Multiple Endocrine Neoplasia

176-week SURMOUNT-1 Phase 3 study in adults with pre-diabetes is the longest completed trial of tirzepatide to date Tirzepatide resulted in sustained weight loss through the treatment period, averaging a 22.9% decrease in body weight with the 15 mg dose at end of treatment Results are consistent with the combined pharmacology of GIP and GLP-1 receptor agonism INDIANAPOLIS, Aug. 20, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) announced today positive topline results from the SURMOUNT-1 three-year study (176-week treatment period) evaluating the efficacy and safety of tirzepatide (Zepbound® and Mounjaro®) once weekly for long-term weight management and delay in progression to diabetes in adults with pre-diabetes and obesity or overweight. Weekly tirzepatide injections (5 mgi, 10 mg, 15 mg) significantly reduced the risk of progression to type 2 diabetes by 94% ii among adults with pre-diabetes and obesity or overweight compared to placebo. Additionally, treatment with tirzepatide resulted in sustained weight loss through the treatment period, with adults on the 15 mg dose experiencing a 22.9% ii average decrease in body weight compared to 2.1% for placebo in adults with pre-diabetes and obesity or overweight at the end of the treatment period. "Obesity is a chronic disease that puts nearly 900 million adults worldwide at an increased risk of other complications such as type 2 diabetes," said Jeff Emmick, M.D., Ph.D., senior vice president, product development, Lilly. "Tirzepatide reduced the risk of developing type 2 diabetes by 94% and resulted in sustained weight loss over the three-year treatment period. These data reinforce the potential clinical benefits of long-term therapy for people living with obesity and pre-diabetes." Tirzepatide was evaluated in 1,032 adults who had pre-diabetes at randomization and obesity or overweight for a treatment period of 176 weeks, followed by a 17-week off-treatment period (193 weeks in total). Results from the SURMOUNT-1 phase 3 study's primary analysis at 72 weeks in all participants were published in the New England Journal of Medicine in 2022. In a key secondary endpoint, tirzepatide led to a significant reduction in the risk of progression to type 2 diabetes in adults with pre-diabetes and obesity or overweight from baseline to week 176 (p<0.0001, controlled for type 1 error). For the efficacy estimandii, pooled doses of tirzepatide achieved significant results, demonstrating a 94% reduction in risk of progression to type 2 diabetes compared to placebo up to week 176. For the treatment-regimen estimandiii, pooled doses of tirzepatide resulted in a significant 93% reduction in risk of progression to type 2 diabetes compared to placebo up to week 176. In an additional key secondary endpoint, tirzepatide (10 mg and 15 mg) led to statistically significant weight reduction compared to placebo in adults with pre-diabetes and obesity or overweight from baseline to week 176 (p<0.001, controlled for type 1 error). For the efficacy estimandii, adults taking tirzepatide achieved average weight reductions of 15.4% (5 mgi), 19.9% (10 mg) and 22.9% (15 mg) compared to placebo (2.1%) at week 176. For the treatment-regimen estimandiii, adults taking tirzepatide achieved average weight reductions of 12.3% (5 mg i), 18.7% (10 mg) and 19.7% (15 mg) compared to placebo (1.3%) at week 176. During the 17-week off-treatment follow-up period, those who had discontinued from tirzepatide began to regain weight and had some increase in the progression to type 2 diabetes, resulting in an 88% reduction (p<0.0001, controlled for type 1 error) in the risk of progression to type 2 diabetes compared to placebo. The overall safety and tolerability profile of tirzepatide over the 193-week study was consistent with the previously published primary results at 72 weeks in SURMOUNT-1 and other tirzepatide clinical studies conducted for chronic weight management. The most frequently reported adverse events were typically gastrointestinal-related and generally mild to moderate in severity. The most common gastrointestinal-related adverse events for patients treated with tirzepatide were diarrhea, nausea, constipation and vomiting. Tirzepatide, a GIP and GLP-1 receptor agonist, works by activating the two hormone receptors. GLP-1 is a regulator of appetite and caloric intake. Nonclinical studies suggest the addition of GIP may further contribute to the regulation of food intake. Tirzepatide decreases calorie intake, and the effects