Ipilimumab

Welcome back to Endpoints Weekly! A programming note: We won’t be sending our usual newsletters on Monday, Feb. 16. Our team will be off for Presidents’ Day. Our reporters closely followed several big updates this week, including Moderna’s response after it received a refusal-to-file letter over its flu vaccine application and Paul Hudson’s exit from Sanofi. Senior editor Max Gelman also dug into what makes clinical trials so costly. And our team reported on readouts for AstraZeneca’s obesity pill and the launch of a head-to-head CAR-T trial. Enjoy the weekend — we’ll be back on Tuesday! — Nicole DeFeudis The FDA refused to review Moderna’s flu vaccine application, in a decision that the company is describing as a shifting of standards for its pivotal trial. The Phase 3 trial tested Moderna’s mRNA-based flu shot against a standard flu dose in adults 50 and older. But in a refusal-to-file letter, the agency criticized Moderna for not using the “best-available standard of care” in the comparison group. Typically, patients 65 and older are advised to get a higher or enhanced dose. Moderna took the debate public on Tuesday, publishing the refusal-to-file letter signed by vaccines and biologics chief Vinay Prasad. In the letter, Prasad wrote that the decision was “consistent with FDA’s advice given to you prior to your study.” In a news release, Moderna said the agency recommended in 2024 that Moderna use a higher-dose flu vaccine in adults 65 and older, but also agreed at the time that “it would be acceptable to use a licensed standard-dose influenza vaccine as the comparator in your Phase 3 study.” “We thought it was pretty clear that it was acceptable, and even agreed it was an acceptable approach in writing,” Moderna president Stephen Hoge said in a Tuesday interview. The debate was further complicated by reports from Endpoints News and others that Prasad overruled the review team and head of the vaccine group as part of the regulator’s refusal to review the application. On Wednesday, a senior agency official told reporters it was “entirely feasible” that Moderna could resubmit the application for adults aged 50 to 64. If approved, the vaccine could be used off-label for the oldest adults, the official said. They also said, “There was a healthy scientific debate on the refuse-to-file.” Moderna has requested a Type A meeting with the FDA to further discuss the application. On its fourth-quarter earnings call Friday, Moderna’s CFO Jamey Mock said it’s “too early to tell” whether the company’s goal of reaching break-even cash flow will be pushed back after the FDA declined to review its flu shot for adults 50 and older. For more discussion, watch our Post-Hoc Live session with the Endpoints reporters who tracked this story. Sanofi’s board elected not to renew Paul Hudson’s director mandate, the company announced this week, ending Hudson’s tenure as CEO . He will be replaced by Merck KGaA’s Belén Garijo, who will start on April 29. Hudson’s last day is Feb. 17, and head of general medicines Olivier Charmeil will take over as interim CEO during the transition. The ouster comes after years of pipeline setbacks for Sanofi. Hudson, who started in his role in September 2019, had attempted to reposition the company as an immunology powerhouse. By acquiring companies like Principia and Kymab, Hudson bet that not only could Sanofi be at the forefront of immunology’s next frontier, but it could also minimize risk from the Dupixent patent cliff in the early 2030s. That strategy ended up being rocky, and Sanofi’s board appeared to have lost patience as the company faced a number of pipeline setbacks. One of the Principia programs was scrapped three years after the acquisition, and another was rejected by the FDA late last year. The centerpiece of the Kymab deal, an anti-OX40L program called amlitelimab, was positioned as a “pipeline-in-a-product,” but reported disappointing data in January despite achieving its primary goal. A new safety concern also cropped up, casting a growing shadow on the mechanism. Despite the change in leadership, reception for Garijo was frosty. Investors are concerned that Garijo doesn’t have a track record of delivering R&D productivity at Merck KGaA, according to analysts who spoke to Endpoints, partly due to pipeline misfires. But some of that criticism may be misplaced. Read more about the challenges Garijo will face here . And be sure to read more about Hudson’s departure, as well as all the other pharma job changes this week, in our weekly Peer Review column here . US clinical trials, particularly in oncology, have become increasingly redundant, inefficient and expensive. In a story this week, senior editor Max Gelman examined why this is the case . A closet full of identical EKG machines, as recounted by Eli Lilly’s head of oncology Jacob Van Naarden, illustrated the issue. Ironically, one of the most commonly cited problems of developing new drugs was the cost of older drugs. Precision oncology has exploded since Herceptin’s approval in 1998, and successful checkpoint inhibitors like