Retatrutide

MONDAY, June 10, 2024 -- An experimental 'supercharged' form of popular GLP-1 weight-loss meds could help ease fatty liver disease, a new trial suggests. The drug under development, survodutide, helped up to 83% of patients gain real improvements in markers of fatty liver disease, a widespread and potentially lethal condition often linked to obesity. Right now, there's only one drug, resmetirom , approved by the U.S. Food and Drug Administration to fight fatty liver disease, and not all patients can use it. Survodutide "could be a game-changer" against the illness, said study lead researcher Dr. Arun Sanyal . He directs the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health and is a professor at Virginia Commonwealth University (VCU) in Richmond. The trial was funded by Boehringer Ingelheim, the drug company developing survodutide. Results were published June 7 in the New England Journal of Medicine . Fatty liver disease is shorthand for metabolic dysfunction-associated steatohepatitis (MASH). According to a news release from VCU, about 1 in every 4 people globally are affected by the condition. A healthy liver has a fat content of just 5% or less by weight, but in MASH fat can rise to unhealthy levels that put people at risk for cirrhosis , liver cancer or even the need for a liver transplant. Obesity is a prime factor driving fatty liver disease. The new trial isn't the first to suggest that a GLP-1 drug -- a class that includes Ozempic , Wegovy , Mounjaro and Zepbound -- might help ease MASH. Another study , also led by Sanyal and funded by drugmaker Eli Lilly, found that its experimental GLP-1 drug, retatrutide, also helped reduce fat in the livers of obese people who took it. That study was presented last November at the annual meeting of American Association for the Study of Liver Diseases in Boston. The survodutide trial involved 282 adults from 25 countries, all of who had MASH with some level of fibrosis (scarring) of liver tissue. Patients received weekly injections of either a placebo or one of three doses of survodutide (2.4 milligrams, 4.8 mg or 6 mg) for 24 weeks. The weekly dosage was gradually increased to 6 mg for another 24 weeks. By the 48-week mark, most (83%) of patients saw improvements in a host of markers for fatty liver: lower levels of liver fat, inflammation and no worsening of fibrosis, Sanyal's team reported. For three-quarters of the patients, their fatty liver disease had "resolved," meaning there was less fibrosis, inflammation and fat in the liver, and for 50% of the patients fibrosis and liver enzymes improved and there was no progression of their disease. In common with other GLP-1 meds, gastrointestinal side effects did occur, such as nausea, diarrhea and vomiting, the researchers noted. As explained by Sanyal, survodutide is a "dual agonist" drug, meaning that it contains two agonists -- hormone mimics -- that bind with brain receptors to help with weight loss. While standard GLP-1 meds like Ozempic contain one agonist mimicking the hormone glucagon-like peptide 1 (GLP-1), survodutide contains a GLP-1 agonist plus an agonist against glucagon, a hormone that helps control blood sugar. From mouse studies, his team believed that a dual-agonist drug might better target fat in the liver, improving on the effect of standard GLP-1 medicines. The new trial seems to have confirmed that in people. “These data demonstrate that direct liver targeting with glucagon agonism in addition to GLP-1 effects helps resolves nonalcoholic fatty liver disease and improve fibrosis while maintaining the benefits of GLP-1 agonism,” Sanyal said in a university news release. “These findings are remarkable and exciting and open a new chapter in drug development for MASH with fibrosis, where a single agent could potentially target both the liver disease and related medical conditions may provide hope for millions who have both MASH with fibrosis and multiple obesity-related ailments,” Sanyal said. Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

One study can start a pharmaceutical revolution.Four years ago, a large clinical trial run by Novo Nordisk showed a drug called semaglutide helped people with obesity lose, on average, around 15% of their weight. The results far exceeded what prior studies of other treatments had suggested was possible pharmaceutically, sparking a rush to research that has quickly reshaped the obesity drug field.Demand for semaglutide, now sold in nine countries by Novo as Wegovy, has surged to such heights the company cant keep up. Physicians see Wegovy and other drugs like it as powerful treatments for obesity as well as its many related health consequences.Analysts forecast annual sales of this new class of medicines to surpass $100 billion by early next decade. Drugmakers are investing billions of dollars in an attempt to get a piece of that market, as would-be competitors test new ways to regulate metabolism and spur weight loss.Some 120 drugs are now in clinical development for obesity, according to a recent report from Iqvia, from Wegovy mimics to psilocybin and coated glucose beads. More than one-third work by stimulating gut hormones like GLP-1 the