent increased cardiometabolic risk, type 2 diabetes, obstructive sleep apnea, NAFLD, musculoskeletal difficulties, and impact on activities of daily living. Setmelanotide is a melanocortin 4 (MC4) receptor agonist and a peptide analogue of endogenous melanocortin peptide alpha-melanocyte stimulating hormone (MSH). It binds to the MC4R to transmit a signal of satiety (sense of fullness). Given that MC4R activation is muted in BBS, treatment with setmelanotide effectively addresses this defect, thereby allowing for better recognition of fullness/satiety, decreased hunger and increased metabolism in those living with BBS. Treatment with setmelanotide will, through this mechanism, decrease risk for severe obesity and lead to weight loss for those already living with severe obesity.
In November of 2020, setmelanotide was approved by the U.S. Food & Drug Administration (FDA) for treatment of genetic conditions of obesity including POMC, PCSK1 and leptin receptor deficiency, all of which led to decreased activation of the MC4R. Given the role of the BBS protein in the MC4R signaling pathway, in June of 2022, setmelanotide was also approved by the FDA for treatment of those with BBS and obesity.
A recent clinical trial evaluating the use of setmelanotide in those with BBS and obesity demonstrated a mean decrease in BMI of 7.9% (with 5% weight loss or decrease in BMI considered clinically significant). Sixty-one percent of participants lost 5% or more of their initial BMI and 39% lost 10% or more. Participants reported a decrease in hunger score and experienced improvements in their lipid profile, contributing to decreased overall cardiovascular disease risk.Haws 2021; Haqq 2022
Setmelanotide is the first approved treatment that would address the underlying hypothalamic dysfunction that contributes to hyperphagia for those with obesity and BBS. No other treatment options have been proven to be safe and effective at managing or treating obesity in this population. Lifestyle interventions have limited benefit and are difficult to sustain in the context of ongoing hyperphagia (appetite deregulation). Further complicating things for those with BBS are co-existing low vision, balance and coordination difficulties, hip dysplasia, and scoliosis that make engagement in weight-management strategies such as physical activity more challenging. Obesity can also make management of existing musculoskeletal issues and balance and coordination difficulties more challenging.
Setmelanotide would become part of the therapy plan (in combination with already existing lifestyle interventions) for those aged 6 years or older with obesity. The addition of setmelanotide would allow for more successful weight management, given that it addresses the underlying hyperphagia directly. The responsiveness to lifestyle interventions would be expected to improve significantly. One could therefore also expect a decrease in prevalence of weight-related health complications such as cardiometabolic risk, type 2 diabetes, hypertension, NAFLD, obstructive sleep apnea, and musculoskeletal pain/discomfort.
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
All individuals with genetically confirmed BBS and obesity who are 6 years of age or older are likely to respond to treatment and benefit from setmelanotide.
At this time, setmelanotide should not be considered for patients under 6 years of age or for those without obesity, as it has not been adequately studied in these populations. It should not be used during pregnancy and/or breast feeding, as the safety of setmelanotide in pregnancy and/or on the fetus and breastfeeding infant is unknown. It is also not recommended in those with moderate to severe renal impairment.
We have no way of identifying which individuals with BBS and obesity are most likely to respond to setmelanotide at this time.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
Response to treatment should be reassessed after 12 to 16 weeks of therapy. If a decrease of 5% or greater in weight or baseline BMI has not been achieved by that time, then the individual is unlikely to experience benefit from setmelanotide.
What factors should be considered when deciding to discontinue treatment with the drug under review?
Response to treatment, presence of side effects and/or contraindications to treatment with setmelanotide should be considered when deciding to discontinue treatment. Response to treatment should be seen within 12 to 16 weeks of initiation of therapy. Therapy should be discontinued if the individual becomes pregnant. It should also be discontinued if there is co-existent moderate to severe renal impairment.
What settings are appropriate for treatment with setmelanotide? Is a specialist required to diagnose, treat, and monitor patients who might receive setmelanotide?
