Human pancreas, gall bladder organ model, 3d rendering.
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Harith Rajagopalan, MD, PhD, founded Fractyl Health with the vision of eliminating obesity, and it looks like his idea for how to do that has gained some preclinical steam.

The metabolic therapeutics company has new data from Rejuva—its adeno-associated virus (AAV)-based glucagon-like peptide-1 (GLP-1) pancreatic gene therapy program designed to enable durable production of GLP-1 in the pancreas for the treatment of obesity and type 2 diabetes. The study, presented at the 84th Scientific Session of the American Diabetes Association’s (ADA), demonstrated that Rejuva can consistently improve body composition and fasting glucose, compared to or better than Ozempic (semaglutide), by restoring GLP-1 production in a “one-and-done” treatment.

“You might think that we’re just bringing two buzzwords together, but we think that gene therapy with GLP-1 solves a massive, massive problem for society that the current drugs are not solving,” Rajagopalan told Inside Precision Medicine. “It happens to be incredibly pertinent and exciting, but from a patient perspective, we think it is a necessary way to move the field forward.”

Don’t slap a bandage on it

Rajagopalan never imagined himself in biotech or as an entrepreneur. But while training as a physician-scientist and cardiologist at the Brigham and Women’s Hospital, he saw family members who had type 2 diabetes taking medications regularly, yet their diseases progressed.

“Even though I had been through medical school at Johns Hopkins and then residency and fellowship at Brigham, it was only when I saw my family members dealing with it that I realized that the medicines that we have are treating the symptoms of diabetes, but not treating the disease itself,” said Rajagopalan. “As I saw patients in the clinic with diabetes and coexisting cardiovascular disease, I started thinking about the difference between addressing symptoms and addressing the root cause and how we never really can hope to solve major health crises like obesity or type 2 diabetes if we continue to rely on medicines that alleviate the symptoms rather than fix what’s going wrong in the body that’s causing the diseases in the first place.”

So, upon finishing his cardiology fellowship, Rajagopalan became an entrepreneur in residence at General Catalyst, a venture capital firm in Boston, and founded Fractyl Health to develop transformative therapies that can prevent and reverse obesity and type 2 diabetes rather than manage them medically. Rajagopalan said that the two products being developed at Fractyl stay true to that vision—what’s going wrong in the body and how to fix it in a way that can have long-lasting benefits for people.

While GLP-1 therapies can be potent, Rajagopalan said that there is a rebound effect when people stop taking the drugs, showing that these drugs alleviate the symptoms of obesity and diabetes but do not permanently change anything that’s causing the disease to progress in the first place.

“Last year, the conversation was about how effective the GLP-1 drugs are and how much weight you can lose,” said Rajagopalan. “Now, the conversation is looking at how people stop taking it, how much weight they regain, and how these benefits get worse rapidly. These drugs have incredible potential, but most of it is unrealized because 50% of people stop taking them within three months, and if they stop working, you stop taking them. Then, there’s gradual attrition thereafter. How many people will benefit from them in the real world?”

According to Rajagopalan, the key to the problem is the required frequency of administration, which is weekly or sometimes even daily. That’s precisely why one-and-done gene therapy is so exciting—the mechanism can be leveraged more physiologically and reap that benefit for the long term, which does not depend on whether people are still taking it three or six months later.

Maintaining physiologic responsiveness 

The pancreas, as well as numerous other organs such as the heart, brain, and digestive tract, express the endocrine peptide hormone GLP-1, which regulates blood sugar and appetite in a very physiological manner by rising and falling in response to food intake. Rajagopalan states that bariatric surgery results in similar changes in GLP-1 levels. After a meal, GLP-1 levels increase and then decrease while fasting. However, when this mechanism is replicated using drugs such as semaglutide or tirzepatide, a single injection on day one leads to GLP-1 levels that are significantly higher than normal levels, remaining elevated for a week before dropping again, requiring another injection. So, the profile of GLP-1 over the day is totally different with the drug than with the natural hormone.

