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Novartis has filed a lawsuit against the FDA after the agency approved a generic version of its top-selling product Entresto. Two weeks ago, Novartis CEO Vas Narasimhan referred to the initial wave of drug pricing effects tied to the Inflation Reduction Act (IRA) as “manageable.”What the company appears to be finding unmanageable, however, is potential near-term generic competition to its heart failure blockbuster Entresto.On Wednesday afternoon in federal court in Washington, D.C., the Swiss company filed a lawsuit against the FDA, claiming that the U.S. regulator’s approval of a generic version of Entresto is unlawful.The complaint comes a week after the FDA approved an Entresto generic from MSN Laboratories. The agency also rejected a Novartis-orchestrated Citizen Petition, which asked it to block the entry of generic versions of Entresto.The petition, which was submitted in September 2022, had asked the agency to deny the approval of any Entresto generic until Feb. 16 of this year. It also petitioned to prevent the FDA from approving any Entresto generics that would violate Novartis patents due to expire in 2033 and 2036. The FDA rejected the first request because it has already passed. The second and third requests were denied because the agency said that generics can avoid infringement simply by adjusting their labels.Novartis is seeking to preserve U.S. exclusivity for Entresto as long as possible. The company owns a series of patents on the drug, with some expiring in 2025, 2026 and 2027, according to FDA records.In 2026, government-negotiated prices Entresto will kick in. Those prices are set to be published Sept. 1 of this year. Entresto was approved by the FDA in 2015. The oral treatment is a combination of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan.In its complaint, Novartis alleges the FDA’s conduct is unlawful because it encourages labeling that “inappropriately rewrites Entresto’s approved indication.” Novartis also argues that MSN’s label for its generic “deletes critical safety information contained in the Entresto labeling.” Further, the company contends that the FDA, in denying Novartis’ petition, has “bound itself to approved generics that do not have identical active ingredients to Entresto.” This is another in Novartis’ attempts to derail generic competition for Entresto. In 2022, the company filed a lawsuit against generic drug makers Viatris, Alembic, Crystal and Nanjing Noratech, as well as MSN. In that complaint, the company claimed infringement against a patent due to expire in November 2026.That suit followed an infringement claim against generics maker Torrent Pharma, which was filed in December 2021.In addition to reaching confidential settlements with "several" generics filers, the company has had mixed success in other court cases against generic drug makers.Entresto is Novartis’ top-selling product, raking in revenue of $6 billion last year and $3.8 billion in the first half of this year.

Medical researchers have used a 3D human neural cell culture model to show that the exercise-induced muscle hormone, irisin, reduces the level of amyloid beta deposits associated with Alzheimer's disease. Researchers who previously developed the first 3D human cell culture models of Alzheimer's disease (AD) that displays two major hallmarks of the condition -- the generation of amyloid beta deposits followed by tau tangles -- have now used their model to investigate whether the exercise-induced muscle hormone irisin affects amyloid beta pathology. As reported in the journal Neuron, the Massachusetts General Hospital (MGH)-led team has uncovered promising results suggesting that irisin-based therapies might help combat AD. Physical exercise has been shown to reduce amyloid beta deposits in various mouse models of AD, but the mechanisms involved have remained a mystery. Exercise increases circulating levels of the muscle-derived hormone irisin, which regulates glucose and lipid metabolism in fat tissue and increases energy expenditure by accelerating the browning of white fat tissue. Studies have revealed that irisin is present in human and mouse brains and that its levels are reduced in patients with AD and in mouse models of the condition. To test whether irisin plays a causal role in the link between exercise and reduced amyloid beta, Se Hoon Choi, PhD and Eun Hee Kim, PhD, of the Genetics and Aging Research Unit at MGH, along with additional research colleagues applied the hormone to their 3D cell culture model of AD. "First, we found that irisin treatment led to a remarkable reduction of amyloid beta pathology," says Choi. "Second, we showed this effect of irisin was attributable to increased neprilysin activity owing to increased levels of neprilysin secreted from cells in the brain called astrocytes." Neprilysin is an amyloid beta-degrading enzyme that has been found to be elevated in the brains of mice with AD that were exposed to exercise or other conditions leading to reduced