Setmelanotide - Pharmacological Aspect

Overview:

The melanocortin 4 (MC4) receptor is an agonist of Setmelanotide acetate. Setmelanotide is a lab-made version of a natural body peptide called α-MSH (alpha-melanocyte-stimulating hormone) and is composed of eight amino acids. Setmelanotide is sterile, clear to slightly cloudy, colorless to light yellow liquid meant for under-the-skin injection. Each milliliter (mL) contains 10 mg (milligrams) of Setmelanotide in the form of Setmelanotide acetate (a salt with two to four parts acetate), along with several other ingredients: 10 mg benzyl alcohol, eight mg carboxymethylcellulose sodium, one mg edetate disodium dihydrate, 100 mg of a specialized salt, 11 mg mannitol, five mg phenol, and water. The pH of Setmelanotide ranges from five to six. United States Food and Drug Administration approved Setmelanotide on November 25, 2020.

Drug Group:

• Active Pharmaceutical Ingredient: Setmelanotide

• Inactive Ingredients: benzyl alcohol, carboxymethylcellulose sodium, edetate disodium dihydrate, a product of polyethylene glycol, mannitol, phenol, and sterile injection water.

Available Concentration and Formulations:

The injection comes as a 10 mg per mL (milligram per milliliter) solution. It is a clear to slightly cloudy liquid, either colorless or light yellow. It comes in one-milliliter vials that are multiple-use for injections.

For Patients:

How Does Setmelanotide Work in Chronic Weight Management?

Setmelanotide is a type of drug called an MC4 receptor agonist. It helps with weight loss by triggering specific pathways in the brain that reduce appetite, lower calorie intake, and boost energy use.

What Is the Dosage of Setmelanotide?

• An injection solution is available at 10 mg per mL (1-mL multidose vial). Begin with two mg injected under the skin once daily for two weeks.

• If two mg daily is not well-tolerated, then lower the dose to one mg once daily. If one mg is tolerated and more weight loss is desired, the dose can be increased to two mg daily.

• If two mg daily is tolerated for two weeks then the dose can be raised to three mg daily. If the three mg dose is not well-tolerated, reduce it back to two mg daily.

What Are the Things to Inform the Doctor Before Taking Setmelanotide?

• Let the healthcare provider know if a person has any darkened or discolored areas on the skin after using Setmelanotide.

• Inform the provider if the person recently had depression or any suicidal thoughts or behavior.

• Let the provider know if the person has kidney problems.

• If the person is pregnant or planning to get pregnant, tell the healthcare provider. Weight loss during pregnancy may harm the baby, so the provider may stop Setmelanotide if the person becomes pregnant.

• Monitor breastfeeding and advise the patient to withhold breastfeeding since it is unknown if it crosses into breast milk.

• Inform the care provider about all medications taken, such as prescription drugs, over-the-counter vitamins, or herbal products.

How Is Setmelanotide Administered?

• Check the detailed instructions on how to prepare and inject Setmelanotide.

• Setmelanotide is injected under the skin, either by the person using it or a caregiver.

• A healthcare provider will demonstrate to the person or caregiver how to properly prepare and give the injection before trying it themselves. Only inject it on your own if been trained.

• Follow the provider's instructions and take Setmelanotide exactly as prescribed.

• For people with POMC (pro-opiomelanocortin), PCSK1 (proprotein convertase subtilisin/kexin type 1), or LEPR (leptin receptor) deficiency, the provider may stop Setmelanotide if there is not enough weight loss after 12 to 16 weeks.

• For those with BBS (Bardet-Biedl syndrome), the provider may stop Setmelanotide if there is not sufficient weight loss after one year.

• Administer Setmelanotide once daily, ideally in the morning when the patient wakes up. It can be given with or without food.

What Are the Side Effects of Setmelanotide?

The side effects of Setmelanotide are severe:

• Sexual Function Problems: It can lead to erection during non-sexual hours or activities in males and unwanted sexual excitement in females. Medical attention is to be sought if the erection lasts for more than four hours.

• Depression or Suicidal Thoughts: A patient should contact his/her physician immediately if the patient experiences any new signs of depression, any kind of suicidal thoughts, or other changes in mood or behavior.

• Skin Darkening and Changes in Pigmentation: The treatment using Setmelanotide is likely to darken the skin or the moles which may already be present on the body of the patient. Such an effect comes as an indirect result of its mechanism of action. Its reversal could be observed if the treatment is stopped. Conduct intensive skin checks on the whole body before administration and throughout such treatment for this change.

• Benzyl Alcohol Toxicity: Benzyl alcohol found in Setmelanotide is highly toxic, harmful, or potentially fatal for premature or low-birth-weight infants if administered to them. Infants cannot be considered patients for administration of this medicine.

Common side effects are:

• Local reactions.

• Skin color change.

• Nausea.

• Vomiting.

• Headache.

• Priapism in male patients.

• Diarrhea.

