Previous experiments have shown that the brains of many obese people do not respond to leptin. Scientists believe this could be why some obese people experience an insatiable appetite, feeling hungry even after consuming large meals.
ERX Pharmaceuticals was founded in 2014 to create this drug. The company did not name the entity it has hired to conduct the trial but said it is a “global clinical research organization” with clinical sites around the world. Madison will be the sole site of this trial. Researchers will begin recruiting and screening healthy obese participants locally next month. The trial will run through July, and results are expected to be reported by January 2022.
Previous stages in the process, conducted in Madison and Dallas, tested the drug at a low dose and found no serious side effects. While that trial was designed only to evaluate the drug’s safety, researchers observed that the participants, all healthy and obese, lost up to 6.8% of their body weight during the four-week study.
The drug could offer an alternative to bariatric surgery and hormone injections, which are among the few treatment options available for obesity.
Obese people, those with a body mass index of 30 or more, are at heightened risk for a variety of serious health conditions including type 2 diabetes, stroke, heart disease, and various cancers, according to the Centers for Disease Control and Prevention, though there is debate among doctors as to exactly how obesity affects a person’s health.
“Obesity is one of the top detrimental diseases in the globe,” said ERX Pharmaceuticals Co-founder and Director Dr. Umut Ozcan, who is also a professor at Harvard Medical School and a researcher at Boston Children’s Hospital.
With around 2.8 million people dying each year due to being overweight or obese, the World Health Organization says obesity has “reached epidemic proportions.” And it’s a costly epidemic, with direct and indirect medical costs estimated at more than $315 billion per year in the U.S. alone.
But measures to address obesity have largely failed, Ozcan said, because they treat excessive eating as a personal failing rather than as a symptom of a medical problem. Hunger is one of the most important instincts, right after the drive to protect oneself and one’s young, Ozcan said. But today, when so many have easy access to high-calorie food, that survival instinct can prove detrimental.
Attempting to solve obesity through self-control is “almost a war against a billion years of evolution,” Ozcan said. “It’s not willpower. It’s the genes that you come to this world with.”
When leptin comes knocking
Research in recent decades has confirmed that obesity is, at least in part, genetic. In 1994, Dr. Jeffrey Friedman of Rockefeller University discovered leptin and its receptor in the brain, a discovery many scientists thought would soon end obesity. Mice who lacked leptin grew to up to three times their normal weight, Friedman and his team showed.
But a later discovery revealed that many obese mice in fact have more leptin in their blood than non-obese mice, yet seemed resistant to its effects. It’s like the hormone is knocking on the brain’s door, telling it that the body has plenty of energy that it can spend, Ozcan said, but the brain just can’t hear it.
“Even if you eat a whole Thanksgiving turkey … you will be starving, or feeling like you’re starving to death, because the brain and body connection is kind of disrupted.”
For years, scientists looked for ways to sensitize leptin-resistant brains, resulting in “one failure after another failure,” Ozcan said. Many began to wonder whether the task was possible.
But Ozcan had a theory about what makes some brains less sensitive to leptin. He thought that a stress response within the endoplasmic reticulum, the protein-producing part of cells, might be preventing cells from communicating as normal. Using mathematical modeling, his lab identified a compound called celastrol that they hoped might reduce this stress response. Celastrol is derived from a plant called thunder god vine and has been used for centuries in Chinese medicine.
They gave the compound to obese mice, and, in less than a week, Ozcan’s research fellow reported that the mice had essentially stopped eating.
“I looked at their food intake and I said, ‘Jesus, this is toxic,’” Ozcan recalled. He asked the researcher if the mice looked sick.
“No, they are running around,” the researcher explained, noting that they seemed healthier than the obese mice who had not received the treatment.
“At that time, we really realized we were at the edge of a big discovery — a really big, huge discovery,” Ozcan said.
The treated mice ultimately lost up to half of their body weight but still seemed healthy and active, and Ozcan’s lab shifted its focus entirely in this direction.
Could obesity soon be history?
Now, following other preliminary studies in humans, the study in Madison will test the drug at a higher dose, at both weekly and twice-weekly frequencies. The double-blind trial will consist of two 16-person cohorts, with some participants receiving a placebo. To be eligible, participants must be obese and healthy, without comorbidities like diabetes. Participants will likely begin receiving doses in April.
Ozcan hopes that the drug causes greater weight loss at this higher dose and that it proves effective even when taken only once a week.
Imagine, Ozcan said, that you’re 30 pounds overweight. “Every Sunday, after your breakfast, you take one pill, and then you lose it. That would be amazing,” Ozcan said. “It’s possible that obesity might be history.”
If the drug proves safe and effective, it will move to Phase 2 in the testing process.
Currently, only around 1% of obese people receive medical treatment for obesity, said Teo Uysal, president and CEO of ERX Pharmaceuticals. That, he said, is because of the limitations of the existing options. Bariatric surgery, while effective, is a major invasive procedure for the most extreme cases, and the few medications available offer “suboptimal efficacy,” sometimes with serious side effects.
If, with better drug options, the share of the obese population receiving such treatment grew to just 5%, Uysal estimates that the market could be worth $10 to $20 billion.
The company has already raised $30 million from investors around the world and aims to raise another $20 to $30 million over the next two years. Uysal anticipates that by the end of Phase 2 trials, the program could be worth more than a billion dollars.
“There’s a good medical case for developing novel drugs with novel mechanisms of action, just like we are doing,” Uysal said, but there’s also an economic case. “There’s just so much unmet need right now in the marketplace.”
