John O’Brien is a pretty familiar face in the northwest corner of Detroit, where he’s worked for decades on affordable housing and community development projects. But in 2013, he had a stroke and found out he has type 2 diabetes. Since then, he’s worked hard to improve his health through diet and medication, though the 69-year-old confesses that he spends more time these days working on grants and less time climbing on rooftops.
“I’d like to get to a point where the diabetes is considered a nonissue,” he says.
O’Brien’s work is cut out for him. He’s one of 30 million Americans trying to manage this chronic disease through a combination of diet, exercise, and drugs. For a lot of people, the drugs they take are oral medications that affect the complex biochemistry of insulin production and glucose uptake.
No offense to needles, he says, recalling a few days of insulin injections after his initial diagnosis, but the metformin tablet he takes each day is just so much easier.
“It’s a bit less invasive,” he says, chuckling, “but I still have to remember to take it.”
This preference for pills underlies a conundrum in diabetes care, says Susan Samson, a clinician and diabetes researcher at Baylor College of Medicine. Although people with diabetes can choose from several types of oral drugs to regulate their blood glucose, their take-with-water conveniences come with side effects, including gastrointestinal problems, weight gain, and hypoglycemia. In the meantime, some classes of injectable drugs have beneficial side effects not always found in pills. For example, injectable peptides that modulate the action of the glucagon-like protein 1 (GLP-1) receptor also lead to weight loss and heart health. This benefit is critical, Samson says, because obesity contributes to diabetes, and cardiovascular disease is often one of the outcomes.
Turning these injectable GLP-1-like peptides, sold as Ozempic, Victoza, and Trulicity, into pills might mean more people will take them, Samson says, and if so, perhaps those beneficial side effects would help them manage their disease.
But how to package a protein into a pill so that it can survive the corrosive environment of the stomach? After years of work, scientists at Novo Nordisk finally figured it out. In September, the Danish drugmaker became the first company to get US Food and Drug Administration approval for an oral GLP-1 receptor agonist. Novo Nordisk’s drug is called Rybelsus, and it’s a combination of semaglutide, the active peptide in Ozempic, and a chemical shield abbreviated as SNAC that spares the molecule from the ravages of stomach acid and protein degrading enzymes.
Packaging semaglutide into a pill took a lot of trial and error, says Todd Hobbs, the chief medical officer of Novo Nordisk, and “it’s a huge scientific achievement.”
Meanwhile, several pharmaceutical companies are bypassing this challenge of peptide packaging and focusing instead on small molecules that activate the GLP-1 receptor. Small molecules are cheaper to produce, some companies tell C&EN, and in theory, they could be given in smaller doses than peptides but achieve the same effect. As these GLP-1 receptor agonists go through human trials, a big question will be whether they have comparable weight loss and cardiovascular benefits as their peptide cousins.
The GLP-1 signaling pathway is among the many intersecting ways that our bodies regulate the metabolism of glucose. Natural GLP-1, part of a class of hormones called incretins, is secreted by intestinal cells and neurons after a meal. When it binds to pancreatic β cells, these insulin factories ramp up the release of insulin, which in turn helps the liver suck up glucose from the bloodstream to be burned or stored as fat. If some step in this process goes awry, our body can no longer respond to insulin. This is diabetes. Glucose builds up, leading to organ and tissue damage, including heart disease.
“Once you become insulin resistant, your insulin levels go up, and it promotes fat storage. Getting out of that cycle with diet and exercise is challenging,” Samson says. “Lifestyle has to be part of the treatment, but giving patients a pharmacological way to help overcome insulin resistance, or in the case of GLP-1, maybe decrease their weight a little bit . . . that is the way to start therapy,” Samson says.
To develop an oral GLP-1 receptor drug, the scientists at Novo Nordisk turned to a well-known absorption-enhancing compound called SNAC: sodium N-[8-(2-hydroxybenzoyl)amino]caprylate. Researchers have long known that SNAC can deliver a drug to the intestines, but Novo Nordisk scientists found that surprisingly, when it comes to semaglutide, SNAC was promoting the peptide’s absorption in the stomach (Sci. Transl. Med. 2018, DOI: 10.1126/scitranslmed.aar7047). The compound seems to help fluidize cells for peptide transport while also creating a less-acidic pH buffer zone within the stomach that deadens pH-dependent enzymes. These low-pH enzymes otherwise destroy semaglutide.
And in a series of clinical trials that enrolled more than 9,500 people, the oral form of semaglutide seemed to be as effective as the injectable form in lowering hemoglobin A1c, a marker for blood glucose levels, and it was as effective as other oral drugs that aren’t GLP-1 receptor agonists.