• Stomach pain.

Missed Dose

If a patient misses one of his prescribed doses of Setmelanotide, the patient will simply take it at the regular time the next day.

Overdose:

If a person overdoses on Setmelanotide, provide the necessary care based on the patient's symptoms and condition.

Storage:

Keep unopened Setmelanotide vials in the refrigerator for two to eight degrees Celsius (36°F (degrees Fahrenheit) to 46°F) in their original packaging. Once taken out of the fridge, unopened vials can be stored between refrigerated and room temperature two to 25 degrees Celsius (36°F to 77°F) for up to 30 days, with brief exposure up to 86°F allowed. After a vial is opened, it should be thrown out after 30 days. Always store the vials in the original carton.

For Doctors:

Indication:

Setmelanotide is a medication for managing weight in adults and children aged six and older. It is specifically used for certain genetic types of obesity:

Genetic Obesity: It is for people with obesity caused by certain genetic changes, specifically in:

• POMC gene (Pro-opiomelanocortin)

• PCSK1 gene (Proprotein convertase subtilisin/kexin type 1)

• LEPR gene (Leptin receptor)

These genetic changes must be confirmed by an approved test, showing they are potentially problematic or of unknown significance.

Dosing Considerations:

For Kidney Issues:

• Mild to moderate impairment (eGFR 30-89 mL /min ((minute)/1.73 m² (meter square)): No dose change needed.

• Severe impairment (eGFR 15-29 mL/min/1.73 m²): Start at 0.5 mg daily for 2 weeks. If tolerated, increase to 1 mg daily for 1 week, then raise to 1.5 mg daily if tolerated. The target dose should be 1.5 mg daily. Discontinue if not tolerated.

• End-stage renal disease (eGFR <15 mL/min/1.73 m²): Not recommended.

What Are the Pharmacological Aspects of Setmelanotide?

• Pharmacodynamics: When given for a short time to 12 healthy patients with obesity, Setmelanotide increased the number of calories burned while at rest and changed the way the body used energy, favoring fat instead of carbohydrates. However, this drug has not been tried in the population and has not been approved for use.

• Mechanism of Action: Setmelanotide acts mainly through the activation of the MC4 receptor in the brain that controls sensations of fullness, hunger, and how the body uses energy. It has about 20 times less effect on two other receptors, MC3 and MC1. By targeting the MC4 receptors, Setmelanotide may help people with obesity—especially those with certain genetic conditions like POMC, PCSK1, or LEPR deficiency, as well as Bardet-Biedl Syndrome (BBS)—by reducing their food intake and increasing the energy they burn. This is especially critical for those whose MC4 receptor is not functioning well. The MC1 receptor is found in melanocytes. The stimulation of these skin cells causes melanin production, hence leading to a darkening of the color irrespective of the level of sunlight.

• Pharmacokinetics: The mean peak level, after administration of the three mg injection of Setmelanotide once a day, is approximately 37.9 ng/mL (nanogram per milliliter), and the steady state occurs within two days of initiation. Over 12 weeks, the amount of Setmelanotide in the body increases by about 30 percent. After an injection, the highest concentration of Setmelanotide in the blood occurs about eight hours later. Once injected, the average amount of fluid in which the drug spreads is 48.7 liters, and it binds to proteins in the blood about 79.1 percent of the time. It has been found that the drug decreases by half its amount in the body within 11 hours and is eliminated from the system at the rate of approximately 4.86 Liters per hour. etmelanotide is broken into smaller peptides in the body. Nearly 39 percent of the drug is estimated to be removed from the body through urine in its unchanged form within 24 hours. There are no significant differences in how Setmelanotide works based on sex or disease, but the effects of being over 65, pregnant, or having liver problems on the drug’s action are not known. In children aged six to under 12 years, the drug concentration in the blood is about 100 percent higher than in adults over 17 years. For those aged 12 to 17 years, it is about 44 percent higher. For patients with kidney issues, the concentration of the drug in the body increases significantly compared to those with normal kidney function, but kidney problems do not seem to affect how Setmelanotide binds to proteins in the blood. The potential for drug interaction is low, given that Setmeanotide is metabolized by the body. No clinical studies exist that examine drug interactions in particular.

Clinical Studies:

Adverse reactions seen in clinical trials are not comparable amongst all the drugs because conditions while conducting the trials may not be the same.

1. POMC, PCSK1, and LEPR Deficiency Trials: The safety of Setmelanotide was studied in two 52-week open-label trials with 27 patients who had obesity caused by genetic changes in the POMC, PCSK1, or LEPR genes. These changes were classified as potentially problematic or unclear. Here are the common side effects experienced by three or more patients in these studies:

Common Side Effects in POMC, PCSK1, and LEPR Deficiency Trials (27 patients):

• Injection site reactions (like redness, itching, swelling).

• Skin darkening.

• Nausea.

• Headache.

• Diarrhea.

