Semaglutide(Hainan Zhonghe)

The new generation of weight loss medicines does an unprecedented job of keeping off the pounds — if people stay on the drugs. Yet numerous studies suggest most of those who start taking GLP-1 drugs quit the medicines within a year. One startup has a bold solution to the problem. Addition Therapeutics is working on a genetic medicine that would turn a patient’s liver cells into little factories to permanently pump out their own weight loss drugs, the startup told Endpoints News in an exclusive interview. It’s a daring first application of the company’s novel technology, which is based on molecular machines known as retrotransposons, also called jumping genes. Addition is attempting to tame these normally wily beasts and coax them to plop a therapeutic code — such as the instructions for a GLP-1 drug — into safe spots in the genome. “It’s a reasonable proposition. And I think it would work,” Daniel Drucker, a scientist at the University of Toronto who discovered how GLP-1 works naturally in the body, told Endpoints. “There’s no reason why having your cells produce more GLP-1 wouldn’t produce benefits.” But Drucker, who isn’t involved with the company, said it could be challenging to get the dose “just right,” since different people need different doses of GLP-1 drugs to strike a balance between weight loss and side effects including nausea. “The susceptibility to side effects is quite different among individuals, and if those side effects are severe, they can be life-threatening, and you would certainly want a way to turn off or dial down the medicines,” Drucker said. “You really have to be thoughtful about how you do this.” Addition isn’t the only company trying to make a GLP-1 gene therapy . But the company’s approach stands out. Addition CEO Ron Park said the company plans to test its drug in a rare and severe form of obesity before expanding into a broader population. Park also said the therapy is reversible because it contains a switch that can turn GLP-1 production down or completely off. The treatment is also redosable because the company is avoiding the viral vectors that many other gene therapy developers use to deliver DNA. Immune reactions to those viruses often preclude additional doses if the first one isn’t good enough. But the unique mechanism of jumping genes allows Addition to make its therapy entirely from RNA, which is packaged into lipid nanoparticles. That means the company could give patients a small starting dose and top-up until their liver produces enough GLP-1 to maintain a desired weight. “You tap into the benefits of an all-RNA product, such as the safety profile, high scalability, and economics you’d expect from an RNA therapeutic. But you get the durability of a gene therapy,” Park said. “It’s the best of genetic medicines writ large.” Addition and its technology are part of a growing movement in the gene editing world searching for new ways to accurately insert large swaths of DNA into precise parts of the genome. Jumping genes could be one way to achieve that goal. Jumping genes have long fascinated scientists. They start as sedentary segments of DNA, often residing in dark and understudied parts of the genome. When that gene gets transcribed into RNA, the jumping gene is free to hop around. Once it finds a new spot, it gets transformed back into DNA before integrating itself into a new place in the genome. University of California, Berkeley biologist Kathleen Collins figured out how to hijack the system to deliver new genes that can treat human diseases. That work formed the basis of Addition, which Collins quietly co-founded nearly five years ago. During that time, the company has refined its jumping genes to get better at making the initial jump and staying put after nailing the landing. The startup emerged from stealth in December, when it announced it had raised more than $100 million . That sum makes it a front-runner among a small number of companies trying to turn jumping genes into medicines. Addition hasn’t said much about how it plans to use the technology until now. Park told Endpoints the company is also developing a gene replacement therapy for Fabry disease, a prototypical genetic condition that other companies have also worked on, as well as an in vivo cell therapy program. It also has funding from the Gates Foundation to use its jumping genes to help the liver produce HIV-neutralizing antibodies. But obesity emerged as a contender for its lead program because it “shows the power of this platform to make a broader impact beyond where traditional genetic medicines have been able to go in the past,” Park said. Addition is starting with a “medically-driven, non-genetic form of obesity” where people are unable to control their hunger, Park said. “This is not, ‘I need to fit into a suit in six months.’ This is not going away. You are going to have this for a lifetime. And you need lifetime therapy,” Park said. “So we think we can make a big difference there, and then be able to make a bigger difference to the broader severe obesity population.” The company wouldn’t disclose the specific form of obesity it is focused on, but one possibility is a subset of hypothalamic obesity that’s a side effect of a life-saving surgery. When people with rare brain tumors called craniopharyngiomas have their cancer surgically removed, the resulting damage to the hypothalamus — a region of the brain important for controlling hunger — leaves people with insatiable appetites. “It is a logical place to start. Those patients have a different risk-benefit profile,” Randy Seeley, an obesity scientist at the University of Michigan School of Medicine who is in the process of becoming an advisor to Addition, told Endpoints. The hypothalamus has long been considered an important site for GLP-1 receptors, but Seeley said that “the most critical aspects” of how these drugs work appear to happen in the brainstem, meaning that Addition’s therapy might still help these patients. Angela Fitch, co-founder and chief medical officer of knownwell — a startup that provides virtual and primary care focused on weight loss and obesity — thinks a permanent alternative to chronic weight loss medications is a good idea. “I’ve been on a GLP-1 for 13 years,” Fitch said. “It gets a little old.” But Fitch said the cost and perceived seriousness of a gene therapy could be barriers to the broader obesity population. One major reason people stop taking their GLP-1 drugs is because they are expensive, she said. Addition would likely need to charge record-low prices for its gene therapy — a class of medicines that often costs millions of dollars — to be competitive. “I think it’s going to be really hard for people with obesity to accept these treatments, because they barely accept bariatric surgery,” Fitch said. “That’s been around and proven to be very safe and very effective since the 1960s, and they still don’t accept that because they think it’s too much.” Addition’s focus on a condition with a potentially massive market is part of a broader trend among gene editing companies, many of which are pitching one-time treatments as a convenient alternative to chronic medicines. But Park said that inserting a GLP-1 gene “has real benefits that go well beyond just this concept of ease of use.” The gene therapy approach should allow patients to maintain steady levels of GLP-1 drugs in their bodies. That could mean more consistent efficacy with fewer side effects, which are partly caused by high levels of the drug coursing through the bloodstream right after an injection, Park said. The company has also incorporated an emergency off-switch that shuts down GLP-1 production. “That switch can be activated by a small molecule,” Addition CSO Francine Gregoire said. “You only take the pill when you want to turn it off.” Other gene therapy developers have dabbled with incorporating on or off switches into their treatments. Gregoire said Addition’s approach is “very similar” to an off-switch that’s been previously tested in a clinical trial. Drucker said that a gene therapy based on natural GLP-1, or modified versions of molecules like liraglutide or semaglutide, would likely be safe. “Hundreds of millions of people have taken these medicines,” he said. “I’m not worried that all of a sudden we’re going to see something that was not discovered in the last 20 years that would be a real sort of showstopper.” But the most potent weight loss medications combine GLP-1 with other molecules. Eli Lilly’s tirzepatide, sold as Zepbound, also contains a mimic of another metabolic hormone called GIP. And the company’s still-experimental retatrutide adds a third molecule. Addition wants to use at least two molecules, including GLP-1, but the company wouldn’t disclose specifics. “If you’re going to make a new combination, or something that’s only been around for two or three years, it’s less attractive to me,” Drucker said. “We have much less safety data.” Seeley noted that there’s also still debate about what combinations of molecules to use, and even whether those molecules should be activating or inhibiting their targets. Zepbound activates the GIP receptor, but Amgen’s promising experimental drug MariTide inhibits it. “If you’re not confused, you’re not paying attention,” Seeley said. “There are elements about how these molecules interact with biology that we do not understand.” Addition is still testing the drugs in animals and plans to share its first data later this year. It wouldn’t say when the therapy will be ready for clinical trials. 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