amyloid beta. The researchers uncovered even more details about the mechanisms behind irisin's link to reduced amyloid beta levels. For example, they identified integrin αV/β5 as the receptor that irisin binds to on astrocytes to trigger the cells to increase neprilysin levels. Furthermore, they discovered that irisin's binding to this receptor causes reduced signaling of pathways involving two key proteins: extracellular signal-regulated kinase (ERK) and signal activator of transcription 3 (STAT3). Reduced ERK-STAT3 signaling was critical for irisin-induced enhancement of neprilysin. Previous studies have shown that in mice, irisin injected into the blood stream can make its way into the brain, making it potentially useful as a therapeutic. "Our findings indicate that irisin is a major mediator of exercise-induced increases in neprilysin levels leading to reduced amyloid beta burden, suggesting a new target pathway for therapies aimed at the prevention and treatment of Alzheimer's disease," says Rudolph Tanzi, PhD, a senior author of the study and director of the Genetics and Aging Research Unit. Additional co-authors include Hyeonwoo Kim, Mark P. Jedrychowski, Grisilda Bakiasi, Joseph Park, Jane Kruskop,Younjung Choi, Sang Su Kwak, Luisa Quinti, Doo Yeon Kim, Christiane D. Wrann, and Bruce M. Spiegelman. This research was supported by Cure Alzheimer's Fund (R.E.T., S.H.C., and C.D.W.); JPB Foundation (R.E.T. and B.M.S.); NIH R56AG072054 and 1R21AG062904 (S.H.C. and C.D.W.); Coins for Alzheimer's Research Trust (S.H.C.), and BrightFocus Foundation Fellowship A2020870F (E.K.).

Novartis has joined several other biopharma companies, filing a lawsuit that challenges the Inflation Reduction Act's provision for Centers for Medicare & Medicaid Services price negotiations. Add Novartis to the list of biopharma giants that have filed lawsuits against the U.S. government as a reaction to the Inflation Reduction Act (IRA).  The company filed its case Friday in New Jersey federal court, three days after the Centers for Medicare & Medicaid Services (CMS) revealed that Novartis’ heart failure treatment Entresto was among 10 drugs subject to price negotiations in 2026. The Swiss company joins Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Johnson & Johnson and Merck in filing separate suits against the IRA. All except for Astellas have at least one blockbuster drug set for the first round of price negotiations. Industry association PhRMA and the U.S. Chamber of Commerce have also registered lawsuits against the IRA. Most of the lawsuits contain the same language. Novartis labeled the negotiation process a “sham” and called the tax to be levied against companies that charge more than the negotiated price “draconian” and “wildly disproportionate to the punished conduct.” “This case challenges an unprecedented and unconstitutional attempt to compel the nation’s drug manufacturers to sell their products at prices dramatically below their market value,” the Novartis lawsuit says. The company charges that the Medicare negotiation setup is an “unconstitutional taking of private property,” which violates the Fifth Amendment. Novartis also argues the CMS action infringes rights established in the First Amendment and the Eighth Amendment. As for Entresto—which was approved in 2015 for heart failure patients—Novartis said in the suit that more than 70% of its sales come through the CMS and estimates that at least a quarter of its market value will be lost through price negotiation. Novartis racked up $4.6 billion in sales of the angiotensin receptor/neprilysin inhibitor last year, a 37% increase from 2021. Novartis added in its lawsuit that the IRA would “imperil” its ability to conduct the research to bring innovative drugs to the market. “This program will stifle innovation and jeopardize the creation of future medicines—harming the millions of patients who count on the pharmaceutical industry to discover life-saving treatments,” Novartis said in a separate statement posted on its website. “The result would fundamentally jeopardize the development and supply of essential, life-saving drugs for the people who depend on them.” Among the drugs the CMS has designated for negotiation are three from J&J: Stelara, Xarelto and Imbruvica, which the company shares with AbbVie. Also included were Eliquis (Pfizer/BMS), Enbrel (Amgen), Farxiga (AZ), Januvia (Merck), Jardiance (BI/Eli Lilly) and Novolog (Novo Nordisk). Legal analysts believe companies with drugs on the list will tweak their lawsuits to indicate more precisely the financial implications of CMS negotiations. They also expect companies to file injunctions and requests for summary judgements in September 2024, when the CMS announces proposed prices for the top 10 drugs. The analysts also expect companies with drugs on the list that have not filed suit—including Novo, Amgen, Lilly and Pfizer—to do so or to join existing cases. There’s also a possibility that judges may try to consolidate the litigation, attorneys told Bloomberg Law.