are likely mediated by affecting appetite. In addition, tirzepatide stimulates insulin secretion in a glucose-dependent manner. Tirzepatide increases insulin sensitivity in patients with type 2 diabetes mellitus and these effects can lead to a reduction of blood glucose. These topline results provide evidence for reduced risk of progression to type 2 diabetes and long-term maintenance of weight loss with tirzepatide in adults with pre-diabetes and obesity or overweight. Detailed results will be submitted to a peer-reviewed journal and presented at ObesityWeek 2024, which will take place November 3-6. About SURMOUNT-1 SURMOUNT-1 (NCT04184622) was a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults without type 2 diabetes who have obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea (OSA) or cardiovascular disease. The 1,032 participants who had pre-diabetes at study commencement remained enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo. About tirzepatide Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilization. Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are also ongoing. Lilly submitted data for tirzepatide in moderate-to-severe obstructive sleep apnea (OSA) and obesity to the U.S. Food and Drug Administration (FDA) and other global regulatory agencies earlier this year. Lilly plans to submit data for tirzepatide in heart failure with preserved ejection fraction (HFpEF) and obesity to the U.S. FDA and other global regulatory agencies later this year. Tirzepatide was approved by the U.S. FDA as Mounjaro® for adults with type 2 diabetes to improve glycemic control on May 13, 2022, and as Zepbound® for adults with obesity (a BMI of 30 kg/m2 or greater) or those who are overweight (a BMI of 27 kg/m2 or greater) who also have a weight-related comorbid condition on November 8, 2023. Tirzepatide is also commercialized as Mounjaro® in some global markets outside the U.S. for adults with obesity or those who are overweight who also have a weight-related comorbid condition. Tirzepatide is the only approved GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) treatment for chronic weight management. Both Mounjaro® and Zepbound® should be used as an adjunct to diet and exercise. INDICATION AND SAFETY SUMMARY WITH WARNINGS Zepbound® (ZEHP-bownd) is an injectable prescription medicine that may help adults with obesity, or with excess weight (overweight) who also have weight-related medical problems, lose weight and keep it off. It should be used with a reduced-calorie diet and increased physical activity. Zepbound contains tirzepatide and should not be used with other tirzepatide-containing products or any GLP-1 receptor agonist medicines. It is not known if Zepbound is safe and effective when taken with other prescription, over-the-counter, or herbal weight loss products. It is not known if Zepbound can be used in people who have had pancreatitis. It is not known if Zepbound is safe and effective for use in children under 18 years of age. Warnings - Zepbound may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have any of these symptoms, tell your healthcare provider. Do not use Zepbound if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC). Do not use Zepbound if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Do not use Zepbound if you have had a serious allergic reaction to tirzepatide or any of the ingredients in Zepbound. Zepbound may cause serious side effects, including: Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Zepbound. Tell your healthcare provider if you have stomach problems that are severe or will not go away. Kidney problems (kidney failure). Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Gallbladder problems. Gallbladder problems have happened in some people who use Zepbound. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), or clay-colored stools. Inflammation of the pancreas (pancreatitis). Stop using Zepbound and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. Serious allergic reactions. Stop using Zepbound and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, or very rapid heartbeat. Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Zepbound with medicines that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, mood changes, hunger, weakness or feeling jittery. Changes in vision in patients with type 2 diabetes. Tell your healthcare provider if you have changes in vision during treatment with Zepbound. Depression or thoughts of suicide. You should pay attention to changes in your mood, behaviors, feelings or thoughts. Call your healthcare provider right away if you have any mental changes that are new, worse, or worry you. Common side effects The most common side effects of Zepbound include nausea, diarrhea, vomiting, constipation, stomach (abdominal) pain, indigestion, injection site reactions, feeling tired, allergic reactions, belching, hair loss, and heartburn. These are not all the possible side effects of Zepbound. Talk to your healthcare provider about any side effect that bothers you or doesn't go away. Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or . Before using Zepbound Your healthcare provider should show you how to use Zepbound before you use it for the first time. Tell your healthcare provider if you are taking medicines to treat diabetes including insulin or sulfonylureas which could increase your risk of low blood sugar. Talk to your healthcare provider about low blood sugar levels and how to manage them. If you take birth control pills by mouth, talk to your healthcare provider before you use Zepbound. Birth control pills may not work as well while using Zepbound. Your healthcare provider may recommend another type of birth control for 4 weeks after you start Zepbound and for 4 weeks after each increase in your dose of Zepbound. Review these questions with your healthcare provider: ❑ Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food? ❑ Do you take diabetes medicines, such as insulin or sulfonylureas? ❑ Do you have a history of diabetic retinopathy? ❑ Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements? ❑ Are you pregnant, plan to become pregnant, breastfeeding, or plan to breastfeed? Zepbound may harm your unborn baby. Tell your healthcare provider if you become pregnant while using Zepbound. It is not known if Zepbound passes into your breast milk. You should talk with your healthcare provider about the best way to feed your baby while using Zepbound. Pregnancy Exposure Registry: There will be a pregnancy exposure registry for women who have taken Zepbound during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry, or you may contact Lilly at 1-800-LillyRx (1-800-545-5979). How to take Read the Instructions for Use that come with Zepbound. Use Zepbound exactly as your healthcare provider says. Zepbound is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Use Zepbound 1 time each week, at any time of the day. Change (rotate) your injection site with each weekly injection. Do not use the same site for each injection. If you take too much Zepbound, call your healthcare provider, seek medical advice promptly, or contact a Poison Center expert right away at 1-800-222-1222. Learn more Zepbound is a prescription medicine. For more information, call 1-800-LillyRx (1-800-545-5979) or go to . This summary provides basic information about Zepbound but does not include all information known about this medicine. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Zepbound and how to take it. Your healthcare provider is the best person to help you decide if Zepbound is right for you. ZP CON CBS 08NOV2023 Zepbound® and its delivery device base are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. INDICATION AND SAFETY SUMMARY WITH WARNINGS Mounjaro® (mown-JAHR-OH) is an injectable medicine for adults with type 2 diabetes used along with diet and exercise to improve blood sugar (glucose). It is not known if Mounjaro can be used in people who have had inflammation of the pancreas (pancreatitis). Mounjaro is not for use in people with type 1 diabetes. It is not known if Mounjaro is safe and effective for use in children under 18 years of age. Warnings - Mounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have any of these symptoms, tell your healthcare provider. Do not use Mounjaro if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC). Do not use Mounjaro if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Do not use Mounjaro if you are allergic to it or any of the ingredients in Mounjaro. Mounjaro may cause serious side effects, including: Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery. Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat. Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration. Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away. Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro. Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools. Common side effects The most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn't go away. Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or . Before using Mounjaro Your healthcare provider should show you how to use Mounjaro before you use it for the first time. Talk to your healthcare provider about low blood sugar and how to manage it. If you take birth control pills by mouth, talk to your healthcare provider before you use Mounjaro. Birth control pills may not work as well while using Mounjaro. Your healthcare provider may recommend another type of birth control for 4 weeks after you start Mounjaro and for 4 weeks after each increase in your dose of Mounjaro. Review these questions with your healthcare provider: ❑ Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food? ❑ Do you take other diabetes medicines, such as insulin or sulfonylureas? ❑ Do you have a history of diabetic retinopathy? ❑ Are you pregnant, plan to become pregnant, breastfeeding, or plan to breastfeed? It is not known if Mounjaro will harm your unborn baby or pass into your breast milk. ❑ Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements? How to take Read the Instructions for Use that come with Mounjaro. Use Mounjaro exactly as your healthcare provider says. Mounjaro is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Use Mounjaro 1 time each week, at any time of the day. Do not mix insulin and Mounjaro together in the same injection. You may give an injection of Mounjaro and insulin in the same body area (such as your stomach area), but not right next to each other. Change (rotate) your injection site with each weekly injection. Do not use the same site for each injection. If you take too much Mounjaro, call your healthcare provider or seek medical advice promptly. Learn more Mounjaro is a prescription medicine. For more information, call 1-833-807-MJRO (833-807-6576) [or go to ]. This summary provides basic information about Mounjaro but does not include all information known about this medicine. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you. TR CON CBS 14SEP2022 Mounjaro® and its delivery device base are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY i Not controlled for type 1 error. ii The efficacy estimand represents efficacy had all patients remained on randomized treatment for the entire planned treatment duration (up to 176 weeks). iii The treatment-regimen estimand represents efficacy regardless of adherence to randomized treatment. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995), including statements about tirzepatide injection for the treatment of adults with type 2 diabetes, tirzepatide as a potential long-term therapy for adults with pre-diabetes and obesity or overweight and the timeline for future presentations and other milestones relating to tirzepatide and its clinical trials, and reflects Lilly's current belief and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of research development and commercialization. Among other things, there can be no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with the results to date, that tirzepatide will receive additional regulatory approvals, or that tirzepatide will be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. SOURCE Eli Lilly and Company

Tirzepatide reduced the risk of heart failure outcomes – heart failure urgent visit or hospitalization, oral diuretic intensification or cardiovascular death – by 38% compared to placebo Tirzepatide significantly improved heart failure symptoms and physical limitations Tirzepatide led to 15.7% weight loss in a combined population of people with and without type 2 diabetes INDIANAPOLIS, Aug. 1, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) announced today positive topline results from the SUMMIT phase 3 clinical trial evaluating the safety and efficacy of tirzepatide injection (5 mg, 10 mg or 15 mg) in adults with heart failure with preserved ejection fraction (HFpEF) and obesity. Tirzepatide demonstrated statistically significant improvements in both primary endpoints with a reduction in the risk of heart failure outcomes, assessed as a composite endpoint, and improvements in heart failure symptoms and physical limitations, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS),i compared with placebo. All key secondary endpoints were also met, including improvement in exercise capacity as measured by the 6-Minute Walk-Test Distance (6MWD), reduction in the inflammation marker high-sensitivity C-reactive protein (hsCRP), and mean body weight reduction from baseline at 52 weeks. For the efficacy estimand,ii tirzepatide led to a 15.7% body weight reduction compared to 