enkephalinase

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.

Novartis has become the latest drugmaker to sue the US government over the Medicare drug price negotiation element of President Biden’s Inflation Reduction Act (IRA). The lawsuit, filed in federal court in New Jersey, comes just days after the Centers for Medicare and Medicaid Services (CMS) announced the first ten prescription drugs that will be subject to pricing negotiations by the health programme. The list includes Novartis’ top-selling heart-failure medicine Entresto (sacubitril/valsartan), which the company says is the only angiotensin receptor-neprilysin inhibitor currently approved by the US Food and Drug Administration (FDA) to treat heart failure, with around 587,000 Medicare patients taking the drug every year. The company also outlined in a statement that, since Entresto’s 2015 approval for heart failure with reduced ejection fraction (HFrEF), it has carried out additional studies to extend the use of the drug in different heart failure indications and paediatric populations. "Under the IRA, which discourages the research and development of additional indications for small molecule medicines by implementing price controls nine years after the first FDA approval, we may not have been able to invest in researching and developing Entresto in these additional indications, depriving patients of a meaningful treatment advance,” Novartis said. The company added that the negotiations were “unconstitutional" because they amounted to a taking of private property and imposed punitive fines on non-compliant manufacturers. Other drugs selected for negotiation were Bristol Myers Squibb and Pfizer’s Eliquis (apixaban), Amgen's Enbrel (etanercept), AstraZeneca's Farxiga (dapagliflozin), Merck & Co's Januvia (sitagliptin), Eli Lilly and Boehringer Ingelheim's Jardiance (empagliflozin) and Novo Nordisk's Novolog/Fiasp (insulin aspart). Johnson & Johnson's Stelara (ustekinumab) and Xarelto (rivaroxaban) were also listed, as well as its AbbVie-partnered Imbruvica (ibrutinib). Collectively, the drugs accounted for more than $45bn in Medicare Part D spending from June 2022 to May 2023, according to the CMS. After the negotiation period, the new prices will be announced in September 2024 and will be effective at the beginning of 2026. The plan is facing court challenges from other leading drugmakers and industry groups, including Merck & Co, Bristol Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, AstraZeneca and the Pharmaceutical Research and Manufacturers of America.