• Abdominal pain.

• Back pain.

• Fatigue.

• Vomiting.

• Depression.

• Upper respiratory infection.

• Unexpected erections in men.

• Joint pain.

• Weakness.

• Dizziness, dry mouth, dry skin, insomnia, and vertigo.

• Hair loss, chills, constipation, flu-like symptoms, muscle spasms, limb pain, rash, suicidal thoughts.

1. Bardet-Biedl Syndrome (BBS) Trial: Setmelanotide’s safety for Bardet-Biedl Syndrome (BBS) was studied over a 66-week period, starting with a 14-week placebo-controlled phase, followed by a 52-week open treatment phase with 44 patients.

Common Side Effects in BBS Trials (14-Week Period):

• Skin darkening and related changes.

• Vomiting.

Common Side Effects in BBS Trials (52-Week Period): (43 patients):

• Skin darkening and hair color changes.

• Injection site reactions (like redness, swelling, or bruising).

• Nausea.

• Unexpected erections in men.

• Vomiting.

• Diarrhea.

• Headache and skin stretch marks.

• Aggression and fatigue.

Warnings and Precautions:

• Sexual Side Effects: Setmelanotide may cause sexual side effects. 24 percent of men experienced unexpected erections, and seven percent of women experienced sexual side effects from those taking Setmelanotide, compared to zero percent in the placebo group. Patients should be warned that these issues might happen. If an erection lasts more than four hours, seek emergency help.

• Risk of Depression and Suicidal Thoughts: Setmelanotide, which affects the brain, can increase the risk of depression in 26 percent of patients and suicidal thoughts in 11 percent of those in studies. The risk may be higher in a patient with a depression history. Patients should be closely observed for changes in mood or suicidal ideations, and Setmelanotide must be withdrawn in case the symptoms are severe or persistent.

• Skin Darkening: Generalized skin darkening was observed in 69 percent of patients who experienced darkened skin with pre-existing moles, possibly darkening. It tends to reverse once the treatment is stopped. A skin check should be done comprehensively before initiation of therapy with Setmelanotide and throughout the course of the treatment to look for a change.

• Risk for Neonates and Infants Due to Benzyl Alcohol: Setmelanotide is not recommended for neonates and infants. The preservative benzyl alcohol in Setmelanotide can result in severe and potentially lethal reactions in neonates and low-weight infants, referred to as "gasping syndrome." Gasping syndrome includes breathing distress, metabolic alterations, and CNS (central nervous system) abnormalities. Benzyl alcohol in Setmelanotide is 10 mg per mL, but the minimal amount that is toxic is not known.

Specific Considerations:

• Pregnancy: Discontinue Setmelanotide unless the potential benefit to the mother outweighs the potential risk to the fetus. The product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with serious adverse reactions and death in neonates when administered intravenously for its local anesthetic effects. The risk of benzyl alcohol dependence in neonates should be considered when the product is administered to a pregnant woman nearing delivery. Reports regarding premature or low birth weight infants that have been administered drugs that contain benzyl alcohol via intravenous use include cases of side effects. Still, there is not enough available information to evaluate its effect on human pregnancy about its use and potential outcomes like major birth defects, miscarriage, and other adverse outcomes. Weight loss during pregnancy is not generally recommended because it can be harmful to the fetus, possibly leading to low birth weight.

• Lactation: Risk Summary Setmelanotide is not recommended for breastfeeding mothers. The medication contains benzyl alcohol, but this is quickly metabolized by a breastfeeding woman, so exposure to the baby is unlikely. However, there have been adverse effects reported in premature or low birth weight babies given benzyl alcohol through an IV. There is no information on whether Setmelanotide (the active ingredient) is present in human breast milk or how it could affect a breastfed baby.

• Pediatric Use: The safety and efficacy of Setmelanotide have been established in the treatment of pediatric patients six years of age or older with obesity due to POMC, PCSK1, or LEPR deficiency. This is based on a clinical study that included 9 children with this type of genetic disorder as well as 22 pediatric patients with Bardet-Biedl Syndrome (BBS). The safety and effectiveness of Setmelanotide have not been established in pediatric patients under six years of age. It is not safe even for babies or infants because very high levels can cause some pretty nasty effects, like the life-threatening "gasping syndrome" due to benzyl alcohol. This preservative can accumulate in premature or low birth weight babies, leading to serious health issues, including neurological damage and cardiovascular collapse.

• Geriatric Use: Setmelanotide has not been studied in adults over 65 and older, so it is unknown how older adults might react to the medication compared to younger adults.

• Renal Impairment: The drug concentration increases in patients with end-stage renal disease. Therefore, the dose for adults and children 12 years of age and older should be reduced. It is not recommended for younger children (six to 11 years old) with severe kidney impairment. For mild to moderate kidney problems, the dosage remains the same as for people with normal kidney function. Setmelanotide is not recommended for people with end-stage kidney disease (deficient kidney function).