The trial involved only 10 patients, but it suggests cholesterol can be permanently reduced with a single treatment for patients at risk of heart disease.The handful of patients had severe heart disease that had caused chest pain and heart attacks. After trying available cholesterol-lowering medications, they could not get their cholesterol as low as cardiologists recommended.So they volunteered for an experimental cholesterol-lowering treatment using gene editing that was unlike anything tried in patients before.The result, reported Sunday by the company Verve Therapeutics of Boston at a meeting of the American Heart Association, showed that the treatment appeared to reduce cholesterol levels markedly in patients and that it appeared to be safe.The trial involved only 10 patients, with an average age of 54. Each had a genetic abnormality, familial hypercholesterolemia, that affects around one million people in the United States. But the findings could also point the way for millions of other patients around the world who are contending with heart disease, which remains a leading cause of death. In the United States alone, more than 800,000 people have heart attacks each year.And while more trials in a broader range of patients will need to be carried out, gene editing experts and cardiologists said the treatment had the potential to transform preventive cardiology.“Even for seasoned veterans of this field like myself, this is a day we will look back on,” said Fyodor D. Urnov, a gene editor at the Innovative Genomics Institute in Berkeley, Calif.. “I see today as crossing a Rubicon, in a good way. This is not a small step. It is a leap into new territory.”Impressed with the data and the potential it shows, the pharmaceutical giant Eli Lilly paid $60 million to to collaborate with Verve Therapeutics and opted to acquire additional rights to Verve’s programs for an additional $250 million. If the editing continues to look promising, Eli Lilly expects to help with larger studies.“Until now, we thought of gene editing as a treatment we should reserve for very rare diseases where there is no other treatment,” said Dr. Daniel Skovronsky, Eli Lilly’s chief scientific and medical officer. “But if we can make gene editing safe and widely available, why not go after a more common disease?”The new study was led by Dr. Sekar Kathiresan, chief executive of Verve. Patients received a single infusion of microscopic lipid nanoparticles containing within them a molecular factory to edit a single gene in the liver, the site of cholesterol synthesis. The gene, PCSK9, raises levels of LDL cholesterol, the bad kind. The plan was to block it.The little lipid spheres were carried through the blood directly to the liver. They entered liver cells and opened up, revealing two molecules. One instructs DNA to make a gene editing tool, and the other is a guide to take the editing tool to the gene that needs editing.The treatment “is almost like science fiction,” said Dr. Martha Gulati, director of preventive cardiology at the Smidt Heart Institute of Cedars-Sinai Medical Center in Los Angeles and president of the American Society for Preventive Cardiology, who was not involved in the trial.The gene editing tool acts like a pencil and an eraser. The eraser wipes out one letter of the target gene, and the pencil writes in a new one, turning off PCSK9.The goal: a single cholesterol-lowering treatment that results in lifelong protection from heart disease.Patients received varying doses. LDL levels in the three who received the highest doses fell by 39 to 55 percent — enough to get them toward their cholesterol goal.In the small study, those who received the higher doses had flulike symptoms for a few hours. Two patients had serious adverse events that the study’s independent data safety and monitoring board deemed a result of their underlying severe heart disease. The board advised the researchers not to stop the study.One had a fatal cardiac arrest five weeks after receiving the infusion. An autopsy showed that several of his coronary arteries were blocked.The other patient had a heart attack the day after the infusion. It turned out that he had been having chest pain before receiving the infusion but had not reported it. If the investigators had known, he would not have received the treatment.In a way, the treatment is a culmination of studies that began a decade ago when researchers discovered rare but healthy individuals with cholesterol levels that seemed impossibly low. The reason was that their PCSK9 gene was mutated and no longer functioned. As a result, these people were protected from heart disease.That led to the development of antibodies to block the gene. Patients inject themselves with the antibodies once a week. Then came a twice-yearly RNA injection that prevents PCSK9 from being made.It seemed possible that those treatments, as well as statins for those whose cholesterol is more easily controlled, could help solve the heart disease problem.But heart disease persists as a killer. Even after people are diagnosed with heart disease, less than 60 percent of all patients take a statin. Only a quarter take one of the more effective, high-intensity statins, Dr. Gulati said.“Patients take it initially, and then they forget or decide they don’t need it,” she explained. “That happens more than you’d think.”Dr. Michelle O’Donoghue, a cardiologist at Brigham and Women’s Hospital, said that because patients so often do not take their pills or injections, “there is a lot of interest, through gene editing, of a one and done — a single treatment and a lifetime response.”Family history was the inspiration for Dr. Kathiresan at Verve Therapeutics. His uncle and grandmother died of heart attacks. His father had a heart attack at age 54. And then, on Sept. 12, 2012, his 42-year-old brother, Senthil, returned from a run dizzy and sweaty. He was having a heart attack. He died nine days later.At that moment, Dr. Kathiresan said, he vowed to find a way to prevent what had happened to his brother from happening to anyone else.Of course, even if gene editing works, applying it to young people with heart risk is well into the future. But, Dr. Gulati said, early gene editing of younger patients with genetically high cholesterol levels might prevent arteries from hardening.“It could be an incredible medicine,” she said.All this depends on success and safety of the gene editing and on its effects lasting. The first patient was treated just six months ago. But a previous study in monkeys lasted two and a half years, and the results of the gene editing persisted.Dr. Urnov, who said he has a genetic risk for heart disease, is optimistic for himself and his 6-year-old daughter.“I honestly cannot wait for this medicine to become available for heart disease prevention,” he said. “I love the idea of having gene editing as a vaccine for the prevention of heart disease.”

Zepbound, which is already sold by Eli Lilly as the diabetes treatment Mounjaro, was shown to reduce patients’ weight by as much as one-fifth in drug trials.The Food and Drug Administration on Wednesday approved an obesity drug from the company Eli Lilly that will be a direct competitor to the wildly popular Wegovy.The drug is called tirzepatide and will be sold under the name Zepbound. It joins a class of new medications that are transforming obesity, a condition that affects 100 million American adults and is linked to a spectrum of diseases including diabetes, heart disease, sleep apnea, liver disease, kidney disease and joint pain.Patients who used tirzepatide lost an average of 18 percent of their body weight, according to the F.D.A., when it was taken at its highest dose in a drug trial. That’s compared with Wegovy, manufactured by Novo Nordisk, which produced an average 15 percent weight loss.The F.D.A. approved Zepbound for people with obesity and for those who are overweight and have at least one obesity-related condition.Tirzepatide is already approved for diabetes under the brand name Mounjaro where it competes with Novo Nordisk’s diabetes drug semaglutide, known better as Ozempic. But until now, Wegovy — also semaglutide but with a higher maximum dose than Ozempic — was the only approved drug that could safely elicit substantial weight loss in people with obesity alone.Side effects with Zepbound, similar to those with Wegovy, Ozempic and Mounjaro, are mostly gastrointestinal, like nausea and diarrhea. Most patients tolerated or overcame them.In a news release, Dr. John Sharretts, director of the Division of Diabetes, Lipid Disorders and Obesity in the F.D.A.’s Center for Drug Evaluation and Research, said, “In light of increasing rates of both obesity and overweight in the United States, today’s approval addresses an unmet medical need.”Susan Yanovski, co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases, said, “Just a few years ago it would be difficult to imagine two medications like semaglutide and tirzepatide that lead to weight loss that previously was only seen when people had bariatric surgery,” referring to a surgical treatment that is a proven effective treatment for obesity.The approval comes at a time when Novo Nordisk is unable to produce enough Wegovy to satisfy the huge demand for the drug. Tirzepatide, which patients take by a self-administered injection once a week, as they do with Wegovy, could ease those shortages.Competition could also result in lower net prices for both drugs, or how much payers actually spend on them. The prices are high for Wegovy — with a list price up to $1,349 every four weeks in one recent analysis, and a net price around $700. Zepbound is starting with a list price of around $1,060, according to Eli Lilly.