Setmelanotide

Mechanism of Action

The deficiencies or mutations in the POMC, PCSK1, or LEPR have been shown to cause hyperphagia resulting in severe childhood-onset obesity leading to multiple endocrinopathies, including adrenocorticotropic hormone deficiency, hypothyroidism, hypogonadism, hypopigmentation, hypoglycemia.[2][4] Setmelanotide is a disulfide cyclic octapeptide that can cross the blood-brain barrier and act on the hypothalamus. It is metabolized into small peptides and amino acids by catabolic pathways with an elimination half-life (t1/2) of approximately 11 hours. Approximately 39% of the administrated drug dose is excreted in the urine unchanged within 24 hours.[5] 

Setmelanotide can bind to and activates multiple melanocortin receptors, including melanocortin-4 receptor (MC4R), melanocortin-3 receptor (MC3R), and melanocortin-1 receptor (MC1R) selectively over melanocortin-2 receptor (MC2R) and melanocortin-5 receptor (MC5R).[6] These melanocortin receptor systems consist of five 7-transmembrane G-protein coupled receptors, which are involved in many key physiological functions of the body, including feeding behavior, energy balance, sexual function and behavior, cardiovascular function, kidney function, immune response, etc.[7] 

Setmelanotide is a type of MC4R agonist with 20-fold less activity at the melanocortin-3 receptor (MC3R) and melanocortin-1 receptor (MC1R). The MC4R can be endogenously activated by the binding of melanocyte-stimulating hormones (MSH), which are involved in responding to acute signal regulations of hunger and satiety.[8][9] Setmelanotide acts on the MC4R pathway to reverse hyperphagia and promote weight loss through decreased caloric intake and increased energy expenditure.[2][10] 

The effectiveness of setmelanotide was assessed in phase 3 clinical trials in which 80% of the patients with POMC deficiency and 46% of the patients with LEPR deficiency lost at least 10% of their body weight.[11] The prevalence of severe obesity in children and adults is more commonly associated with the heterozygous loss of function mutation in MC4R. It is hypothesized that the setmelanotide might increase signaling through the wild-type MC4R allele, thereby leading to weight loss in patients with MC4R deficiency.[12]

Administration

Setmelanotide is administered subcutaneously and is available as a 1 mL multidose vial with a concentration of 10 mg/mL. The starting dose in the pediatric population between the ages of 6 and < 12 is 1 mg (0.1 mL) injected daily for two weeks. Patients must be simultaneously monitored for side effects, specifically gastrointestinal (GI) and hypersensitivity reactions.[5][11][13] 

The dose is further adjusted to 2 mg if the initial dose is tolerated. However, if side effects are noted, the dose is decreased to 0.5 mg once daily in pediatric patients. The starting dosage in patients 12 years of age and older is 2 mg (0.2 mL) injected subcutaneously once daily while also monitoring for GI side effects. The dosage is then adjusted from 1 mg (0.1 mL) to 3 mg (0.3 mL), depending on the patient's tolerance.[3][13]

The weight evaluation of the patient is necessary after 12 to 16 weeks of treatment. Recommendations include discontinuing the drug if the patient has not lost either 5% of their baseline body weight or 5% of their baseline body mass index (BMI). Continued treatment with Setmelanotide in patients who exhibit this may not cause significant weight loss.[3][11][13]

Adverse Effects

The most common side effect of setmelanotide is a hypersensitivity reaction at the injection site, which can lead to blistering, burning, hives, inflammation, infection, itching, lumps, and discoloration of the skin [3]. Specific side effects are also associated with setmelanotide therapy, including skin hyperpigmentation, sexual dysfunction, depression, suicidal ideation, etc.[3][14]

Skin hyperpigmentation occurs because the melanocortin receptors are expressed on melanocytes, and activation of this receptor leads to the accumulation of melanin, thereby increasing skin pigmentation, independent of ultraviolet light.[3] The hyperpigmentation of the skin is reversible with the discontinuation of the drug.[3][15] Theoretically, chronic stimulation of melanocytes may promote the development of melanocytic tumors, including the benign nevus to malignant melanoma.[14] Therefore, it is important for regular skin examination before and during the treatment to rule out any underlying malignancy.[16]

Sexual dysfunctions are noted in male and female patients treated with setmelanotide, including spontaneous penile erection in males, and sexual adverse reactions, including labial hypersensitivity in females.[17][5] This occurs because the agonism of MC4R modulates sexual brain processing which increases sexual desire and sexual imagery, reduces self-consciousness, and sensitizes the patient to erotic stimuli.[18] Penile erection, which lasts more than 4 hours, unrelated to sexual stimulation or orgasm, is called priapism and is considered a medical emergency because it can cause ischemia of the corpora cavernosa.[19] 

Kühnen P et al. mention that patients with severe obesity are 30% more likely to have depression than non-obese patients; however, setmelanotide can cause depression and suicidal ideation as a side effect.[20] These patients should consider discontinuing the treatment in case of new onset or worsening depression.[5]

Setmelatonide is not approved for use in neonates or infants because it contains benzyl alcohol as a preservative which can cause fatal adverse reactions, including gasping syndrome.[5] Gasping syndrome is characterized by unremitting gasping respirations and may cause anion gap metabolic acidosis, neurologic deterioration, renal failure, convulsions, intraventricular hemorrhage, and cardiovascular collapse.[21][22]