But as effective as peptides can be in treating diabetes, small molecules could have some advantages. They are likely better absorbed in the bloodstream and cheaper to manufacture. So several companies, including Pfizer, Eli Lilly and Company, and vTv Therapeutics, are throwing their efforts behind small-molecule GLP-1 receptor agonists.
One challenge of creating a small molecule to bind to the GLP-1 receptor is that until recently, there was no full crystal structure available, say executives at vTv Therapeutics, a company with a GLP-1 receptor small molecule that has gone through early-stage clinical trials. The company worked on its GLP-1 small molecule using a partial structure for years, says Carmen Valcarce, the chief scientific officer of vTv and a former Novo Nordisk scientist.
Designing an inhibitor is also complicated by the somewhat fleeting nature of GLP-1 and the receptor. Natural GLP-1 is quickly degraded by a protease, and the GLP-1 receptor is also quickly recycled when it’s bound to natural GLP-1. Small-molecule activators of the GLP-1 receptor might also need to be designed to be like the synthetic peptides on the market, which appear to slow down that receptor recycling.
Lilly, which has an investigational peptide diabetes drug in trials, bought the rights to OWL833, a small molecule compound developed by Chugai Pharmaceutical. Lilly spokesman Greg Kueterman would not discuss the company’s effort to develop a GLP-1 receptor small molecule.
Pfizer’s lead candidate for a GLP-1 receptor small molecule agonist, the structure of which was revealed at the 2019 spring meeting of the American Chemical Society, is in clinical trials.
Pfizer clinical scientist Aditi Saxena would not discuss the results of the trials or the development of the candidate, PF-06882961, but an investor report suggests that the company’s initial approach to drugging the receptor involved an allosteric modulator to bind the GLP-1 receptor, followed by iterative testing of small molecules to find one that could boost the GLP-1 receptor signal.
Scientists at vTv tell C&EN that the stakes are high in developing a GLP-1 drug.
“This is a very competitive area,” says Robert Andrews, a medicinal chemist who led the team that discovered vTv’s lead molecule, TTP273.
Andrews describes the company’s technology as a combination of computational work and real-life testing of candidates in animals and cell lines, what he calls “fast, parallel chemistry.” Using a library of 60,000 probes, the team at vTv first set out to find what might bind to any part of the GLP-1 receptor on the surface of cells. At the same time, the researchers were docking all 60,000 of these probes in their modeling system, looking for hits that could have some biological readout.
The likely candidates are where there are similarities between their computer experiments and their cell experiments, Andrews says. These candidates become the building blocks for molecules like TTP273 and its predecessor, TTP054.
Developing the compounds was full of bumps, he says.
“We hit at least four, maybe five progression cliffs where we worked for a while to get agonist activity increases, and suddenly we found it, and then worked to improve first-pass metabolism, and got that,” he says. “You might work for a month or two and not see any progress, and then one compound changes everything.”
In a Phase II study completed in 2017, TTP273 appeared safe, but it didn’t lower A1c levels and prompt weight loss as well as vTv had hoped. The company has partnered with Hangzhou Zhongmei Huadong Pharmaceutical to further develop the molecule.
Hobbs, the Novo Nordisk executive, says that besides patient preference, one thing that motivated the company to develop Rybelsus was getting more doctors to prescribe its peptides. Physician have been a little more reluctant than it would have liked, he says, and a pill might change their prescribing patterns and boost sales.
Samson isn’t so sure about this. While she would like to see more people with diabetes benefit from GLP-1 receptor agonists, getting insurers on board will likely be a challenge. Metformin, the pill that O’Brien takes every day, is cheap. And as far as glucose management, it works. Insurers might not be so fast to cover the costs of an oral GLP-1 drug, despite the beneficial side effects because of its cost. “I think having patient choice is a good thing,” she says, but “we are really fettered by using many of these new-to-market drugs because of insurance coverage.”
When O’Brien was prescribed an injectable diabetes drug by his doctor, he balked and decided to stick with his pill because of its ease. Metformin is one of many pills he takes to manage diabetes and other concurrent health issues. Multiple concurrent health issues are common in people with diabetes, Samson says. But he’s not banking his health on medication alone. Like the neighborhoods in Detroit that he has invested in, O’Brien is trying to repair himself.
“I’ve gotten my diet under control,” he says, crediting his wife, Carol, with keeping their meals healthy. “I don’t even see things that I shouldn’t be eating.”