“You’d want the price competition to come sooner rather than later,” said Craig Garthwaite, a health care economist at Northwestern University. Once people start taking one of these drugs, he said, “they get locked in.” They resist switching even if a competing drug costs less.Development of Zepbound began in 2017 with a small study involving 300 people with type 2 diabetes. After 3 months, many lost at least 13 percent of their body weight. Eli Lilly presented the data at a diabetes meeting in Germany. Some in the audience gasped. Then came a large 72-week study sponsored by Eli Lilly of tirzepatide in 2,539 people with obesity.In a packed room at a meeting of the American Diabetes Association last year, the study’s principal investigator, Dr. Ania Jastreboff of Yale, revealed the results. More than half the patients receiving the highest dose lost at least 20 percent of their body weight.No drug has ever before shown such a profound weight loss.For Eli Lilly, the results were a culmination of research that began a decade ago. But like Novo Nordisk, the company was trying to produce a new diabetes drug.“Obesity wasn’t a main focus for us,” Dr. Daniel Skovronsky, the chief scientific and medical officer at Eli Lilly, said, adding that “it was not seen as a commercial opportunity.”The sad history of weight loss drugs was a lesson, he thought. “There had never been a successful obesity drug,” he said, “and previous drugs didn’t cause enough weight loss to have an impact on peoples’ health.”But researchers at Eli Lilly had started investigating a diabetes drug that combined two molecules. One molecule acts like a hormone, GLP-1, that prompts the body to secrete insulin when blood sugar rises. That was similar to the effects of Novo Nordisk’s Ozempic and Wegovy. And like those drugs, it also suppresses appetite.But more than one hormone is involved when the body regulates blood sugar, so the company’s scientists decided to try combining the molecule that mimics GLP-1 with a second molecule that acts like the gut hormone GIP. Although GIP has a more modest effect when given alone, it amplified GLP-1’s effect when the two hormone mimics were combined.In mice, the two-drug combination not only lowered blood sugar but also had a profound effect on weight. It was “the most weight loss we’d ever seen,” Dr. Skovronsky said.The company’s scientists tested the drug in healthy volunteers. Even though they did not have obesity, the people lost weight.Suddenly, Eli Lilly’s opinion of studying weight loss changed.“We thought, ‘This medicine can change the world,’” Dr. Skovronsky said. “We said: ‘This is the one. This is our priority.’”They decided to speed development with an approach known as “investing at risk” in which they do not wait for each stage of testing to be completed before starting the next, and in which they start building manufacturing capability before studies are completed. The result was a pace that was a record for the company — six years from the first dose in human volunteers to F.D.A. approval. A similar strategy was also used to speed up Covid vaccine development.The hope is that Zepbound can reduce the chances that people with obesity will develop the potentially deadly complications that accompany the condition.But Zepbound is only the beginning for Eli Lilly. The company and other pharmaceutical manufacturers are working on drugs that could be even more powerful.The next Lilly drug adds glucagon, another gut hormone, to the two in Zepbound. It apparently stimulates metabolism and draws fat out of the liver.And, like Novo Nordisk and other companies, Eli Lilly is working on a pill form of tirzepatide. It is undergoing clinical testing.Making injectable drugs is complicated and challenging. Pills are simpler and cheaper, which could improve the supply problem that has affected patients who use Ozempic and Wegovy.It is estimated that by 2030, a billion people in the world will have obesity.“All the companies in the world cannot make that many injections,” Dr. Skovronsky said. “Clearly if we are going to meet the needs of the global epidemic, we need oral drugs.”

The decision by an advisory committee may lead to Food and Drug Administration approval of the first treatment for humans that uses the CRISPR gene-editing system.A panel of experts said on Tuesday that a groundbreaking treatment for sickle cell disease was safe enough for clinical use, setting the stage for likely federal approval by Dec. 8 of a powerful potential cure for an illness that afflicts more than 100,000 Americans.The Food and Drug Administration had previously found that the treatment, known as exa-cel and jointly developed by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland, was effective. The panel’s conclusion on Tuesday about exa-cel’s safety sends it to the F.D.A. for a decision on greenlighting it for broad patient use.Exa-cel frees patients from the debilitating and painful effects of this chronic, deadly disease. If approved, the Vertex product would be the first medicine to treat a genetic disease with the CRISPR gene-editing technique.It could also be the first of a series of new options to cure the excruciating illness. By Dec. 20, the F.D.A. will decide on a second potential cure for sickle cell, a gene therapy devised by the company Bluebird Bio of Somerville, Mass.Sickle cell disease is caused by a gene mutation that makes blood cells misshapen, so that they resemble sickles or crescents. It affects millions of people worldwide, most of whom have African ancestry. The misshapen cells get stuck in blood vessels, causing strokes, organ damage and episodes of agonizing pain as muscles are starved of oxygen.Sickle cell’s toll starts early in life. Evelyn Islam of Milwaukee, now 8, had 22 blood transfusions and had to have her spleen removed before she was 3. “Gene therapy is our last hope for a cure,” said her mother, Melissa Nicole Allen.Ashley Valentine, a co-founder of the national advocacy group Sick Cells, at her parents’ home in Lisle, Ill. Her brother Marqus, pictured on the wall, died in 2020.Mustafa Hussain for The New York TimesBut the new gene therapies will come too late for many.Ashley Valentine, a co-founder of the national advocacy group Sick Cells, had to take three months off from work in 2016 to help her brother Marqus deal with symptoms of sickle cell. When he had a hip replacement in 2018, her father ended up accepting a layoff from his job to help care for him.“And that’s just us,” she said.Marqus died in 2020, at age 36, from a stroke caused by sickle cell.New treatments like the one that was endorsed on Tuesday are expected to cost millions of dollars per patient, though Vertex has not yet said what it will charge. But lifelong care for patients with the disease is also enormously expensive, costing the health care system an estimated $3 billion a year.It’s not yet clear how many people will seek the new therapy. The new therapies are also not easy to endure and come with hardships for patients, who will have to undergo chemotherapy and spend more than a month in the hospital. Family members are affected too — they may need to take time off work during the most intensive phase of the treatment.Additionally, most Americans with sickle cell are Black and may not trust a health care system that has often failed to provide the most basic preventive and therapeutic care for those with the disease. Some with sickle cell are anxious about undergoing a medical treatment that is on the cutting edge of biotechnology.But for doctors who have spent years watching patients suffer, and many parents who have seen their children endure years of agony, there is elation at what lies ahead.“We are finally at a spot where we can envision broadly available cures for sickle cell disease,” said Dr. John Tisdale, director of the cellular and molecular therapeutics branch at the National Heart, Lung and Blood Institute and a member of the advisory committee.Dana Jones of San Antonio wants her daughters Kyra, 18, and Kami, 20, to have a chance at one of the new therapies. Both had strokes that left them with learning disabilities — injuries that could probably have been avoided if they had been given a screening test and treatment long known to prevent nine out of 10 strokes in children with the disease. Kyra is now in intensive care as doctors try to control her pain.Ms. Jones is overwhelmed by the possibility that her daughters could be cured.