Previously, an obese person had only one option to achieve rapid and significant weight loss—bariatric surgery.
And the advent of the GLP-1 class drug, simethicone, has made it possible for people to achieve approximately 15% weight loss with the drug. And tilprotectin achieved 22.5% weight loss in a phase 3 clinical trial, a figure that is close to the effectiveness of surgical weight loss.
But both of these GLP-1 analogs face some of the same problems, requiring weekly injections to administer, and, once the drugs are discontinued, they're likely to be slow to regain their weight. This is because of the biological basis of obesity, where the human brain seems to have a set value for how much fat the body stores, and the drugs are able to mask this set value without completely changing it. Are you still guaranteed not to regain weight when you stop taking the medication? This idea doesn't fit the biological basis of the human body.
But a company called Fractyl Health is developing a once-and-for-all weight-loss drug that hopes to achieve long-term obesity prevention with a single injection.
Recently, at the annual meeting of the European Association for the Study of Diabetes (EASD), Fractyl Health presented data from head-to-head experiments of its GLP-1-based pancreatic gene therapy candidate (GLP-1 PGTx), Rejuva®, with simethicone in a preclinical obese mouse model.
The results showed that single administration of GLP-1 PGTx delivered by adeno-associated virus (AAV) in a high-fat diet-induced obese mouse model resulted in a 24.8% reduction in total body weight on day 15, compared to an 18.4% reduction in total body weight in obese mice administered simethicone at a dose of 10 nmol/kg/day. This result provides further evidence for single-dose GLP-1 transgenic pancreatic gene therapy to overcome the barriers faced by existing GLP-1-based classes of drugs in the treatment of type 2 diabetes and obesity.
On day 15 of the study, neither the gene therapy group nor the simethicone-treated group of mice reached a stable body weight. Food intake was reduced in both the simethicone-treated and gene therapy-treated groups of mice compared to the control mice that continued through day 15, providing a mechanistic explanation for their weight loss.
Mark Kay, PhD, a professor at Stanford University School of Medicine and scientific advisor to Fractyl Health, said that the success that gene therapy has had in some rare diseases may open the door to sustained benefits of gene therapy in more common diseases, such as obesity and type 2 diabetes. The efficacy of GLP-1 PGTx in preclinical mouse models of obesity and the accumulation of so-far toxicology studies suggest that localized gene therapy to the pancreas may now be feasible to treat some of society's most vexing chronic diseases.
Our goal is to design a better GLP-1 therapy that has the potential for better weight loss, better tolerability, and greater durability," said Dr. Timothy Kieffer, Chief Scientific Officer of Fractyl Health. Our GLP-1 PGTx has the potential to provide these benefits because it targets the pancreas, is designed to mimic human physiology, and is likely to provide lasting benefits.
The role of the GLP-1 mechanism in obesity and type 2 diabetes is clear, but we also know that we need treatments for type 2 diabetes and obesity that remain effective even after a patient stops taking their medication," said Dr. Harith Rajagopalan, Chief Executive Officer of Fractyl Health. Our goal with the Rejuva platform is to develop candidate gene therapies that can durably alter the trajectory of obesity and type 2 diabetes development, and preclinical proof-of-concept data now further solidify the feasibility of this approach."
Overall, they delivered the GLP-1 gene via adeno-associated virus (AAV) to specifically, once treated, durably express GLP-1 in the pancreas. achieved better weight loss than long-term use of simethicone in a diet-induced obese mouse model.
The results of this preclinical study improve the efficacy of GLP-1 analogs for obesity treatment and are expected to overcome the challenges of existing GLP-1 analogs. The company reportedly plans to advance the approach into clinical trials for the treatment of type 2 diabetes in humans in 2024.
Long-acting weight-loss drugs don't actually address the root cause of the obesity epidemic; many people are obese because they don't get healthy food or don't exercise enough. But for those who are already obese and want to get rid of it fast, these new weight-loss drugs are a good option.