Contraindications

Setmelanotide has a low potential for pharmacokinetic drug-drug interactions related to the cytochrome P450 enzyme, transporters, and plasma protein binding. However, no currently available clinical studies evaluate the risk of patient drug-drug interaction with setmelanotide.[23]

Setmelanotide is contraindicative in pregnancy and should be discontinued during the entire course of the pregnancy unless the benefits outweigh the potential risk to the fetus.[23] No data is available for the drug-associated risks for major congenital disabilities and miscarriage or adverse maternal or fetal outcomes. However, benzoyl alcohol-associated gasping syndrome may still be a potentially fatal side effect in the unborn fetus.[23][24] Furthermore, weight loss during pregnancy is generally not recommended as weight loss may increase the risk of fetal comorbidities.[24][25]

Setmelanotide is not recommended for use while breastfeeding as there is no data available on the presence of setmelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.[23] However, a nonclinical study showed that setmelanotide is excreted in the milk of nursing rats; hence, it is likely to be present in human milk; therefore, the potential risk to the newborn cannot be excluded.[24]

Setmelanotide is not recommended in pediatric patients six years of age and less and in geriatric patients 65 years of age and over because there is no clinical data available for the efficacy and safety of the drug for these age groups.[3][11][13]

Renal impairment impacts the pharmacokinetics and efficacy of the drug. Hence, setmelanotide is not recommended for patients with moderate to severe renal impairment and is contraindicative in patients with end-stage renal disease (ESRD).[23]

The degradation of subcutaneous or intramuscular peptides allows for avoiding hepatic enzymes. Degradation of the subcutaneous peptide at the injection site occurs due to protease or peptidase activity in the interstitial space while degradation in the lymphatic system leads to lower drug bioavailability compared to intravenous administration. However, setmelanotide is not recommended for patients with hepatic impairment as there is no data available for the efficacy and safety of the drug.[11][23]

Monitoring

As mentioned above, monitoring the patient's weight loss periodically, typically after 12 to 16 weeks of therapy in the pediatric and adult populations, is recommended. Evaluation for appropriate growth and maturation in pediatric patients is important as well. Adverse drug reactions (ADR), such as new or worsened depression, hyperpigmentation, and sexual dysfunction in both males and females, should be monitored. In case of severe ADR, setmelanotide therapy should be discontinued.[3][11][13][23]

Toxicity

There is no known antidote on the market today for the overdose or toxicity of setmelanotide. In the case of an overdose or toxicity, it is recommended to initiate appropriate supportive treatment based on the clinical signs and symptoms of the patient.[1][17][26]

Enhancing Healthcare Team Outcomes

The management of setmelanotide requires both extensive supervision and team collaboration to ensure patient safety and the best possible outcomes. Interprofessional communication among physicians, psychiatrists, pharmacists, and geneticists is crucial. The clinician's role is to determine the screening eligibility of the patient. Since obesity is the number one cause of many ailments, psychiatrists must manage patient concerns to monitor depressive episodes and any new mental health diagnoses.

Setmelanotide is administered subcutaneously; therefore, the pharmacist's role is to double-check any contradictions and drug-drug interactions and monitor the long-term effects of the dose. Lastly, the most important role goes to the geneticist, who determines whether the patient is eligible to receive the medication depending on their genetic testing to look for specific deficiencies as described above. All these clinical professionals must constantly communicate with each other regarding the patient's conditions and the therapeutic effects to avoid severe adverse drug reactions (ADR). 

The management of this medication requires safety in ordering the medication, handling and preparing the subcutaneous administration, proper and detailed documentation, and detailed ongoing evaluations. The administration of drugs should follow strict protocols to ensure patient safety. In efforts to coordinate care for patients on Setmelanotide, the following steps must be taken to ensure positive outcomes:

• The physician recommends setmelanotide based on eligibility according to the patient's Body Mass Index (BMI) and other risk factors like cardiovascular health, diabetes, hyperphagia, etc.   
• The physician then orders genetic testing for the patient to evaluate them for the setmelanotide therapy. 
• The geneticists must then determine whether the patient is eligible to receive setmelanotide after a precise genetic testing report.
• The physician/nurse administers setmelanotide via subcutaneous therapy while following all strict precautions to keep the patient safe from infection and other adverse events.
• The physician and psychiatrist continue to monitor all side effects and long-term management of the drug.

Setmelanotide has been known to cause depression and suicidal ideation, as described above.[20] Patients who are obese may also have existing psychiatric disorders, including anxiety and substance use disorder which may be exacerbated with this medication.[27] It is the responsibility of the clinical team involved in the care of the patient to ask the right questions and monitor for side effects.  

Overall, the goal of the interprofessional team is to improve patient outcomes and put patient safety at the forefront. However, the impact goes beyond the clinical outcomes. Among clinicians, geneticists will increase genetic testing with the increased use of this medication.[20] 

In long-term usage of Setmelanotide, if the medication effects are sub-minimal and the expected weight loss is not achieved, or if the side effects outweigh the therapeutic effects of the drug, then it is the physician's responsibility to reevaluate the drug dosage and concentration while keeping the pharmacokinetics and pharmacodynamics of the drug in mind.