“It is my prayer that Kami and Kyra can be cured of this awful disease and finally be able to truly live,” she said.A New Treatment and a New TechnologySickle cell disease is caused by a gene mutation that makes blood cells misshapen. The misshapen cells can get stuck in blood vessels, causing strokes, organ damage and episodes of agonizing pain.F. Gilbert/CDC, via Associated PressThe cause of sickle cell has been known for nearly 70 years, but research lagged, a situation many say occurred at least in part because so many patients were Black and from poor and working-class families.There are a number of treatments to reduce sickle cell’s impact. Some patients are able to get bone marrow transplants that can cure the condition. But that requires finding a donor and, after the transplant, taking drugs to prevent the body from rejecting the foreign cells.In recent years, a number of biotechnology companies have tried novel approaches. While Bluebird Bio is advancing its gene therapy technique, Vertex and CRISPR Therapeutics focused on the gene-editing system CRISPR-Cas9, which can home in on specific areas of DNA and turn genes on or off. CRISPR has allowed researchers to disable genes to assess their importance in biomedical research. But until now it has not been used as a treatment for patients with a genetic disease.To treat sickle cell, CRISPR snips a piece of DNA in bone marrow stem cells. That frees a blocked gene to make a form of hemoglobin that normally is produced only by a fetus. The fetal gene directs the production of hemoglobin that does not form into the sickle shape. In clinical trials, patients no longer had the complications of sickle cell disease and no longer needed blood transfusions.But there is a concern that CRISPR could inadvertently snip a piece of DNA in the wrong part of a patient’s genome. That might disrupt a gene and cause a blood cancer.No such issues have turned up in the clinical trials, but the Vertex trial involved only 44 patients, and just 30 have been followed for at least 16 months. The company did extensive comparisons of patients’ DNA with that of people in large databases asking how likely such CRISPR misfires could be.Vertex said it plans to follow clinical trial patients for 15 years. The company’s data were sufficiently reassuring that the expert committee said on Tuesday they saw no reason to hold the treatment back.There can always be additional studies, noted committee member Alexis Komor, a professor of chemistry and biochemistry at the University of California, San Diego. But, she said, that would be “expecting perfection at the expense of progress.”Dr. Joseph Wu of Stanford added, “We all agree that the benefits outweigh the risks. These patients are quite sick and this is a good therapy.”Scot Wolfe of the University of Massachusetts Chan Medical School said, “We want to be careful not to let the perfect be the enemy of the good.”“There is a huge unmet need,” he added.If It’s Safe, Who Gets It?Vertex Pharmaceuticals’ headquarters in Boston.Bill Sikes/Associated PressVertex estimates that 20,000 people could be eligible for its treatment, and says Medicaid and private insurers have suggested a willingness to pay for it.“There is almost no way they could not pay,” said Dr. David Williams, chief of the division of hematology and oncology at Boston Children’s Hospital.Dr. Williams, who has consulted for Vertex and Bluebird Bio, added that insurers pay “$3 million a pop” for other gene therapies produced by Bluebird Bio for the diseases thalassemia and adrenoleukodystrophy. With sickle cell, and its large number of Black patients, he said, there is an issue of “equity in access and the tremendous medical need.”Some people with the disease may not be eligible, depending on the F.D.A.’s decisions. They could include young children with sickle cell and older patients whose bodies have been so damaged that the treatment could pose heightened risks.Kevin Wake of Kansas City, Mo., hopes he is not too old, at 55, or too damaged. He has had three strokes caused by the disease.The treatments, though curative, are difficult.Patients first have eight weeks of blood transfusions followed by a treatment to release bone marrow stem cells into their bloodstream. The stem cells are then removed and sent to the companies to be treated. Next, patients receive intense chemotherapy to clear their marrows for the treated cells. The treated cells are infused back into the patients, but they have to remain in the hospital for at least a month while the new cells grow and repopulate their marrows.That treatment “cannot be delivered at most hospitals,” said Dr. Alexis Thompson, chief of the division of hematology at Children’s Hospital of Philadelphia, who consults for Vertex.Another issue is how quickly Vertex can ramp up production. Each patient’s cells must be treated individually in a sterile environment, an arduous prospect.Stuart Arbuckle, executive vice president and chief operating officer at Vertex, is confident. “We are launch ready,” he said. But he added that he did not expect a huge wave of patients immediately.“This is a pretty big decision for a patient to go through,” Mr. Arbuckle said. Dana Jones with her daughter Kyra, now 18, in 2020. Kyra and her sister Kami have had strokes that caused them to have learning disabilities, and Kyra is currently in intensive care as doctors try to control her pain.Ilana Panich-Linsman for The New York TimesOne of the Vertex clinical trial patients, Marie-Chantal Tornyenu, 22, who is a senior at Cornell University, said patients also had to be prepared for “mental adjustment” after treatment.Ms. Tornyenu said she no longer had the pain crises that plagued her, especially in high school when she was hospitalized nearly every month.But she has spent much of her life taking precautions and worrying about pain and complications from sickle cell. Those habits are hard to break.“It’s a major learning curve from having sickle cell my whole life,” she said. “I’m still struggling with that mind-set — ‘sickle cell is you.’”

The treatment from the company Vertex would be the first medicine to use the gene editing tool CRISPR.The LatestOn Tuesday, Oct. 31, an advisory committee to the Food and Drug Administration will consider a gene editing treatment for sickle cell disease, a potentially deadly, excruciatingly painful, lifelong condition in which blood cells are deformed.If the panel finds the safety data acceptable and does not think the treatment needs additional study, and the F.D.A.’s commissioner concurs with its assessment, it will be the first medicine to use the revolutionary tool, CRISPR, to snip out a piece of DNA. Other comparable treatments for sickle cell could follow.“This is a huge deal,” said Dr. John Tisdale, director of the cellular and molecular therapeutics branch at the National Heart, Lung and Blood Institute.A sickle cell disease patient received a blood transfusion to alleviate his pain at a hospital in Kansas City, Mo.Tammy Ljungblad/The Kansas City Star/Tribune News Service, via Getty ImagesWhy It Matters: A disease with a toll that is difficult to imagine.An estimated 100,000 people in the United States have sickle cell disease, most of whom have African ancestry. Sickle cell shortens lives, injures organs and bones and causes episodes of searing pain that can repeatedly send patients to emergency rooms, or lead to lengthy hospital stays.A report by the Institute for Clinical and Economic Review said that for people who don’t have sickle cell disease, “it is hard to understand the physical, emotional and mental toll.” People with the disease, the report added, “not only described intense fatigue, anxiety and depression, but at times extreme hopelessness.”One patient, Mariah Jacqueline Scott, 32, who lives in Highland Park, N.J., has had two hip replacements, two shoulder replacements, a splenectomy, a gall bladder removal and a tonsillectomy because of the disease. She spent the year after her daughter was born in and out of the hospital being treated for extreme pain caused by blocked blood vessels. She had her second shoulder replacement after her shoulder collapsed while she was holding her baby.The only cure has been a bone-marrow transplant, which requires finding a donor, undergoing intensive chemotherapy and taking immunosuppressive drugs. But gene editing offers an alternative. Vertex and CRISPR Therapeutics, the makers of the treatment being taken up by the F.D.A. committee on Tuesday, said that in clinical trials, symptoms of the disease went away after patients had the treatment. So far, the patients appear to be cured. The technique activates a gene that can make normally functioning blood cells.Ms. Scott said she knew gene editing was arduous, but she was seriously considering undergoing the treatment when it became available.Facts to Keep in Mind: Gene therapies bring their own challenges.Vertex’s therapy starts when doctors remove stem cells from the blood and send them for treatment. Next comes intense chemotherapy to completely clear the bone marrow before the treated cells are injected. After that, patients must spend at least a month in a hospital while the treated cells repopulate the bone marrow.Because each patient’s cells must be treated individually there are questions about how quickly companies can ramp up production.“Manufacturing is very complicated,” said Dr. Stephan Grupp, chief of the cellular therapy and transplant section of Children’s Hospital of Philadelphia, who consults for Vertex.Treatment will be extremely expensive, potentially in the millions of dollars per patient, and the companies will not say how many patients they expect to be able to treat at first.Gene editing can also impose personal hardship on patients and their families. A hospital with the expertise to administer the treatment and care for patients may be far from home. And patients must stay there for a long period of time.What’s next: More F.D.A. decisions and more drugs.If the advisory committee recommends the Vertex treatment, the F.D.A. will decide whether to approve it on Dec. 8.On Dec. 20, the F.D.A. will decide on another application for sickle cell gene therapy made by Bluebird Bio. Two other companies and an academic center, Boston Children’s Hospital, are testing their own sickle cell gene therapies.While these therapies could reduce the suffering of sickle cell patients in the United States and other wealthy countries, there is an even greater need for them in some developing countries like Nigeria. However, they will be difficult to export to developing countries because the treatments are extremely expensive and they can only be administered at hospitals where doctors have expertise in a number of advanced techniques.One company, Beam, is testing a way to provide gene editing that requires nothing more than a single infusion in a doctor’s office. Vertex has what it calls an “aspirational” method that would deliver gene editing in a pill.