“We’re seeing things with the drugs full blast that you do not see with bariatric surgery—gastroparesis and all of these gastrointestinal (GI) issues, which are not typically associated with complications of bariatric surgery,” said Rajagopalan. “What that implies to us is that turning it on full blast contributes to some of the tolerability and GI issues that we’re seeing with these drugs, which you do not see with the GLP-1 that’s circulating through your body right now. The reason to have it on full blast is because it allows for weekly or daily dosing. If you’re a drug developer and you want to figure out how to make this convenient, then you’ve got to figure out how to keep the drug in your body and functional for a long time. But you’re reversing what the body wants because that’s the convenience frequency for making it reasonable as a therapy. Unless there’s a reason to have it on full blast, having it follow physiological function makes the most sense.” 

These issues led Rajagopalan and the team at Fractyl to formulate a one-and-done, nutrient-responsive, and pancreas-specific GLP-1 gene therapy. Their solution consists of three elements. Element number one is a proprietary local delivery catheter developed by Fractyl Health, enabling reliable delivery of the AAV particles to the pancreas directly. The second is the therapeutic GLP-1 transgene itself. The third element is the viral particle and the plasmid construct. Fractyl has chosen to use an AAV serotype 9 (AAV9) with a human insulin promoter, which is highly specific to pancreatic beta cells and provides nutrient-responsive regulation. Human insulin is produced at a low level following the body’s basal needs, and then it gets turned up after a meal and dialed down again when fasting, just like the normal GLP-1 signal.

“We saw an opportunity to mimic the natural hormone physiology, but dial it up by leveraging the pancreas because the beta cells of the pancreas can respond to blood sugar and release insulin,” said Rajagopalan. “We’ve engineered our gene therapy construct to respond to blood sugar and to release GLP-1 along with that insulin. So, you get this increase when you need it and then a decrease when you don’t, just like native GLP-1.”

Walking the walk

This week at the ADA, Fractyl is showing data from investigational new drug (IND) studies for their candidate Rejuva in a diet-induced obesity model in mice—the de facto regulatory standard for preclinical drug development for obesity candidates, including the GLP-1 treatments currently marketed.

“There are a lot of companies out there developing GLP-1 drugs that they hope will be incrementally more potent by a variety of different mechanisms, but all of them suffer, as far as we can tell, from the same fundamental weaknesses of the current drugs, which are discontinuation-rebound and the need for permanent, ongoing compliance for the rest of your life,” said Rajagopalan. “As massive as this GLP-1 market has become, we do not see anybody else who is working on truly addressing the fundamentally most important weaknesses of the current drugs that exist. Everyone else is trying to build a little bit of a better mousetrap. You know, can I eke out 0.1% more weight loss? Can I make it, you know, every two weeks or a monthly injection versus a weekly injection? But they all still have those same structural flaws, which we hope to address.” 

The head-to-head study compared a single Rejuva injection against chronic administration of semaglutide. After 28 days of semaglutide treatment, mice were randomized and either got a placebo or a single Rejuva injection. What the data show is that the weight loss in the group that crosses over from semaglutide to gene therapy is on par with the weight loss that occurs when you do the administration once right at the very beginning, meaning that the gene therapy construct can be used for durable weight loss or to cross over from chronic GLP-1 therapy to a one-time administration that’s going to preserve that benefit for a long time. However, the mice that went from semaglutide to placebo regained much, if not all, of their body weight back to baseline levels.

At the end of the study, pancreatic islets were isolated from Rejuva-treated mice and grown in tissue culture. At low blood sugar concentrations, these islets secreted very little GLP-1 transgene, but when glucose levels were increased, the islets secreted the transcript, demonstrating the nutrient responsiveness of the system.

“We’re incredibly excited about what these data could mean for the impact of Rejuva or the gene therapy platform, not just on type 2 diabetes but also on obesity and its ability to address a major challenge in the market today with the GLP-1 drugs.”

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