Copanlisib dihydrochloride

In 2022, Gilead announced that it would voluntarily withdraw Zydelig from the U.S. market for two lymphoma treatments, a full six years after it suspended the trial due to patient deaths. A Gilead spokesperson clarified that the withdrawal was not due to safety concerns, but rather because of insurmountable obstacles to recruiting subjects for additional research trials required by the FDA. Nevertheless, Zydelig retains its eligibility for the treatment of chronic lymphocytic leukemia and remains on the market for patients. Notably, the withdrawal of Zydelig coincides with the withdrawal of several other PI3K inhibitors used to treat follicular lymphoma: Secura Bio's duvelisib (trade name Copiktra) withdrawn in December 2021, TG's umbralisib (trade name Ukoniq) withdrawn in 2022 (here may be a clerical error, read "February" or adjusted to another month), Bayer's copanlisib (trade name Aliqopa) also withdrew from the market in November 2023. Together, these events outline an industry trend. A study published in JAMA Internal Medicine reveals an interesting data point: Before Gilead decided to withdraw some uses of Zydelig from the U.S. market, its global sales had reached a staggering $842 million. This reflects the wide application and high recognition of the drug in the market, although it ultimately failed to fully meet all expectations for various reasons. Interestingly, the pharmaceutical industry sometimes employs a series of ingenious strategies to speed up the process of bringing a product to market. Eli Lilly, for example, successfully used all four avenues of acceleration to bring oncology product Lartruvo to market in 2016. The key clinical data for the product is based only on the results of a trial involving 133 patients, and while the results showed a possible positive impact on survival outcomes for sarcoma, a cancer that affects muscles and other soft tissues, the specific effect on slowing cancer growth is unclear. However, just over two years later, a larger study revealed that Lartruvo had no significant impact on patient survival, and Eli Lilly had to withdraw it from the market. Despite this, Lartruvo still managed to achieve a whopping $500 million in sales during its short market life. Among the many drugs approved for accelerated marketing, oncology products have become the hardest hit by ineffective drugs. However, as the development of therapies continues to deepen and progress, new questions continue to emerge and are presented to the FDA. In particular, advanced therapies represented by cell and gene therapies, when they meet with the accelerated approval system, have brought unprecedented challenges to this "old revolution". Given the complexity of cell and gene therapies and the relative lack of understanding of their safety, once ineffective advanced therapies are released to the market, the consequences and impacts will be far beyond the scope of small molecule ineffective drugs. For example, the tragic death of a three-year-old boy in a clinical trial of Pfizer's fordadistrogene movaparvovec, a gene therapy for Duchenne muscular dystrophy, highlights the shortcomings and limitations of researchers in predicting the potential for serious adverse events. As vectors of ssRNA (single stranded RNA), viruses (such as AAV) play a critical role in gene therapy, but can also cause a series of serious adverse events including cardiopulmonary failure, myocarditis, thrombotic microangiopathy, and acute liver failure. These potential risks have forced the FDA to be more cautious and rigorous in approving gene therapies. Speaking at the annual meeting of the American Society for Gene and Cell Therapy, CBER director Peter Marks said speeding up the withdrawal of approved gene therapies could be easier and faster than for small-molecule therapies. At the same time, he stressed that "accelerated approval of gene therapy is not a get-out-of-jail-free ticket." The FDA will not hesitate to withdraw accelerated approval of rare disease gene therapies if they fail subsequent confirmatory trials." Marks further points out that the "one-size-fits-all" nature of gene therapy makes confirmatory studies easier to follow and monitor patients over time. It also makes for greater clarity and clarity on the question of whether to withdraw gene therapy. In contrast, there may be more controversy and disagreement in the decision process of withdrawing cancer therapy. Marks, however, said the FDA would only withdraw gene therapy if it was clear that the patient benefit was likely to be "minimal" but the side effects were significant. He cited a case in which Bluebird Bio's sickle cell gene therapy Lyfgenia (lovotibeglogene autotemcel) caused patients to develop myelodysplastic syndrome and leukemia during treatment. The product was approved by the FDA in December 2023 with a boxed warning about hematologic malignancies. Marks said it is unclear whether these malignancies are related to the preconditioning regimen associated with Lyfgenia treatment, the underlying disease, or the gene therapy itself. In addition, the case of drug manufacturers refusing to voluntarily withdraw the market is not unique in the history of FDA accelerated approval. Everything from the withdrawal of Makena, a drug that reduced the risk of preterm birth, after 12 years on the market, to the legal battle between Pepaxto and the FDA highlights the complexity and seriousness of the issue. In the face of these challenges, FDA has to seek the support of legislation to strengthen its regulatory power and capability. Fortunately, the introduction of the FDORA (Comprehensive Food and Drug Reform Act) bill provides the FDA with greater flexibility and autonomy to act without public hearings.

Pictured: Bayer's office in Berlin, Germany/iStock, Elenasfotos Bayer on Wednesday revealed a new operating model meant to cut back on bureaucracy and hierarchies, as well as streamline the company’s structures, in an effort to boost its operational efficiency. The model, dubbed Dynamic Shared Ownership (DSO), is designed to “make the company much more agile,” according to Bayer’s announcement. The restructuring initiative will include job cuts over the next couple of months to be completed by the end of 2025, at the latest. “In line with the principles of DSO, the implementation will be largely decentralized, meaning that its scope cannot be quantified for the time being,” according to the company. Bayer employs some 22,200 staff in Germany and, as of the end of 2023, had a global headcount of more than 101,000. Though Bayer has not specified how many posts the layoffs will affect, Barbara Gansewendt, chairwoman of the Group Executives’ Committee at the company, said in a statement that it “will come at the expense of many managerial employees.” The committee represents the interests of manager-level staff at Bayer. Gansewendt called these layoffs an “extremely bitter development” for Bayer, adding that there is “no viable alternative” for the company. Affected staff will receive an “attractive” severance pay and will be given adequate support to help them find “new employment as quickly as possible,” she said. The new DSO operating model comes after new Bayer CEO Bill Anderson hinted at major structural changes during its third-quarter earnings report in November 2023. At the time, Anderson was expressed disappointment in the company’s performance, pointing to its “zero cash flow” which he called “simply not acceptable.” A Roche alum, Anderson won his seat at Bayer in February 2023, with the unanimous support of the company’s supervisory board. He formally assumed the helm in June 2023. Anderson inherits from the previous CEO—Werner Baumann, who had served Bayer for 35 years—a company reeling from the disastrous acquisition of the agricultural giant Monsanto. The buyout, signed in September 2016 for $66 billion, was at the time touted by Baumann as a “major step forward” for the company’s crop science business. In the years that followed, however, Monsanto’s weed-killer Roundup would be plagued by claims of cancer, ultimately racking up more than 42,000 lawsuits for Bayer. In its third-quarter 2023 financial report, Bayer posted a net debt of around $42.18 billion. Beyond the Monsanto debacle, Bayer’s pharmaceuticals business also suffered major setbacks last year. In November 2023, the company voluntarily pulled its follicular lymphoma therapy Aliqopa (copanlisib) from the U.S. market after it failed its confirmatory Phase III study. Aliqopa was given accelerated approval in September 2017. A few days later, Bayer decided to pull the plug on the Phase III OCEANIC-AF study of its inhibitor factor XIa asundexian after an Independent Data Monitoring Committee found that it had “inferior efficacy” to BMS and Pfizer’s Eliquis (apixaban). Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.