Setmelanotide is giving new hope to patients with acquired hypothalamic obesity, a group for whom no other treatment approach has proven effective.
A study undertaken by Vanderbilt University Medical Center researchers showed dramatic results from the new treatment.
“The results were remarkable. Some patients had normalization of their body weight. All of them showed that they were losing weight,” said Ashley Shoemaker, M.D., an associate professor of pediatrics at Vanderbilt University Medical Center and the coauthor of a recent article that appeared in The Lancet Diabetes & Endocrinology.
Acquired hypothalamic obesity often arises following surgery to remove brain tumors; craniopharyngioma is often involved. But it can result from any injury to the hypothalamus, including traumatic brain injuries and swelling in the brain.
“We see the condition a lot in endocrine clinics,” Shoemaker said. “Patients often have fairly benign tumors that won’t spread, and we can address the initial tumor with surgery or radiation. But then the patients have a lot of consequences due to the tumor’s location, includes trouble with the hypothalamus.”
The hypothalamus regulates many basic bodily functions such as temperature, blood pressure, heart rate and weight.
A Visible, Distressing Problem
In the case of children, they are typically growing and gaining weight normally before the problem. After the onset of acquired hypothalamic obesity, the patient’s metabolism slows down.
“They may have difficulty with physical activity,” she said. “Some eat more than they need, but not huge amounts. Others have a lot of extreme hunger.
“These patients have a before and an after. No one wants to be different, and they have not dealt with obesity all their lives. It’s stigmatizing.”
It also may shorten their life span, Shoemaker said, citing the many chronic conditions exacerbated by excess weight.
To date, there have been no approved, effective treatments for acquired hypothalamic obesity. Patients have generally derived little benefit from lifestyle adjustments, bariatric surgery, or from drug treatments, including treatment with glp-1 agonists.
Setmelanotide is already FDA-approved for weight management patients six years or older who are obese due to genetic causes involving three genes.
Replacing the Missing Hormone
Giving patients Setmelanotide is basically replacing a hormone that is normally made in the hypothalamus, α-MSH, which these patients lack enough of due to the damage, Shoemaker explained.
“We knew that there were receptors for the α-MSH in other areas of the brain and in the spinal cord, but we didn’t know how important they were,” she said. “We thought if we gave patients the hormone, those receptors outside the hypothalamus could respond to it. The strategy worked extremely well.”
A Multicenter Trial
The phase 2 clinical trial was conducted at five U.S. centers between June 6, 2021, and January 13, 2022, and involved 18 patients with obesity between the ages of 6 and 40 years. The patients had all undergone treatment for craniopharyngioma or another non-malignant tumor and experienced damage to the hypothalamus, confirmed by MRI.
For the first four weeks of the study, patients underwent age-dependent dosing of setmelanotide, which is given subcutaneously. They received no instructions regarding diet or exercise.
After that initial period, all patients received 3.0 milligrams of the drug as tolerated, daily for 12 weeks. The total treatment period was 16 weeks.
The mean reduction in BMI across all patients was 15 percent, the authors wrote.
“Everybody seemed to respond,” Shoemaker said. “Sixteen of the 18 patients (89 percent) …met the study’s primary endpoint of reduction in BMI of at least five percent from baseline after 16 weeks (p<0.00001). The mean reduction in BMI across all patients was 15 percent,” the authors wrote.
Phase 3 Trial Underway
All of the patients who participated in the Phase 2 trial described above, including those who had been on placebo, were allowed to join a Phase 3 trial which is ongoing. The researchers expect to have results from that Phase 3 trial in early 2025.
Because the drug is FDA-approved for other indications, the process for winning approval for its use in acquired hypothalamic obesity should be quicker than it would be for a drug without other approved purposes.
Setmelanotide is expensive, however. Per patient, its cost runs into six figures per year, and millions over a lifetime of treatment.
“We are all really excited that there appears to be a targeted drug that may work for this condition,” Shoemaker said. “Our goal is to understand why each individual is struggling with obesity and to pick a medication that works for that reason.”