2.2% for placebo. For the treatment-regimen estimand,iii tirzepatide led to a 13.9% body weight reduction compared to 2.2% for placebo. "HFpEF accounts for nearly half of all heart failure cases, and in the U.S. almost 60% of those impacted also live with obesity.1,2 Despite a continuing increase in the number of people with both HFpEF and obesity, treatment options remain limited,1" said Jeff Emmick, MD, PhD, senior vice president, product development, Lilly. "Previous incretin studies in this population focused on symptoms and physical limitations. In a first-of-its-kind trial, tirzepatide reduced severity of symptoms and improved heart failure outcomes in people with HFpEF and obesity." Topline Primary Endpoint Results HFpEF is a condition in which the heart's left pumping chamber becomes stiff and unable to fill properly. It is associated with a high burden of symptoms and physical limitations affecting daily life, including fatigue, shortness of breath, reduced ability to exercise and swelling of extremities. The overall safety profile of tirzepatide in the SUMMIT trial was consistent with previously reported tirzepatide studies, including SURMOUNT and SURPASS. The most frequently reported adverse events in SUMMIT were primarily gastrointestinal in nature and generally mild to moderate in severity. The most common adverse events for patients treated with tirzepatide were diarrhea, nausea, constipation and vomiting. Lilly will continue to evaluate the SUMMIT results, which will be presented at an upcoming medical meeting and submitted to a peer-reviewed journal. Lilly plans to submit the SUMMIT study results to the U.S. Food and Drug Administration (FDA) and other regulatory agencies starting later this year. About SUMMIT SUMMIT (NCT04847557) was a multi-center, randomized, double-blind, parallel, placebo-controlled phase 3 study comparing the efficacy and safety of tirzepatide to placebo in adults living with heart failure with preserved ejection fraction (HFpEF) and obesity, with or without type 2 diabetes. The trial randomized 731 participants across the U.S., Argentina, Brazil, China, India, Israel, Mexico, Puerto Rico, Russia and Taiwan in a 1:1 ratio to receive tirzepatide maximum tolerated dose (MTD) 5 mg, 10 mg or 15 mg or placebo. The two primary objectives were to reduce the risk of the composite endpoint of time-to-first occurrence of urgent heart failure visit, heart failure hospitalization, oral diuretic intensification and cardiovascular death to study completion (median follow up of 104 weeks), and change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) from baseline to week 52. SUMMIT utilized MTD of 5 mg, 10 mg or 15 mg once weekly. The starting dose of 2.5 mg tirzepatide was increased by 2.5 mg every four weeks until MTD was achieved. Participants who tolerated 15 mg continued on 15 mg as their MTD. Participants who tolerated 10 mg but did not tolerate 15 mg continued on 10 mg as their MTD, and participants who tolerated 5 mg but did not tolerate 10 mg continued on 5 mg as their MTD. About tirzepatide Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilization. Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are also ongoing. Lilly submitted data for tirzepatide in moderate-to-severe obstructive sleep apnea (OSA) and obesity to the U.S. Food and Drug Administration (FDA) and other global regulatory agencies earlier this year. Tirzepatide was approved by the FDA as Mounjaro® for adults with type 2 diabetes to improve glycemic control on May 13, 2022, and as Zepbound® for adults with obesity (a BMI of 30 kg/m2 or greater) or those who are overweight (a BMI of 27 kg/m2 or greater) who also have a weight-related comorbid condition on November 8, 2023. Both Mounjaro and Zepbound should be used as an adjunct to diet and exercise. INDICATION AND SAFETY SUMMARY WITH WARNINGS Mounjaro® (mown-JAHR-OH) is an injectable medicine for adults with type 2 diabetes used along with diet and exercise to improve blood sugar (glucose). It is not known if Mounjaro can be used in people who have had inflammation of the pancreas (pancreatitis). Mounjaro is not for use in people with type 1 diabetes. It is not known if Mounjaro is safe and effective for use in children under 18 years of age. Warnings - Mounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have any of these symptoms, tell your healthcare provider. Do not use Mounjaro if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC). Do not use Mounjaro if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Do not use Mounjaro if you are allergic to it or any of the ingredients in Mounjaro. Mounjaro may cause serious side effects, including: Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery. Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat. Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration. Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away. Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro. Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools. Common side effects The most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn't go away. Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or . Before using Mounjaro Your healthcare provider should show you how to use Mounjaro before you use it for the first time. Talk to your healthcare provider about low blood sugar and how to manage it. If you take birth control pills by mouth, talk to your healthcare provider before you use Mounjaro. Birth control pills may not work as well while using Mounjaro. Your healthcare provider may recommend another type of birth control for 4 weeks after you start Mounjaro and for 4 weeks after each increase in your dose of Mounjaro. Review these questions with your healthcare provider: ❑ Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food? ❑ Do you take other diabetes medicines, such as insulin or sulfonylureas? ❑ Do you have a history of diabetic retinopathy? ❑ Are you pregnant, plan to become pregnant, breastfeeding, or plan to breastfeed? It is not known if Mounjaro will harm your unborn baby or pass into your breast milk. ❑ Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements? How to take Read the Instructions for Use that come with Mounjaro. Use Mounjaro exactly as your healthcare provider says. Mounjaro is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Use Mounjaro 1 time each week, at any time of the day. Do not mix insulin and Mounjaro together in the same injection. You may give an injection of Mounjaro and insulin in the same body area (such as your stomach area), but not right next to each other. Change (rotate) your injection site with each weekly injection. Do not use the same site for each injection. If you take too much Mounjaro, call your healthcare provider or seek medical advice promptly. Learn more Mounjaro is a prescription medicine. For more information, call 1-833-807-MJRO (833-807-6576) or go to . This summary provides basic information about Mounjaro but does not include all information known about this medicine. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you. TR CON CBS 14SEP2022 Mounjaro® and its delivery device base are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. INDICATION AND SAFETY SUMMARY WITH WARNINGS Zepbound® (ZEHP-bownd) is an injectable prescription medicine that may help adults with obesity, or with excess weight (overweight) who also have weight-related medical problems, lose weight and keep it off. It should be used with a reduced-calorie diet and increased physical activity. Zepbound contains tirzepatide and should not be used with other tirzepatide-containing products or any GLP-1 receptor agonist medicines. It is not known if Zepbound is safe and effective when taken with other prescription, over-the-counter, or herbal weight loss products. It is not known if Zepbound can be used in people who have had pancreatitis. It is not known if Zepbound is safe and effective for use in children under 18 years of age. Warnings - Zepbound may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have any of these symptoms, tell your healthcare provider. Do not use Zepbound if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC). Do not use Zepbound if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Do not use Zepbound if you have had a serious allergic reaction to tirzepatide or any of the ingredients in Zepbound. Zepbound may cause serious side effects, including: Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Zepbound. Tell your healthcare provider if you have stomach problems that are severe or will not go away. Kidney problems (kidney failure). Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Gallbladder problems. Gallbladder problems have happened in some people who use Zepbound. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), or clay-colored stools. Inflammation of the pancreas (pancreatitis). Stop using Zepbound and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. Serious allergic reactions. Stop using Zepbound and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, or very rapid heartbeat. Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Zepbound with medicines that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, mood changes, hunger, weakness or feeling jittery. Changes in vision in patients with type 2 diabetes. Tell your healthcare provider if you have changes in vision during treatment with Zepbound. Depression or thoughts of suicide. You should pay attention to changes in your mood, behaviors, feelings or thoughts. Call your healthcare provider right away if you have any mental changes that are new, worse, or worry you. Common side effects The most common side effects of Zepbound include nausea, diarrhea, vomiting, constipation, stomach (abdominal) pain, indigestion, injection site reactions, feeling tired, allergic reactions, belching, hair loss, and heartburn. These are not all the possible side effects of Zepbound. Talk to your healthcare provider about any side effect that bothers you or doesn't go away. Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or . Before using Zepbound Your healthcare provider should show you how to use Zepbound before you use it for the first time. Tell your healthcare provider if you are taking medicines to treat diabetes including insulin or sulfonylureas which could increase your risk of low blood sugar. Talk to your healthcare provider about low blood sugar levels and how to manage them. If you take birth control pills by mouth, talk to your healthcare provider before you use Zepbound. Birth control pills may not work as well while using Zepbound. Your healthcare provider may recommend another type of birth control for 4 weeks after you start Zepbound and for 4 weeks after each increase in your dose of Zepbound. Review these questions with your healthcare provider: ❑ Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food? ❑ Do you take diabetes medicines, such as insulin or sulfonylureas? ❑ Do you have a history of diabetic retinopathy? ❑ Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements? ❑ Are you pregnant, plan to become pregnant, breastfeeding, or plan to breastfeed? Zepbound may harm your unborn baby. Tell your healthcare provider if you become pregnant while using Zepbound. It is not known if Zepbound passes into your breast milk. You should talk with your healthcare provider about the best way to feed your baby while using Zepbound. Pregnancy Exposure Registry: There will be a pregnancy exposure registry for women who have taken Zepbound during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry, or you may contact Lilly at 1-800-LillyRx (1-800-545-5979). How to take: Read the Instructions for Use that come with Zepbound. Use Zepbound exactly as your healthcare provider says. Zepbound is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Use Zepbound 1 time each week, at any time of the day. Change (rotate) your injection site with each weekly injection. Do not use the same site for each injection. If you take too much Zepbound, call your healthcare provider, seek medical advice promptly, or contact a Poison Center expert right away at 1-800-222-1222. Learn more: Zepbound is a prescription medicine. For more information, call 1-800-LillyRx (1-800-545-5979) or go to . This summary provides basic information about Zepbound but does not include all information known about this medicine. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Zepbound and how to take it. Your healthcare provider is the best person to help you decide if Zepbound is right for you. ZP CON CBS 08NOV2023 Zepbound® and its delivery device base are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY i The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) is a patient-reported outcome instrument that uses a 1-100 point scale to assess heart failure symptoms and physical limitations. Higher KCCQ-CSS values indicate better symptom management and reduced physical limitations in people with heart failure. ii The efficacy estimand represents efficacy prior to discontinuation of study drug. iii The treatment-regimen estimand represents the estimated average treatment effect regardless of treatment discontinuation. References Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2023;118(18):3434-3450. doi:10.1093/cvr/cvac120 Allen LA, Tang F, Jones P, Breeding T, Ponirakis A, Turner SJ. Signs, symptoms, and treatment patterns across serial ambulatory cardiology visits in patients with heart failure: insights from the NCDR PINNACLE® registry. BMC Cardiovasc Disord. 2018 May 3;18(1):80. doi: 10.1186/s12872-018-0808-2. PMID: 29724164; PMCID: PMC5934811. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about tirzepatide as a potential treatment for people with heart failure with preserved ejection fraction (HFpEF) and obesity and the timeline for future readouts, presentations, and other milestones relating to tirzepatide and its clinical trials, and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that tirzepatide will prove to be a safe and effective treatment for HFpEF and obesity, that tirzepatide will receive additional regulatory approvals, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. SOURCE Eli Lilly and Company