Drug companies are making billions from a new class of in-demand weight-loss treatments. But the prices are not what they seem.The problem is daunting: Powerful but expensive new drugs could help many of the 100 million American adults who have obesity and alleviate a grave public health concern.But how can the nation afford lifelong treatments for so many people, with sticker prices for each patient ranging from about $900 to $1,300 every four weeks?Some researchers, like Dr. Walter C. Willett, professor of epidemiology and nutrition at the Harvard T.H. Chan School of Public Health, have warned that the drugs could add 50 percent to the country’s health care spending.“You can see this ballooning completely out of control,” he said.But there is one factor often left out of these discussions: The drugs’ list prices are generally very different from the net prices, which companies receive after making secret deals with health insurers or the intermediaries known as pharmacy benefit managers. Companies generally do not reveal net prices, but there are data sources that can be used to estimate them.A recent paper published by the American Enterprise Institute revealed that the net prices for the new obesity drugs are just a fraction of the published annual list prices.And while the drugs’ prices remain out of reach for many, economists anticipate they will soon be driven down. More than a dozen companies are developing obesity drugs. As they enter the market, greater choice is expected to make prices plummet, as has happened with other expensive drugs.“My prediction is that as competition increases, prices will decrease accordingly,” said Jalpa Doshi, professor of medicine and director of the economics evaluation unit at the University of Pennsylvania.Strong Demand, Falling Prices?For now, manufacturers are reaping the rewards of soaring demand.Investors expect Novo Nordisk, the manufacturer of Wegovy, to earn $4 billion in revenue this year. The company’s other drug, Ozempic, is expected to bring in $11 billion. The drugs are driving such a bonanza that they account for almost all of the latest economic growth in Denmark, the home of Novo Nordisk.Those revenues are based on the net prices.For their analysis, Benedic N. Ippolito, an economist at the American Enterprise Institute, and Joseph F. Levy, a health economist at Johns Hopkins Bloomberg School of Public Health, relied on data from SSR Health, which uses company financial filings and estimates of the number of prescriptions filled.The economists derived net prices by using data from SSR Health for the second quarter of 2022 through the first quarter of 2023. The exception is Mounjaro, made by Eli Lilly, for which only data from the first quarter of 2023 was available.Net prices, the revenue divided by the number of prescriptions in their analysis, appear to be around $700 every four weeks for Wegovy, or about $650 less than the list price; about $300 for Ozempic, or nearly $650 less than the list price; and approximately $215 for Mounjaro, or about $800 less than its list price.That means Wegovy’s net price is about half of its list price, Ozempic’s is nearly two-thirds lower and Mounjaro’s net price is nearly 80 percent lower than its list price.Dr. Ippolito cautioned that because prices and prescriptions are in flux, these figures might change over time, but added that “these estimates give a good sense for the likely amount paid by many insurers and give a good sense for the amount of discounting going on.”Pragya Kakani, an economist at Weill Cornell Medical College, analyzed similar data with similar results but was not involved in Dr. Ippolito and Dr. Levy’s research.Novo Nordisk’s other drug, Ozempic, is expected to bring the company $11 billion.Tom Little/ReutersCraig Garthwaite, a health care economist at Northwestern University, is especially intrigued by the net prices of Ozempic and Mounjaro. Both are approved for people with diabetes but also cause weight loss. Wegovy, the same drug as Ozempic, is approved for weight loss. But the price of Ozempic is substantially lower than Wegovy’s price.The reason may be that Ozempic has a direct competitor in Mounjaro.But even Wegovy, which so far has the market for the new obesity drugs to itself, has an unexpectedly low net price, Amitabh Chandra, a health care economist at Harvard, said.“One might have naïvely thought that these are new medicines that are in great demand, so rebates would be small to nil,” Dr. Chandra said.“I was shocked,” he said, “by the extent of the rebates.”A Price We Already PayOne question looms, experts say: What is weight loss worth to patients and society?Obesity itself is expensive because it increases the risk for expensive diseases like diabetes and heart disease. One study found that obesity was associated with $1,861 excess yearly health costs per person, accounting for $172.74 billion in annual extra costs.The Institute for Clinical and Economic Review, an influential nonprofit group, asked about a year ago if the new weight-loss drugs are cost-effective, meaning that their value in terms of a better quality of life, a longer life and benefit to society exceeds their cost.Wegovy, the group reported, was not cost-effective. But the institute relied on an early and less precise estimate of the drug’s net price.When shown Wegovy’s estimated net price in the A.E.I. research, the group’s chief medical officer, Dr. David M. Rind, said that if the calculations were correct, Wegovy was cost-effective but “still poses major budget challenges.”Ozempic’s price is substantially lower than Wegovy’s price, which may be because Ozempic has a direct competitor in Mounjaro. George Frey/ReutersDr. Willett, of Harvard, added in an interview: “I don’t think anyone can predict exactly where this will go because competition may reduce prices, and the uptake is still not clear, but the potential cost could go way beyond anything we have seen.”Still, the expectation is that with less obesity, there will be fewer expensive obesity-related health problems, including type 2 diabetes.Not only can diabetes lead to kidney failure, blindness and amputations, it also doubles the risk for heart attacks and strokes.Patients may also get relief from the extreme social stigma and, often, self-loathing that accompanies obesity.Until recently, the idea that treating obesity would reduce obesity-related health risks was based on anecdotes and correlations, not cause and effect.Then in August Novo Nordisk announced the results of a large study, showing that Wegovy can reduce the risk of heart attacks, strokes, hospitalizations for heart failure and heart disease deaths by 20 percent.That outcome alters the picture, Dr. Garthwaite said.Some insurers do not cover drugs like Wegovy and may view obesity medications as vanity drugs. In response, some patients are suing their insurers.With a cardiovascular benefit, he said, that rationale for not covering the drugs is “out the window.”Costs We Can’t All AffordWhile the net prices of the drugs may be lower than expected, they remain too expensive for many potential patients.Those on Medicare, for instance, have no insurance coverage for Wegovy because Medicare is prevented by law from covering weight-loss drugs. Few state Medicaid programs cover the drug.And while Novo Nordisk says that 80 percent of private insurers cover Wegovy, the drug is not affordable for all insured patients.Katherine Baicker, a health economist, provost at the University of Chicago and an Eli Lilly board member, said that cheaper health insurance includes co-pays and deductibles that often render Wegovy out of reach. Patients with low-premium plans offered through the Affordable Care Act would similarly be priced out.A large study by Novo Nordisk showed that Wegovy can reduce the risk of heart attacks, strokes, hospitalizations for heart failure and heart disease deaths by 20 percent.Tom Little/ReutersDr. Scott Ramsey, a health economist at Fred Hutchinson Cancer Center, worries that poorer patients, who are uninsured or whose insurance requires high co-pays, will be looking on longingly as wealthier patients get the drugs.“We spent 15 years talking about the soaring cost of obesity to the health care system,” Dr. Garthwaite, the Northwestern economist, added. But with a way to cut that cost in reach, he said the attitude of some insurers seems to be, “we don’t want you to come up with a fix that costs money.”Waves and PeaksRelief should be coming soon, health economists predict, with companies rushing to develop their own drugs. Competition may lead to lower prices.That happened, for example, with drugs for hepatitis C. An effective cure for the liver disease initially cost as much as $84,000, leading to dire warnings that the cost would be comparable to “total spending in the United States on all drugs.”The list price of the hepatitis C treatment plunged, as competitors entered the market. Pharmacy benefit managers, which negotiate with drug makers, had more leverage as companies competed. Net prices fell accordingly.A similar scenario may play out with Wegovy, which “is riding the wave of not having any direct competition,” Dr. Doshi said. But that status will end soon.A version of Mounjaro by Eli Lilly is expected to be approved this year for obesity — a potential opening for insurers to agree to cover Wegovy but not Mounjaro, for example, if Wegovy’s price were to be sufficiently reduced.Dr. Ippolito added that with more than 70 obesity drugs in development, he expected that competition would only increase.For now, although the price of the drugs is likely at its peak, Dr. Chandra, the Harvard health care economist, argued that it is imperative for access to the drugs to be increased, even if that imposes a cost to society.The purpose of health insurance is not to save money, he said, but “to improve the quality of life, happiness and self-esteem.”