target of Wegovy.To succeed, theyll likely have to at least match the double-digit weight loss numbers shown in testing for Wegovy and Zepbound, a rival drug from Eli Lilly approved in the U.S. last year. Heres where the field stands:How well do current drugs work?Until the early 2010s, physicians had only a few drugs they could prescribe for obesity, one of which, phentermine, was first approved in 1959. A spurt of research in the early 2000s led to the 2012 and 2014 approvals of three more treatments: Qsymia, Belviq and Contrave.While those drugs showed greater weight loss than placebo in testing, their effects were largely seen as unexceptional, resulting in limited uptake. Qsymia in particular was linked with safety issues, including the risk of fetal toxicity and heart problems. Belviq, meanwhile, was withdrawn in 2020 due to an association with higher rates of cancer.Their launches came around the time the the first GLP-1 drugs arrived on the market for diabetes. Novo, after seeing the weight loss effects of its diabetes drug Victoza, developed a daily injectable version specifically for obesity. Dubbed Saxenda, it had only a modest impact on weight and never caught on widely, either.Novo was quick to advance successor GLP-1s, however. While working on the weekly injection that became the diabetes drug Ozempic, Novo simultaneously studied a formulation for weight loss. Importantly, the company also committed to a longer-term plan designed to prove the expected weight loss benefit would help protect the heart.Both bets paid off. Treatment with Wegovy, which contains the same active drug as Ozempic, reduced weight by an average of 10% to 16% across a range of studies approaching levels typically achieved via bariatric surgery.A large study, meanwhile, proved weight loss from Wegovy reduced the relative risk of heart attacks, strokes or cardiovascular death by 20%, compared to a placebo. U.S. approval for this use last year made Wegovy the only weight loss drug that can be marketed as having such benefits. The new label helped push Medicare, which is prohibited by law from reimbursing for obesity treatment, into covering Wegovy for some people.Yet Lilly may ultimately have an upper hand with its rival drug Zepbound. On a surface-level comparison, Zepbound led to greater average weight loss in testing, showing reductions between 13% and 21%, depending on the study and dose. Additionally, a larger share of participants in Lillys studies experienced at least 10% weight loss than did participants in Novos testing of Wegovy.The two medicines have never been compared head to head in a trial, however, so no definitive conclusion can be drawn about their relative weight loss benefits.Lilly doesnt have heart data to match Novo yet. A similarly large Zepbound trial, called SURPASS-CVOT, should produce data in 2025, potentially putting an expanded label for the drug two years behind Wegovy. Lilly is testing Zepbound against an active medicine, its older GLP-1 drug Trulicity, however, which could strengthen its case.Zepbound is likely to show a similar heart benefit to Wegovy, according to Angela Fitch, president of the Obesity Medical Association and chief medical officer at the Massachusetts clinic Knownwell.Theres been a positive effect on cardiovascular health from the less potent GLP-1s, she noted.What could new drugs improve upon?Novo and Lilly have set the bar high with Wegovy and Zepbound, so much so that some in the industry are describing those drugs benefits as table stakes for would-be rivals. Competitors will need to show an advantage in efficacy, safety or convenience.Current GLP-1 drugs for weight loss are delivered via an under-the-skin injection. (Although Novo does sell an oral version of Wegovy for diabetes.) A pill with similar potency could be attractive to people whod prefer to avoid needles. However, peptide-based drugs like GLP-1s are difficult to deliver through the digestive tract, where they are broken down by enzymes and absorbed only slowly due to their relatively large size.Key GLP-1 and related drugs in developmentCompanyDrugStatusTypeKey datesEli LillyZepboundMarketedGLP-1/GIP agonistLate 2024 heart outcomes data readoutEli LillyorforglipronPhase 3Oral GLP-1 agonist2025 data readoutsEli LillyretatrutidePhase 3GLP-1/GIP/Glucagon agonist2026 data readoutsNovo NordiskOral semaglutidePhase 3GLP-1 agonist2024 FDA filing, adtl. data readoutsNovo Nordiskcagrilintide/semaglutidePhase 3GLP-1/amylin agonistLate 2024/2025 data readoutBoehringer / ZealandsurvodutidePhase 3GLP-1/glucagon agonistLate 2025 data readoutPfizerdanuglipronPhase 2Oral GLP-1 agonist2024 data on once-daily versionAmgenmaridebart cafraglutidePhase 2GLP-1 agonist, GIP antagonistLate 2024 data readoutViking TherapeuticsVK2735Phase 1/2GLP-1 agonist2024 oral Phase 2 trial startRocheRG 6641 (CT-868)Phase 2GLP-1/GIP agonist2024 data readoutRocheRG 6640 (CT-388)Phase 1GLP-1/GIP agonist2024 data readoutRocheRG 6652 (CT-996)Phase 1GLP-1 agonist2024 data readoutSOURCE: Company disclosuresAnother approach could target the drugs known side effects. GLP-1s are often associated with gastrointestinal problems such as nausea and vomiting. There