Yervoy and Keytruda mean that even before a patient gets a dose of an experimental medicine, trials can cost hundreds of thousands of dollars a year. Other factors only compound the problem. Companies must staff trial sites and manufacture new therapies while contending with American patients’ unwillingness to take experimental medicines and payers’ reluctance to foot the bill. As costs have risen, many big companies — and some smaller biotechs — have turned to China, but it’s not a simple solution. Unfortunately, there’s no silver bullet to fixing this problem. The solution depends on who you ask. Read more from Max here . The Bay Area biotech announced this week that it treated the first patient in a Phase 3 trial that pits its experimental cell therapy ronde-cel against two currently available CAR-T treatments for certain patients with aggressive large B cell lymphoma. Lyell CEO Lynn Seely told Endpoints’ Lei Lei Wu that the company “wanted a randomized, controlled trial so we could have a very fair evaluation” of whether ronde-cel can beat the existing therapies. Lyell, Gilead and Johnson & Johnson are all studying next-generation CAR-T therapies for lymphoma that target two proteins — CD19 and CD20 — typically found at abnormally high levels in cancers, as opposed to CD19 alone. Gilead has outlined plans for a head-to-head Phase 3 trial in which it will go up against its existing therapy, Yescarta. Click here for more details. AstraZeneca added to the obesity pill mania this week when it reported that its oral GLP-1 elecoglipron succeeded in two Phase 2b studies — one for obesity and one for diabetes. Specific data were not announced, but the drugmaker said they would come in June. According to the trial protocol, senior biopharma journalist Elizabeth Cairns says it can be inferred that the drug produced greater weight loss than placebo at the 26-week mark and also allowed more subjects to lose at least 5% of their weight at the same point. AstraZeneca will start Phase 3 trials this year. The UK pharma licensed elecoglipron from the Hong Kong company Eccogene in November 2023. AstraZeneca paid $185 million upfront for the asset. Eccogene is aiming to go public, probably this year. Read more from Elizabeth here . DON’T MISS

When Jake Van Naarden visits a hospital running clinical trials, he runs into an odd sight. Van Naarden, the head of Eli Lilly’s oncology unit, opens a supply closet and sees more than a dozen EKG machines stacked on shelves. They’re essentially identical. But they’re all labeled with the names of different drug companies. “They’re basically all the same machines,” Van Naarden said. “But some of them were sent by Lilly for the Lilly studies, and some of them were sent by Novartis for the Novartis studies. You look at this and are like, ‘What is going on here?’” The cluttered closet is a small but telling example of how US clinical trials, particularly in oncology, have become increasingly redundant, inefficient and expensive. And the growing costs come just as China’s biotech industry has blossomed, in part because of its ability to often move faster and cheaper than US rivals. There’s a growing push to solve some of those issues by simplifying data collection or making Phase 1 work easier in the US , for example. Some biotechs have found partners in China, where they can move quickly through early trials. But the expense of doing development work remains a major, growing problem for the industry, increasing the investment needed to fund new drugs and companies. Even before the pandemic, costs were rising. In a paper published in JAMA last year, researchers found that in 2019, every additional month a patient spent in a clinical trial added $9,615 in direct R&D costs. The median clinical trial cost of a drug approved that year was about $150 million, according to the study. And costs have only grown since then. David Epstein, a former top executive at Novartis and Seagen who is now CEO of Ottimo Pharma, said the cost to enroll a single patient in a cancer trial could be as much as $250,000 right now. “If it’s $200,000 a patient — it could even be more — and you’re going to enroll a few hundred patients in that trial, you can start to figure out these trials can get incredibly expensive,” Epstein said of oncology development. “You can spend hundreds of millions of dollars, or even billions of dollars, if the trial is big enough.” Ironically, one of the biggest expenses in developing new drugs is the cost of older drugs. Since the approval of Herceptin in 1998 for HER2-positive breast cancer, the field of precision oncology has exploded. The advent of checkpoint inhibitors in the early 2010s — namely Yervoy (CTLA-4) and Keytruda (PD-1) — pushed what people now call “immuno-oncology” to even greater heights. Keytruda, for example, has a list price of more than $200,000 in the US, and other approved PD-1 drugs have similar prices. For many cancers, the standard of care involves multiple different, often very expensive, therapies. That means that even before a patient gets a dose of an experimental