While a narrative emerged that the pandemic indiscriminately struck the young and healthy, new evidence suggests that frail young adults were most vulnerable.The flu typically kills the very young, the old and the sick. That made the virus in 1918 unusual, or so the story goes: It killed healthy young people as readily as those who were frail or had chronic conditions.Doctors of the time reported that, among those in the prime of their lives, good health and youth were no protection: The virus was indiscriminate, killing at least 50 million people, or between 1.3 and 3 percent of the world’s population. Covid, in contrast, killed 0.09 percent of the population.But a paper published on Monday in the Proceedings of the National Academy of Sciences challenges that persistent narrative. Using evidence in skeletons of people who died in the 1918 outbreak, researchers reported that people who suffered from chronic diseases or nutritional deficiencies were more than twice as likely to die as those who did not have such conditions, no matter their age.The 1918 virus did kill young people, but, the paper suggests, it was no exception to the observation that infectious diseases kill frail and sicker people most readily.Sharon DeWitte, an anthropologist at the University of Colorado, Boulder, and an author of the paper, said the finding had a clear message: “We should never expect any nonaccidental cause of death to be indiscriminate.”The analysis of skeletons, said J. Alex Navarro, a historian of the flu pandemic at the University of Michigan, makes for “a fascinating paper and a very interesting approach to studying this issue.”The lead author of the paper, Amanda Wissler, an anthropologist at McMaster University in Ontario, said she was intrigued by claims that the 1918 virus killed young and healthy people as readily as those with pre-existing conditions. In those days, there were no antibiotics or vaccines against childhood diseases, and tuberculosis was widespread among young adults.There was a puzzle about who died from that flu, though, which helped fuel speculation that health was no protection. The flu’s mortality curve was unusual, shaped like a W. Ordinarily, mortality curves are shaped like a U, indicating that babies with immature immune systems and older people have the highest death rates.The W arose in 1918 because death rates soared in people aged from about 20 to 40, as well as in babies and older people. That seemed to indicate that young adults were extremely vulnerable and, according to numerous contemporaneous reports, it did not matter if they were healthy or chronically ill. The flu was an equal opportunity killer.In one report, Colonel Victor Vaughn, an eminent pathologist, described a scene at Fort Devens in Massachusetts. He wrote that he had seen “hundreds of young men in uniforms of their country, coming into the wards in groups of 10 or more.” By the next morning, he added, “the dead bodies are stacked about the ward like cord wood.”The influenza pandemic, he wrote, “was taking its toll of the most robust, sparing neither soldier nor civilian, and flaunting its red flag in the face of science.”Dr. Wissler and Dr. DeWitte, who have done similar research on the Black Death, saw a way to test the hypothesis about young people. When people have had lingering illnesses like tuberculosis or cancer, or other stressors like nutritional deficiencies, their shin bones develop tiny bumps.Assessing frailty by looking for those bumps “is quite legitimate” as a method, said Peter Palese, a flu expert at the Icahn School of Medicine at Mount Sinai.The researchers used skeletons at the Cleveland Museum of Natural History. Its collection of 3,000 people’s remains, kept in large drawers in a massive room, includes each person’s name, age of death and date of death.Dr. Wissler said she treated the remains “with great respect,” as she examined the shin bones of 81 people aged 18 to 80 who died in the pandemic. Twenty-six of them were between the ages of 20 and 40.For comparison, the researchers examined the bones of 288 people who died before the pandemic.The results were clear: Those whose bones indicated they were frail when they got infected — whether they were young adults or older people — were, by far, the most vulnerable. Many healthy people were killed, too, but those who were chronically ill to start with had a much greater chance of dying.That makes sense, said Dr. Arnold Monto, an epidemiologist and professor emeritus at the University of Michigan’s School of Public Health. But, he said, although the new study makes “an interesting observation,” the skeletons were not a random sample of the population, so it can be difficult to be specific about the risk that came with frailty.“We are not used to the fact that younger healthy adults are going to die,” which often occurred in the 1918 pandemic, Dr. Monto said.Dr. Palese said there was a reasonable explanation for the W-shaped mortality curve of the 1918 flu. It means, he said, that people older than 30 or 40 had most likely been exposed to a similar virus that had given them some protection. Younger adults had not been exposed.

Some neurosurgeons are testing an acrylic prosthesis that lets them peer into patients’ heads with ultrasound.Tucker Marr’s life changed forever last October.He was on his way to a wedding reception when he fell down a steep flight of metal stairs, banging the right side of his head so hard he went into a coma.He’d fractured his skull, and a large blood clot formed on the left side of his head. Surgeons had to remove a large chunk of his skull to relieve pressure on his brain and to remove the clot.“Getting a piece of my skull taken out was crazy to me,” Mr. Marr said. “I almost felt like I’d lost a piece of me.”But what seemed even crazier to him was the way that piece was restored.Mr. Marr, a 27-year-old analyst at Deloitte, became part of a new development in neurosurgery. Instead of remaining without a piece of skull or getting the old bone put back, a procedure that is expensive and has a high rate of infection, he got a prosthetic piece of skull made with a 3-D printer. But it is not the typical prosthesis used in such cases. His prosthesis, which is covered by his skin, is embedded with an acrylic window that would let doctors peer into his brain with ultrasound.A few medical centers are offering such acrylic windows to patients who had to have a piece of skull removed to treat conditions like a brain injury, a tumor, a brain bleed or hydrocephalus.“It’s very cool,” Dr. Michael Lev, director of emergency radiology at Massachusetts General Hospital, said. But, “it is still early days,” he added.Advocates of the technique say that if a patient with such a window has a headache or a seizure or needs a scan to see if a tumor is growing, a doctor can slide an ultrasound probe on the patient’s head and look at the brain in the office. That way a patient can avoid costly, time-consuming and onerous CT scans or M.R.I.s. Instead of waiting for a radiologist to read the scan, a patient and a doctor can know right away what the patient’s brain looks like.Dr. Mark Luciano, a professor of neurosurgery at Johns Hopkins, is using ultrasound to monitor hydrocephalus patients, who have shunts in their brains to drain excess cerebrospinal fluid. Patients need regular CT scans to see if the fluid is draining properly.In an attempt to assess the windows, Dr. Luciano recently published a study of 37 patients who had the windows placed in their skulls, compared with a larger group of similar patients from the year before the method was developed.Over a one-year period, he saw no risk of infection. The challenge now, he said, is to make the images from ultrasound scans better and to quantify what they show, he said, as well as to monitor their safety for several years.But not everyone is won over.Dr. Ian McCutcheon, a professor of neurosurgery at the University of Texas MD Anderson Cancer Center, said the window “is an intriguing idea.” But, he said, before he uses it to assess brain tumor patients he’d need evidence from a rigorous clinical trial that ultrasound is as accurate as an M.R.I. in detecting changes, like a growing tumor.That trial, he said, “has not been done yet.”Research showed that some patients receiving the acrylic prostheses did not face greater infection risk.Lenox Hill HospitalBy enabling ultrasound scans, the windows into the skull may reduce the number of CT and M.R.I. scans needed by patients with damaged brains.Lenox Hill HospitalOthers, like Dr. Joseph Watson, director of the brain tumor program at Georgetown University, called the technique “frivolous.”“You are going through a small port,” he said. “It doesn’t give you enough of a picture of the whole brain” that he gets with a CT scan or M.R.I.But Mr. Marr’s doctor, Netanel Ben-Shalom, assistant professor of neurosurgery at Lenox Hill Hospital in New York, disagrees. In his experience, he said, “as long as the window is located above the tumor, the cavity is clearly demonstrated.”Dr. Ben-Shalom was won over from the moment he tried implanting a window a few years ago. He was a resident at Johns Hopkins, and his patient had a brain tumor.