are also concerns, based on an animal and biomarker data, of a possible link to certain types of cancer. This could make other proposed mechanisms for stimulating weight loss, such as blocking cannabinoid or opioid receptors, more attractive.Companies hoping to make inroads on Wegovy and Zepbound might also try to improve on how readily existing GLP-1s are absorbed and used by the body. Both Novo and Lilly have had difficulty manufacturing enough of the drugs, and a formulation thats more easily taken up by the body could allow for lower doses.Drug developers are looking, too, at how to preserve lean mass, as the rapid weight loss from current GLP-1s also leads to unwanted reduction in muscle tissue. Patients taking Zepbound lost 11% of their muscle mass in a substudy of a major trial that led to its FDA approval, for example.Shrinking muscle mass is particularly concerning for older people for whom less strength could increase frailty. And if people regain weight after significant losses, the subsequent gains tend to be disproportionately fat.Lean mass also plays an important role in metabolism, as muscles burn more energy at rest than fatty tissue and secrete a hormone that spurs glucose uptake.We tend to think of a muscle as a motor it moves things from one place to another, said Peter Ackerman, vice president for clinical development at Biohaven, which is developing a muscle-building drug in both obesity and the rare disease spinal muscular atrophy. I think it has many more important roles to play in our overall health.Whats next?Lilly and Novo aim to maintain their current hold on the market. Both companies are testing several experimental drugs with the goal of launching oral versions or even more effective treatments than their current products.Novo is already close to completing a Phase 3 trial program testing an oral form of Wegovy. It also has in late-stage development a combination of Wegovy with a compound called cagrilintide that acts on a gut hormone called amylin.Lilly has two drugs in Phase 3: an oral GLP-1 dubbed orforglipron that is approaching key data readouts next year and an injectable treatment called retatrutide that stimulates GLP-1, GIP and a third hormone known as glucagon. Results in obesity are due in 2026.Lilly has four experimental drugs in Phase 1 or 2, while Novo has five.[Lilly and Novo] cover all the bases, said Clive Meanwell, CEO of Metsera, a newly launched startup that has two obesity drugs in clinical testing. Our belief is it's going to be a portfolio play, with mix and match, with different clinical circumstances and different markets.Select non-GLP1 drugs in clinical developmentCompanyDrug(s)StatusTypeKey datesEli LillybimagrumabPhase 2activin inhibitor2024 data readoutNovo NordiskINV-202Phase 2CB1 inhibitor2025 data readoutShionogiS-309309Phase 2MGAT2 inhibitor2024 data readoutKallyopeK-757, K-833Phase 2Nutrient receptor agonist2024 data readoutAmgenAMG 786Phase 1UnknownMid-2024 data readoutRegenerontrevogrumab, garetosmabPhase 1myostatin, activin A inhibitorsMid-2024 Phase 2 trial startBiohaventaldefgrobep alfaPhase 1myostatin inhibitor2024 Phase 2 trial startSkye BiosciencenimacimabPhase 1CB1 inhibitorMid-2024 Phase 2 trial startSOURCE: Company disclosuresThe rush by drugmakers large and small to test GLP-1 rivals means clinical trial data could soon prove which approaches work best.Already, some companies have been forced to adjust. For example, Pfizer developed two non-peptide oral drugs targeting GLP-1, but both returned mixed results. One was scrapped because of safety concerns. The other remains in testing, but Pfizer is reworking its dosing because of a high rate of gastrointestinal side effects.Viking Therapeutics has had better luck. The biotech reported encouraging early data for a GIP-GLP1 combination its developing as both a shot and a pill. The drug appears more tolerable than Wegovy or Zepound.A Phase 2 trial of the pill is expected to begin later this year. In the meantime, Vikings valuation has swelled to around $8 billion, suggesting investors see it as an acquisition target for larger drugmakers looking to build their pipeline.Zealand Pharma and Boehringer Ingelheim, meanwhile, are partnered on a drug called survodutide that targets GLP-1 and glucagon and has also produced encouraging early results. Phase 3 study data could come late next year.Investors are also watching closely two drugs from Amgen called AMG 133 and AMG 786. The first activates GLP-1, like Wegovy and Zepbound, but blocks another hormone called GIP opposite of Zepbounds mechanism.The big biotech hasnt disclosed exactly how AMG 786 works.Regeneron Pharmaceuticals, Biohaven and Lilly are exploring treatments designed to preserve lean mass, results from which could reveal how much this strategy might contribute.Further afield are companies like Japans Shionogi and startups Kallyope and Skye Bioscience. The former drugmaker is working on an inhibitor of an enzyme involved in dietary fat absorption, while Kallyopes drugs target gut proteins that themselves stimulate hormones like GLP-1. Skye is testing a drug designed to regulate appetite by blocking certain proteins in the nervous system. '