引言 核旁斑组装转录本1 (NEAT1)是一种高度丰富且保守的长链非编码 RNA (lncRNA)，从多发性内分泌肿瘤 (MEN) 基因座转录，编码 NEAT1-1（或 MEN-ε，~3.7 kb）和 NEAT1-2（或 MEN-β，~22.7 kb）。NEAT1-2 lncRNA是核旁斑 (paraspeckles)的主要结构支架。它招募多种 RNA 结合蛋白 (RBP)，包括 NONO、SFPQ、FUS 和 TDP43，驱动液-液相分离 (LLPS) 并塑造这种动态、无膜、和分层的核体。通过组织和调控核内多种重要RBP的定位和富集，NEAT1 在调节染色质状态、转录、剪接、RNA 加工和稳定性【1, 2】，以及在器官发育、神经变性、抗病毒免疫和癌症中发挥多种功能【3, 4】。 NEAT1，MALAT1，以及其他至少130个后生动物的lncRNA 缺失稳定多数mRNA的 3′ poly(A) 尾。这些lncRNA则利用它们3′ 末端的稳定RNA三螺旋（triplex）结构以免受外切核酸酶快速降解【5, 6】。NEAT1 和 MALAT1的前体均通过模仿tRNA结构以招募RNase P切割其5′ 引导序列，产生成熟lncRNA。与此同时，被RNase P切割后的tRNA类似结构生成两个新的小非编码RNA，被分别命名为mascRNA （来自MALAT1）和menRNA（来自NEAT1）【7】。随后，ELAC2（ElaC同源蛋白2，或RNase Z）去除menRNA 的3′ 尾部，然后CCA-添加酶对mascRNA 和menRNA添加3′ CCA尾。这里，有趣的是mascRNA仅接收一次CCA 添加，形成类似tRNA的正常3′ CCA末端尾。然而menRNA 连续接受两次CCA加尾，形成较长的CCACCA尾，造成了核酸外切酶的a招募而在胞内快速降解【8】。目前为止menRNA 的三维结构仍然未知。关于menRNA重复加尾的分子机制，一个从蛋白质角度出发的“分子台虎钳 （molecular vise）”模型提出，在第一次添加 CCA 时，CCA添加酶的“头部”区域通过自身的螺旋运动并协同在远端静态固着在menRNA臂肘（elbow）的“尾部”区域对menRNA或者有结构缺陷的tRNA进行旋转性的机械压缩，造成menRNA局部构象变化，产生一个三个碱基长的侧面凸起，剩余的碱基重新配对，从而实现RNA底物重置，可以重复添加 CCA【9】。然而，目前尚不清楚menRNA是否只是被动地被蛋白酶操控，或者通过调控其自身构象从而指导蛋白酶的功能，以决定其自身的命运。并且，上述模型中蛋白机械做功的能量来源，以及此酶需要对RNA施加多大的扭矩来驱动其构象改变，并不明确。2024年7月18日，美国国立卫生研究院（NIH）资深研究员张金伟研究组在Nature Structural & Molecular Biology杂志上再次发表题为Structural basis of NEAT1 lncRNA maturation and menRNA instability的文章解析首个menRNA晶体结构。menRNA结构和张金伟研究组最近报道的mascRNA结构整体相当类似【10】，但是在氨基酸接受茎环区域有序列上，结构上和稳定性上的差异, 为menRNA之后发生构象变化奠定了基础。 a. NEAT1 lncRNA 末端成熟和menRNA产生的流程图。b. 人源menRNA的整体结构 c. 对比menRNA， mascRNA， 和tRNA的结构相似性和差异。（Credit: Nature Structural & Molecular Biology） 作者而后通过酶动力学、时间相关单光子计数 (TCSPC)、圆二色性 (CD)、实时荧光定量PCR等多种生物化学和生物物理手段揭示了menRNA招募RNase P， ELAC2， 和CCA-添加酶等多个tRNA加工酶的分子机理。利用高精度时间相关单光子计数 (TCSPC) 和圆二色性 (CD) 分析，文章作者发现3’端带有一个CCA尾的menRNA在没有蛋白酶结合或者作用的情况下自身发生了显著构象变化，自主产生了三碱基的侧凸并重组了附近的碱基配对，以此指示CCA添加酶进行第二轮的CCA添加。然后，文章作者去除了CCA添加酶的尾部或者与尾部直接接触menRNA的臂肘区域，发现第二轮CCA添加仍然可以正常进行。这些实验结果与之前提出的分子台虎钳模型明显不符【9】，并且与menRNA驱动自身构象转变的新机理模型完全一致。 a. RNase P和ELAC2 加工NEAT1产生menRNA的前体。b. menRNA和CCA添加酶的结合体结构模型。c. menRNA通过自发构象转变指示CCA添加酶重复CCA 添加，产生CCACCA尾，促进胞内迅速降解。（Credit: Nature Structural & Molecular Biology） 综上，一大类后生动物内以NEAT1 和MALAT1为例的lncRNA采用一种新颖的、异常精简的准tRNA结构来招募指定的tRNA加工酶，同时避免被其他不利的tRNA酶识别，以驱动精准定制的RNA生成、加工和成熟。在核内实现NEAT1 成熟和稳定化之后，menRNA 氨基酸接受茎环区域特异的的序列和结构造成热力学驱动的自主构象转变和茎区配对重组，从而操控CCA添加酶实现两轮CCA添加，促进其自身的快速降解。因此，menRNA的这种作用模式类似于原核生物里广泛存在的转录衰减子和核糖开关。后期出现的下游RNA序列改变了整体RNA的最稳定构象，通过热力学过程驱动预先指定的自身构象转变。这种趋同机制赋予了多种非编码RNA实质性的构象自控能力，并通过自主构象变化来指导RNA聚合酶、核糖体和RNA加工酶发挥RNA预先制定的功能，最终自身决定这些RNA在转录、翻译和降解过程的命运。 参考文献 1. Butler, A.A., et al., Long noncoding RNA NEAT1 mediates neuronal histone methylation and age-related memory impairment. Sci Signal, 2019. 12(588). 2. Hirose, T., et al., NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. Mol Biol Cell, 2014. 25(1): p. 169-83. 3. Adriaens, C., et al., p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat Med, 2016. 22(8): p. 861-8. 4. Imamura, K., et al., Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli. Mol Cell, 2014. 53(3): p. 393-406. 5. Zhang, B., et al., Identification and Characterization of a Class of MALAT1-like Genomic Loci. Cell Rep, 2017. 19(8): p. 1723-1738. 6. Brown, J.A., et al., Formation of triple-helical structures by the 3'-end sequences of MALAT1 and MENbeta noncoding RNAs. Proc Natl Acad Sci U S A, 2012. 109(47): p. 19202-7. 7. Wilusz, J.E., S.M. Freier, and D.L. Spector, 3' end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell, 2008. 135(5): p. 919-32. 8. Wilusz, J.E., et al., tRNAs marked with CCACCA are targeted for degradation. Science, 2011. 334(6057): p. 817-21. 9. Kuhn, C.D., et al., On-enzyme refolding permits small RNA and tRNA surveillance by the CCA-adding enzyme. Cell, 2015. 160(4): p. 644-658. 10. Skeparnias, I., et al., Structural basis of MALAT1 RNA maturation and mascRNA biogenesis. Nat Struct Mol Biol, 2024. https://www-nature-com.libproxy1.nus.edu.sg/articles/s41594-024-01361-z 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述