“It was amazing,” Dr. Ben-Shalom said. He could see the entire brain, he said, and all its structures.He moved to Lenox Hill in January 2022, became a consultant for Longeviti, the company that makes the windows, and has been implanting and using its clear polymethylmethacrylate windows ever since.Tucker Marr at left before a prosthetic piece of skull was installed, and after on the right. “I almost felt like I’d lost a piece of me,” he said.Lenox Hill HospitalOn an afternoon earlier this year, Mr. Marr sat on a wooden chair in a tiny office at Lenox Hill, grinning as Dr. Ben-Shalom slid an ultrasound probe over the window in his skull. A cluster of medical students looked on.For Mr. Marr, life was difficult after the removal of the piece of his skull to treat his swelling brain. His head was distorted, with a large dent. He was left with fatigue and dizziness because his brain was inadequately shielded from atmospheric pressure.During the scan, Mr. Marr’s brain looked perfect, Dr. Ben-Shalom said. The midline that separates the two hemispheres — and which had been pushed to one side after Mr. Marr’s injury — was exactly where it should be. The structures of his brain looked normal, Dr. Ben-Shalom said. The ultrasound even showed his brain’s pulsing.Mr. Marr is young and healthy but, Dr. Ben-Shalom said, anyone who has had brain surgery needs surveillance. If Mr. Marr comes in one day with nausea and vomiting or a severe headache, or if he had a seizure, his doctors would need to look at his brain. The acrylic window makes it easy, Dr. Ben-Shalom said.At the University of Southern California, Dr. Charles Liu and his colleagues are taking the ultrasound idea a step further. In a research project, he is studying the use of ultrasound as a simpler and cheaper way to do the sort of studies now done with f.M.R.I., a method that uses M.R.I. scanners to examine the brain’s activity.For the study, he needed a patient who required a skull restoration for medical reasons and who would volunteer to have one with a specially designed window. If the idea succeeded, he and the team thought they might some day be able to use the method on intact skulls.The hope is to detect tiny signals from changes in blood flow in different parts of the brain as patients perform different activities. That, Dr. Liu said, “could give unprecedented insights into brain functions.”He found such a patient — Jared Hager, 39, who had a traumatic brain injury when he crashed his skateboard. He had spent two and a half years with a large piece of his skull missing.Dr. Liu met Mr. Hager when he was admitted to Rancho Los Amigos National Rehabilitation Center in Downey, Calif., part of the Los Angeles County public safety net health system.When Dr. Liu met Mr. Hager, he was uninsured and homeless — he and his brother were living in a van. And Mr. Hager was missing a large chunk of skull. He was scheduled to have his skull restored, but Dr. Liu offered him a choice: a standard prosthesis or one with a specially designed window optimized for brain studies.Before his surgery, the Rancho Los Amigos Foundation provided free housing at a facility next to the hospital for patients and their families. But Dr. Liu worried about what would happen after Mr. Hager was discharged.“When you do this kind of surgery, it’s a big operation,” he said. “My goodness, what if we do surgery on this guy and he ends up in a van in downtown L.A.?”Through the Rancho Los Amigos Foundation Dr. Liu got Mr. Hager an apartment in Long Beach.Mr. Hager has become a regular presence in Dr. Liu’s lab, working with its scientists to discover as much about his brain as they can.“I’m never going to stop helping with anything Dr. Liu needs,” he said.

Every so often a drug comes along that has the potential to change the world. Medical specialists say the latest to offer that possibility are the new drugs that treat obesity — Ozempic, Wegovy, Mounjaro and more that may soon be coming onto the market.It’s early, but nothing like these drugs has existed before.“Game changers,” said Jonathan Engel, a historian of medicine and health care policy at Baruch College in New York.Obesity affects nearly 42 percent of American adults, and yet, Dr. Engel said, “we have been powerless.” Research into potential medical treatments for the condition led to failures. Drug companies lost interest, with many executives thinking — like most doctors and members of the public — that obesity was a moral failing and not a chronic disease.While other drugs discovered in recent decades for diseases like cancer, heart disease and Alzheimer’s were found through a logical process that led to clear targets for drug designers, the path that led to the obesity drugs was not like that. In fact, much about the drugs remains shrouded in mystery. Researchers discovered by accident that exposing the brain to a natural hormone at levels never seen in nature elicited weight loss. They really don’t know why.“Everyone would like to say there must be some logical explanation or order in this that would allow predictions about what will work,” said Dr. David D’Alessio, chief of endocrinology at Duke, who consults for Eli Lilly among others. “So far there is not.”Although the drugs seem safe, obesity medicine specialists call for caution because — like drugs for high cholesterol levels or high blood pressure — the obesity drugs must be taken indefinitely or patients will regain the weight they lost.Dr. Susan Yanovski, a co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases, warned that patients would have to be monitored for rare but serious side effects, especially as scientists still don’t know why the drugs work.But, she added, obesity itself is associated with a long list of grave medical problems, including diabetes, liver disease, heart disease, cancers, sleep apnea and joint pain.“You have to keep in mind the serious diseases and increased mortality that people with obesity suffer from,” she said.The drugs can cause transient nausea and diarrhea in some. But their main effect is what matters. Patients say they lose constant cravings for food. They find themselves satisfied with much smaller portions. They lose weight because they naturally eat less — not because they burn more calories.And results from a clinical trial reported last week indicate that Wegovy can do more than help people lose weight — it also can protect against cardiac complications, like heart attacks and strokes.But why that happens remains poorly understood.“Companies don’t like the term trial and error,” said Dr. Daniel Drucker, who studies diabetes and obesity at the Lunenfeld-Tanenbaum Research Institute in Toronto and who consults for Novo Nordisk and other companies. “They like to say, ‘We were extremely clever in the way we designed the molecule,” Dr. Drucker said.But, he said, “They did get lucky.”A Lonely Origin StoryDr. Joel Habener in 2007.Ruby Arguilla-Tull/Bloomberg NewsIn the 1970s, obesity treatments were the last thing on Dr. Joel Habener’s mind. He was an academic endocrinologist starting his own lab at Harvard Medical School and looking for a challenging, but doable, research project.He chose diabetes. The disease is caused by high blood sugar levels and is typically treated with injections of insulin, a hormone secreted by the pancreas that helps cells store sugar. But an insulin injection makes blood sugar plummet, even if levels are already low. Patients have to carefully plan injections because very low blood sugar levels can result in confusion, shakiness and even a loss of consciousness.Two other hormones also play a role in regulating blood sugar — somatostatin and glucagon — and little was known then about how they are produced. Dr. Habener decided to study the genes that direct cells to make glucagon.That led him to a real surprise. In the early 1980s, he discovered a hormone, GLP-1, that exquisitely regulates blood sugar. It acts only on insulin-producing cells of the pancreas, and only when blood sugar rises too high.It was perfect, in theory, as a targeted treatment to replace sledgehammer-like insulin injections.Another researcher, Dr. Jens Juul Holst at the University of Copenhagen, independently stumbled on the same discovery.But there was a problem: When GLP-1 was injected, it vanished before reaching the pancreas. It needed to last longer.Dr. Drucker, who led the GLP-1 discovery efforts on Dr. Habener’s team, labored for years on the challenge. It was, he said, “a pretty lonely field.”When he applied to the Endocrine Society to give talks, he found himself scheduled at the very end of the last day of the annual meetings.“Everyone had left for the airport — people were taking down the exhibits,” he said.From the late 1980s to the early 1990s, he spoke to nearly empty auditoriums.Dr. Eng’s MonsterPeter DaSilva for The New York TimesSuccess came from a chance discovery that was not appreciated at the time.In 1990, John Eng, a researcher at the Veterans Affairs medical center in the Bronx, was looking for interesting new hormones in nature that might be useful for medications in people.He was drawn to the venomous Gila monster when he learned that it somehow kept its blood sugar levels stable when it did not have much to eat, according to a report from the National Institutes of Health, which funded his work. So Dr. Eng decided to search for chemicals in the lizards’ saliva. He found a variant of GLP-1 that lasted longer.Dr. Eng told The New York Times in 2002 that the V.A. had declined to patent the hormone. So Dr. Eng patented it himself and licensed it to Amylin Pharmaceuticals, which began testing it as a diabetes drug. The drug, exenatide or Byetta, went on sale in the United States in 2005.But Byetta had to be injected twice a day, a real disincentive to its use. Drug company chemists sought even longer-lasting versions of GLP-1.At Novo Nordisk, chemists began by using a well-known trick. They loosely attached GLP-1 to a blood protein that kept it stable enough to remain in circulation for at least 24 hours. But when GLP-1 slips off the protein, enzymes in the blood quickly degrade it. So chemists had to alter the hormone’s building blocks — a chain of amino acids — to find a more durable variant.After tedious trial and error, Novo Nordisk produced liraglutide, a GLP-1 drug that lasted long enough for daily injections. They named it Saxenda, and the F.D.A. approved it as a treatment for diabetes in 2010.It had an unexpected side effect: slight weight loss.A Dismal HistoryDr. Jeffrey Friedman, who discovered the hormone that tells the brain how much fat is on the body, in 1995.Remi Benali/Gamma-Rapho, via Getty ImagesObesity had become a dead end in the pharmaceutical industry. No drug that was tried worked very well, and every one that led to even modest weight loss had serious side effects.For a flickering moment in the late 1990s, there was hope when Dr. Jeffrey Friedman at Rockefeller University in New York found a hormone that told the brain how much fat was on the body. Lab mice genetically modified to have none of the hormone ate voraciously and grew enormously fat. Researchers could fine-tune an animal’s weight by altering how much of the hormone it got.Dr. Friedman named the hormone leptin. Amgen bought the rights to leptin and, in 1996, began testing it in people. They did not lose weight.Dr. Matthias Tschöp at Helmholtz Munich in Germany tells of the frustration. He left academia three decades ago to work at Eli Lilly in Indianapolis, excited by leptin and determined to use science to find a drug for weight loss.