medicine, it can cost hundreds of thousands of dollars a year to pay for baseline therapies. “Most cancer regimens are two or three drugs put together, so you’re going to have to add to the standard of care,” Epstein said. “You can imagine, if you want to combine your drug with a $200,000-per-year PD-1 drug, then that trial is very, very expensive.” A Merck spokesperson told Endpoints in an email that the company offers “two mechanisms that help provide Keytruda clinical supply to facilitate ongoing research,” which includes programs for collaboration with companies and for working directly with academics and clinical investigators. A confluence of other factors only compounds the problem, like staffing and operational costs of trial sites; manufacturing the new therapy itself; American patients’ unwillingness to take experimental medicine; and payers’ reluctance to foot the bill. (One exception is Medicare, which usually covers some or most associated costs.) But more costs have also seemed to dovetail with less efficiency. Another recent paper from the Tufts Center for the Study of Drug Development found nearly one-third of trial procedures and data collected since 2018 don’t support primary or key secondary endpoints in Phase 2 and Phase 3 studies. Much of those extra data are collected just in case it might be needed later. A potential FDA request for more information is one such hypothetical, Tufts CSDD director Ken Getz said. And companies will often take a Phase 2 protocol and use it as a template for Phase 3 instead of modifying it or scaling it back, he said. Trial sponsors usually reason “if we don’t collect this data and it’s requested in the future, or if we want to be able to compare this to data we’ve collected in the past, why don’t we just collect it anyway?” Getz said in an interview. “When you’re managing armies of people and all these different functional silos in highly scientific cultures, that are also extremely risk-averse and very keenly aware of all of the regulatory pressures, it’s just really hard to rein it in,” he said. As costs have risen, many big companies — and some smaller biotechs — have turned to China, signing licensing deals for drugs or using development work there to get human data faster and cheaper . It’s not a complete solution. US regulators have been clear that they want trial data that are representative of American demographics. In 2022, FDA officials excoriated Eli Lilly executives at a hearing after the company attempted to use a China-only trial to get a PD-1 inhibitor approved. More recently, the FDA has threatened to make it more expensive for companies that do Phase 1 work in China — though it has also said the US ultimately needs to make itself more competitive. But companies can speed early human work and cut costs by running part of their studies in China, according to Stifel managing director Tim Opler, or by doing early testing in China and then going global with larger, later studies. Enrollment is much easier in China, since the average Chinese patient is much less heavily pretreated than the average American patient. The Chinese government has also set up “tumor hospitals,” Opler said, where different cancers each have their own floors for treatment. “They might treat two million people a year,” Opler said of the hospitals. “I went to one of these places for a tour, and you go around, like, ‘Well, let’s go to the head and neck floor.’ And there’s something like 600 people on that floor with head and neck cancer. It’s just a lot easier to enroll over there.” So what’s the solution? It depends on who you ask. The pharma industry is seen as a slow-moving ocean liner. Turning it is hard. Getz, the Tufts researcher, said companies need to focus on trimming clinical trial protocols. Senior management tends to be receptive about this, he said. Others like Gwen Nichols, the chief medical officer of Blood Cancer United and a former oncology executive with Roche, said the standardization of certain tests could alleviate the burden at specialized treatment centers. Blood tests are performed the same almost everywhere (so are the EKGs that are done on Van Naarden’s closet full of machines, for that matter). “If you’re doing a CBC [complete blood count] at Sloan Kettering, that costs a whole lot more than a CBC at your doctor’s office in Westchester,” Nichols said. “Some of the standard tests could easily be done at your local doctor’s office at half the cost.” Hesham Abdullah, the head of oncology R&D at GSK, said he wants that kind of standardization to come to different regulatory bodies. Particularly at larger pharma companies, Abdullah said the goal is to develop drugs globally, but companies end up “designing different drug development programs for different regions.” Van Naarden, the Eli Lilly oncology executive, said he’d be willing to spend even more on trials if it could make them move faster. But that doesn’t solve everything. “If I could pay more money, if that was the unlock, I would do that in a heartbeat,” he said. “It turns out that’s not the unlock.”