Care of patients with BBS requires a multidisciplinary team approach. The diagnosis of BBS should be confirmed through genetic testing. A physician with expertise in weight management should treat and monitor patients with BBS on setmelanotide, in consultation with other healthcare providers involved in their care (e.g., ophthalmologist, nephrologist, endocrinologist, internal medicine specialist, gastroenterologist, primary care physician, dietitian, and mental health care provider).
Parents of children with BBS find obesity and hyperphagia to be two of the most distressing features of BBS. Oftentimes, parents utilize measures such as locking cabinets or refrigerators to limit the child's access to food. Parental guilt and an awareness of stigmatization by extended family or peers, as well as a perception of being negatively judged by healthcare providers, is also frequently reported. Obesity accelerates long-term, co-existing health concerns in BBS, including cardiovascular disease, obstructive sleep apnea, NAFLD, type 2 diabetes, and other negative effects on quality of life. Vision loss resulting from retinal degeneration, poor balance or ataxia, and musculoskeletal disorders including hip dysplasia, talipes equinovarus, and scoliosis all hamper activity in children with BBS, thus aggravating the effects of underlying hyperphagia and obesity.Pomeroy J, 2021
The paucity of reported successful treatments for obesity suggests that current interventions have limited efficacy in the BBS population. Likewise, available pharmacotherapy has been unsuccessful. Targeted therapy with setmelanotide offers significant hope for this population, as it directly addresses the hypothalamic dysfunction that leads to hyperphagia in this condition.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission? If yes, please detail the help and who provided it.
Medical writer, Cynthia Lank (Cynthia N. Lank Editorial Services, Halifax, NS), provided logistical support in the form of participating in initial interviews with Dr. Hadjiyannakis, reviewing and proofreading, and incorporating feedback as directed by Dr. Hadjiyannakis.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission? If yes, please detail the help and who provided it.
Medical writer, Cynthia Lank (Cynthia N. Lank Editorial Services, Halifax, NS), provided logistical support in the form of participating in initial interviews with Dr. Hadjiyannakis, reviewing and proofreading, and incorporating feedback as directed by Dr. Hadjiyannakis.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review.
Name: Dr. Stasia Hadjiyannakis
Position: Assistant Professor, University of Ottawa and Medical Director of Centre for Healthy Active Living at the Children’s Hospital of Eastern Ontario (CHEO), Ottawa, Ontario
Date: 03-03-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 1.
Name: Dr. Sue D. Pedersen
Position: Endocrinologist and Obesity Specialist (Diplomate of the American Board of Obesity Medicine), C-ENDO Diabetes & Endocrinology, Calgary, Alberta
Date: 28-02-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 2.
Name: Dr. Laurent Legault
Position: Head of Pediatric Endocrine Division, McGill University, Montreal, Quebec
Date: 28-02-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 3.
Name: Dr. Jill Hamilton
Position: Professor of Paediatrics, University of Toronto, Head, Division of Endocrinology, Hospital for Sick Children, Toronto, Ontario
Date: 28-02-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 4.
Name: Dr. Munier Nour
Position: Associate Professor, University of Saskatchewan, Saskatoon, Saskatchewan
Date: 28-02-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 5.
Name: Dr. Marie-Phillipe Morin
Position: General Internal Medicine and Bariatric Medicine Specialist, Quebec Heart and Lung Institute; Associate Professor of Department of Medicine, Laval University, Quebec City, Quebec
Date: 28-02-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 6.
Name: Dr. Andrea Marie Haaq
Position: Professor of Pediatrics, University of Alberta, Edmonton, Alberta
Date: 01-03-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 7.
Name: Dr. Celine Huot
Position: Professor of Pediatrics, University of Montreal, Montreal, Quebec
Date: 02-03-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 8.
Name: Dr. Shahebina Walji
Position: Clinical Assistant Professor, Department of Family Medicine, University of Calgary, Calgary, Alberta
Date: 03-03-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 9.
Name: Dr. Vasudhevan Chetty
Position: Associate Professor, Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario
Date: 03-03-2023
COI Declaration for Canadian Endocrinologists Treating Bardet-Biedl Syndrome — Clinician 10.
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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