“I was so inspired,” Dr. Tschöp said.When leptin failed, he tried a different gut hormone, ghrelin, whose effects were the opposite of leptin’s. The more ghrelin an animal had, the more it would eat. Perhaps a drug that blocked ghrelin would make people lose weight.“Again, it wasn’t that simple,” said Dr. Tschöp, who left Lilly in 2002.The body has so many redundant circuits of interacting nerve impulses and hormones to control weight that tweaking one simply did not make a difference.And there was another obstacle, noted Dr. Tschöp’s former colleague at Lilly, Dr. Richard Di Marchi, who also was an executive at Novo Nordisk.“There was very little interest in the industry in doing this,” said Dr. Di Marchi, now at Indiana University. “Obesity was not thought to be a disease. It was looked at as a behavioral problem.”Dr. Friedman studied mice that had been genetically modified to have none of a hormone that told their brains how much fat was on their bodies. Researchers could fine-tune an animal’s weight by altering its hormones, but the study failed in humans.Remi Benali/Gamma-Rapho, via Getty ImagesStarving RatsNovo Nordisk, which today has 45.7 percent of the global insulin market, thought of itself as a diabetes company. Period.But one company scientist, Lotte Bjerre Knudsen, could not stop thinking about tantalizing results from studies with liraglutide, the GLP-1 drug that lasted long enough to be injected just once a day.In the early 1990s, Novo researchers, studying rats implanted with tumors of pancreas cells that produced copious amounts of glucagon and GLP-1, noticed that the animals had nearly stopped eating.“These rats, they starved themselves,” Dr. Knudsen said in a video series released by the Novo Nordisk Foundation. “So we kind of knew there was something in some of these peptides that was really important for appetite regulation.”Other studies by academic researchers found that rats lost their appetites if GLP-1 was injected into their brains. Human subjects who got an intravenous drip of GLP-1 ate 12 percent less at a lunch buffet than those who got a placebo.So why not study liraglutide as both a diabetes drug and an obesity drug, Dr. Knudsen asked .She faced resistance in part because some company executives were convinced that obesity resulted from a lack of willpower. One of the champions of investigating GLP-1 for weight loss, Lars Rebien Sorensen, chairman of the board at Novo Nordisk, said in the video posted by the company’s foundation that he “had to spend half a year convincing my C.E.O. that obesity is not just a lifestyle condition.”Dr. Knudsen also noted that the company’s business division had struggled with the idea of promoting liraglutide for two distinct purposes.“It’s either diabetes, or it’s a weight loss,” she recalled in the foundation video series.Finally, after liraglutide was approved in 2010 for diabetes, Dr. Knudsen’s proposal to study the drug for weight loss moved forward. After clinical trials, the F.D.A. approved liraglutide, or Saxenda, for obesity in 2014. The dose was about twice the diabetes dose. Patients lost about 5 percent of their weight, a modest amount.But Dr. Martin Holst Lange, executive vice president of development at Novo Nordisk, said in a telephone interview that it was at least as good as other weight-loss drugs, and without side effects like heart attacks, strokes and death.“We were super excited,” he said.Beyond DiabetesA Novo Nordisk site outside Copenhagen.Scanpix Denmark/ReutersDespite the progress on weight loss, Novo Nordisk continued to focus on diabetes, trying to find ways to make a longer-lasting GLP-1 so patients would not have to inject themselves every day.The result was a different GLP-1 drug, semaglutide, that lasted long enough that patients had to inject themselves only once a week. It was approved in 2017 and is now marketed as Ozempic.It also caused weight loss — 15 percent, which is three times the loss with Saxenda, the once-a-day drug, although there was no obvious reason for that. Suddenly, the company had what looked like a revolutionary treatment for obesity.But Novo Nordisk could not market Ozempic for weight loss without F.D.A. approval for that specific use.In 2018, a year after Ozempic’s approval for diabetes, the company started a clinical trial. In 2021, Novo Nordisk got approval from the F.D.A. to market the same drug for obesity with a weekly injection at a higher maximum dose. It named the drug Wegovy.But even before Wegovy was approved, people had begun taking Ozempic for obesity. Novo Nordisk, in its Ozempic commercials, mentioned that many taking it lost weight.Hinting turned out to be more than enough. Soon, said Dr. Jeffrey Mechanick, an endocrinologist at Mount Sinai’s Icahn School of Medicine, patients latched onto Ozempic. Doctors prescribed it off label for those who did not have diabetes.“There was a little bit of gaming going on,” Dr. Mechanick said, with some doctors coding patients as having pre-diabetes to help them get insurance coverage.By 2021, fed by social media, a general frenzy for weight loss and aggressive marketing by Novo Nordisk, the news that Ozempic made people lose weight had reached a tipping point, said Dr. Caroline Apovian, a co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital and a consultant for Novo Nordisk and other companies. Ozempic was on everyone’s lips, even though Wegovy was the drug approved that year for obesity.But Wegovy caught up.In July, doctors in the U.S. wrote about 94,000 prescriptions a week for Wegovy compared with about 62,000 a week for Ozempic. Wegovy is in such demand, though, that the company is unable to make enough, its spokeswoman Ambre James-Brown said. So for now, while it ramps up production, the company sells the drug only in Norway, Denmark, Germany and the United States. And at pharmacies in those countries, shortages are frequent.And Dr. Apovian, like many other obesity medicine specialists, is now booked with patients a year in advance.Cydni Elledge for The New York TimesMore Medicines, More MysteriesThe reason Ozempic and Wegovy are so much more effective than Saxenda remains a mystery. Why should a once-a-week injection produce much more weight loss than a once-a-day injection?The drugs, said Randy Seeley, an obesity researcher at the University of Michigan, are not correcting for a lack of GLP-1 in the body — people with obesity make plenty of GLP-1. Instead, the drugs are exposing the brain to hormone levels never seen in nature. Patients taking Wegovy are getting five times the amount of GLP-1 that they would produce in response to a Thanksgiving dinner, Dr. Seeley said.And, he added, in the brain, “the drugs go to unusual places.” They are not just going to areas thought to involve control overeating.“If you were designing a drug, you would say that’s a bad idea,” said Dr. Seeley, who has consulted for Novo Nordisk and Eli Lilly, among others. Drug designers try for precision — a drug should go only to the cells where it is needed.GLP-1, because of its chemical structure, should not even get into some areas of the brain where it slips in.“Nobody understands that,” Dr. Seeley said.Wegovy, though, is just the start.Lilly’s diabetes drug, tirzepatide or Mounjaro, is expected to get F.D.A. approval for obesity this year. It hooks GLP-1 to another gut hormone, GIP.GIP, on its own, produces, at best, a modest weight loss. But the two-hormone combination can allow people to lose a median of about 20 percent of their weight.“No one fully understands why,” Dr. Drucker said.Lilly has another drug, retatrutide, that, while still in early stages of testing, seems to elicit a median 24 percent weight loss.Amgen’s experimental drug, AMG 133, could be even better, but is even more of a puzzle. It hooks GLP-1 to a molecule that blocks GIP.There is no logical explanation for why seemingly opposite approaches would work.Researchers continue to marvel at these biochemical mysteries. But doctors and patients have their own takeaway: The drugs work. People lose weight. The constant chatter in their brains about food and eating is gone.And, while the stigma of obesity and the cultural stereotype that obese people aren’t trying hard enough to lose weight endures, some experts are optimistic. Now, they say, patients no longer have to blame themselves or feel like failures when they can’t lose weight.“The era of ‘just go out and diet and exercise’ is now gone,’” said Dr. Rudolph Leibel, a professor of diabetes research at Columbia University Irving Medical Center. “Now clinicians have tools to address obesity.”

The LatestA national survey released on Friday by KFF, a nonprofit organization focused on health policy, has found that Americans long for safe and effective drugs for weight loss. But the more they learn about new drugs like Wegovy that are transforming obesity treatment, the more their enthusiasm fades.The survey found that 59 percent of people who were trying to lose weight said they were interested in taking a safe and effective drug. But only 23 percent remained interested when asked if they would take such a drug if it had to be injected. And just 16 percent were still interested if their insurance would not pay for the drug. The list price of the drugs is about $1,300 a month.When they heard they would regain their lost weight it they stopped taking the drug, interest declined to 14 percent.“People always want that magic pill,” said Ashley Kirzinger, director of survey methodology at KFF. “There is no magic.”The survey was conducted in July online and by telephone with a representative sample of 1,327 U.S. adults.Cydni Elledge for The New York TimesA Statistic That Sums It Up: 15 percent.That’s the median weight loss experienced by people who take Wegovy, a drug from Novo Nordisk.The new drugs are the first truly effective obesity medicines. They act by stemming people’s appetites and cravings for food. Many patients started by taking Ozempic, a diabetes drug also by Novo Nordisk that led to weight loss as a side effect. But many more patients are asking for Wegovy, which is approved for obesity. Mounjaro, made by Eli Lilly and approved for treating diabetes, is expected to be approved soon for obesity. People taking it lose a median of 20 percent of their body weight.Background: Attitudes about obesity and the drugs are shifting.Obesity is a chronic disease that can result in diabetes and other conditions like high blood pressure, heart disease, sleep apnea and joint problems.But it was so difficult to treat obesity that many doctors and patients had all but given up.Dr. David A. D’Alessio, director of endocrinology at Duke University and a member of Eli Lilly’s scientific advisory board, said he had resisted starting a weight-loss clinic at his university. Patients who are told to diet and exercise “get defeated over and over again,” he said.Now, he said, he has changed his mind.The shifts in attitude about obesity can also be seen in the KFF survey, said Dr. Ania Jastreboff, an endocrinologist and obesity-medicine specialist at Yale University and a consultant for the makers of the new drugs. After decades of hearing that losing weight was just a matter of exerting willpower, most of the public is intensely interested in medical treatments.“Previously,” she said, “that was not the case.”What’s Next: New drugs and methods.Obesity-medicine specialists say new drugs that are even more powerful than Wegovy and Mounjaro are going to change prospects for people with obesity in a way that has eluded researchers for decades.While price and insurance coverage pose problems for patients, health economists expect prices to come down as more drugs are approved and companies face competition. Private insurers are also being pressured to pay; for now, many do not. Medicare is forbidden by law to pay for weight-loss drugs, although there is an intense lobbying effort to change that.While the KFF survey showed that many potential patients resisted injection, the delivery of the drug with a thin, short needle is quick and easy, said Dr. Robert F. Kushner, an obesity-medicine specialist at Northwestern University Feinberg School of Medicine.“In my experience, people find a weekly self-injection OK since it takes less than one minute and is a lot easier than they thought,” said Dr. Kushner, who is on the advisory board for Novo Nordisk.Some companies are also studying an oral version of the medications.

Researchers at Stanford devised a strange new molecule that could lead to drugs that arm genes and make cancers work against themselves.Within every cancer are molecules that spur deadly, uncontrollable growth. What if scientists could hook those molecules to others that make cells self-destruct? Could the very drivers of a cancer’s survival instead activate the program for its destruction?That idea came as an epiphany to Dr. Gerald Crabtree, a developmental biologist at Stanford, some years ago during a walk through the redwoods near his home in the Santa Cruz mountains.“I ran home,” he said, excited by the idea and planning ways to make it work.Now, in a paper published Wednesday in the journal Nature, Dr. Crabtree, a founder of Shenandoah Therapeutics, which is developing cancer drugs, along with Nathanael S. Gray, a professor of chemical and systems biology at Stanford, and their colleagues report that they have done what he imagined on that walk. While the concept is a long way from a drug that could be given to cancer patients, it could be a target for drug developers in the future.“It’s very cool,” said Jason Gestwicki, professor of pharmaceutical chemistry at the University of California, San Francisco. “It turns something the cancer cell needs to stay alive into something that kills it, like changing your vitamin into a poison.”“This is a potentially new way to turn cancer against itself,” said Dr. Louis Staudt, director of the Center for Cancer Genomics at the National Cancer Institute. Dr. Staudt wrote an editorial to accompany Dr. Crabtree’s paper.Once the treatment is further developed, he added, “I would love to try it in a clinical trial with our patients who have exhausted all other options.”In laboratory experiments with cells from a blood cancer, diffuse large B-cell lymphoma, the researchers designed and built molecules that hooked together two proteins: BCL6, a mutated protein that the cancer relies on to aggressively grow and survive, and a normal cell protein that switches on any genes it gets near.The new construction, a dumbbell shaped molecule, is unlike anything seen in nature. BCL6, at one end of the dumbbell, guides the molecule toward cell-death genes that are part of every cell’s DNA and are used to get rid of cells that are no longer needed. But when a person has diffuse large B cell lymphoma, BCL6 has turned off those cell-death genes, making the cells essentially immortal.A computational model of the molecule TCIP1 that hooked together the BRD4 and BCL6 proteins together.Andrey KrokhotinWhen the dumbbell, guided by BCL6, gets near the cell-death genes, the normal protein on the end of the dumbbell arms those death genes. Unlike other processes in the cell that can be reversed, turning on cell-death genes is irreversible.The new approach could be an improvement over the difficult task of using drugs to block all BCL6 molecules. With the dumbbell-shaped molecules, it is sufficient to rewire just a portion of BCL6 molecules in order to kill cells.The concept could potentially work for half of all cancers, which have known mutations that result in proteins that drive growth, Dr. Crabtree said. And because the treatment relies on the mutated proteins produced by the cancer cells, it could be extremely specific, sparing healthy cells.Dr. Crabtree explained the two areas of discovery that made the work possible. One is the discovery of “driver genes” — several hundred genes that, when mutated, drive the spread of cancer.The second is the discovery of death pathways in cells. Those pathways, Dr. Crabtree said, “are used to eliminate cells that have gone rogue for one reason or other” — 60 billion cells in each individual every day.The quest was to make the pathways driving cancer cell growth communicate with silenced pathways that drive cell death, something they would not normally do.When the hybrid molecule drifted to the cells’ DNA, it not only turned on cell-death genes but also did more. BCL6 guided the hybrid to other genes that the cancer had silenced. The hybrid turned those genes on again, creating internal chaos in the cell.“The cell has never experienced this,” Dr. Staudt said.“BCL6 is the organizing principle of these cancer cells,” he explained. When its function is totally disrupted, “the cell has lost its identity and says, ‘something very wrong is happening here. I’d better die.’”But the main effect of the experimental treatment was to activate the cell-death genes, Dr. Crabtree said. “That is the therapeutic effect,” he said.The group tested its hybrid molecule in mice, where it seemed safe. But, Dr. Staudt noted, “humans are a lot different than mice.”The work is “exciting,” said Stuart L. Schreiber, professor of chemistry and chemical biology at Harvard and a previous collaborator with Dr. Crabtree. But he offered words of caution.What Dr. Crabtree created “is not a drug — it still has a long way to go,” he said.