Lovastatin

Tyenne® is the first tocilizumab biosimilar by Fresenius Kabi, an operating company of Fresenius SE, with an intravenous and subcutaneous formulation approved by the FDA. The tocilizumab biosimilar provides increased access and an affordable, high-quality, and safe treatment option for U.S. patients. Excellent performance of the (Bio)Pharma business in 2024 so far, also driven by Tyenne® which became the first tocilizumab biosimilar available in Europe in November 2023. The launch of the tocilizumab biosimilar contributes directly to growing Fresenius’ (Bio)Pharma platform, a substantial cornerstone of the #FutureFresenius strategy. BAD HOMBURG, Germany--(BUSINESS WIRE)-- Fresenius, via its operating company Fresenius Kabi, announced today the immediate U.S. availability of Tyenne® (tocilizumab-aazg), a biosimilar of Actemra® (tocilizumab). Tyenne®, for use in the treatment of chronic autoimmune diseases, is available in an intravenous (IV) formulation. This press release features multimedia. View the full release here: Fresenius Kabi announced that Tyenne® (tocilizumab-aazg), a biosimilar of Actemra® (tocilizumab) is now available in the U.S. in an IV presentation. Tyenne tocilizumab-aazg) is for use in the treatment of chronic autoimmune diseases. (Photo: Business Wire) Michael Sen, CEO of Fresenius: “With the launch of Tyenne® in the U.S., we have reached another important milestone in accelerating our strong (Bio)Pharma momentum. Growing this platform is a substantial cornerstone of our #FutureFresenius journey. Overall, we have seen an excellent performance of our (Bio)Pharma business in 2024 so far. We are particularly happy with the good progress of our majority-owned biotechnology company mAbxience and the traction of Tyenne®, the first tocilizumab biosimilar available in Europe since November 2023.” Tyenne® is the first tocilizumab biosimilar with an intravenous and subcutaneous formulation approved by the FDA. The biosimilar received FDA approval on March 5, 2024. Tyenne® is Fresenius’ third approved biosimilar available in the U.S. and the second within its immunology portfolio. The biologic medicine is indicated for the treatment of several autoimmune diseases, including rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. Pierluigi Antonelli, CEO of Fresenius Kabi: “Tyenne® will impact the treatment landscape for inflammatory and immune diseases in the U.S. Reaching ever more patients with our state-of-the-art biopharma portfolio signals a clear growth path in a highly promising market segment. We will continue to roll out our comprehensive pipeline of autoimmune and oncology biosimilars with several molecules in late-stage development.” Supported by Fresenius Kabi’s support program for health care professionals and patients, the company’s biologic medicine provides wider access to more treatment options and contributes to the viability of health care systems. Next to its two available biosimilars, Idacio® (adalimumab) and Stimufend® (pegfilgrastim), Fresenius Kabi has a growing pipeline of autoimmune and oncology biosimilars with several molecules in late-stage development. To learn more about how Fresenius Kabi provides comprehensive patient support for Tyenne® in the U.S. please click here. With #FutureFresenius, Fresenius successfully set the course last year to become a leading therapy-focused company. In line with the strategy, Fresenius has simplified its structure, is sharpening its focus by concentrating on its operating companies Fresenius Kabi and Fresenius Helios and is continuously enhancing its performance. About Tyenne®, a Tocilizumab Biosimilar Tyenne® (tocilizumab-aazg), a biosimilar to Actemra® (tocilizumab), is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. It was developed by Fresenius Kabi using advanced analytical and manufacturing technologies for use in the treatment of several autoimmune diseases, including rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving the product. Tyenne is contraindicated in patients with known hypersensitivity to tocilizumab products. For more information about Tyenne, please see the full prescribing information for the U.S. here. IMPORTANT SAFETY INFORMATION RISK OF SERIOUS INFECTIONS Patients treated with TYENNE® (tocilizumab-aazg) are at increased risk for developing serious infections that may lead to hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral, or other opportunistic infections. If a serious infection develops, interrupt TYENNE until the infection is controlled. Reported infections include: Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before TYENNE use and during therapy. Treatment for latent infection should be initiated prior to TYENNE use. Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with TYENNE should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with TYENNE, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. CONTRAINDICATION TYENNE is contraindicated in patients with known hypersensitivity to tocilizumab products. WARNINGS AND PRECAUTIONS Gastrointestinal Perforations Events of gastrointestinal (GI) perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TYENNE with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with new-onset abdominal symptoms for early identification of GI perforation. Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation. Most cases presented with marked elevations of transaminases (> 5 times ULN), and some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. Treatment with tocilizumab was associated with a higher incidence of transaminase elevations; increased frequency and magnitude of these elevations were observed when tocilizumab was used in combination with potentially hepatotoxic drugs (e.g., methotrexate). It is not recommended to initiate TYENNE treatment in RA, GCA, PJIA, and SJIA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN discontinue TYENNE. Measure liver tests promptly in patients who report symptoms that may indicate liver injury. If the patient is found to have abnormal liver tests, TYENNE treatment should be interrupted. TYENNE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. Laboratory Parameters Laboratory monitoring is recommended due to potential consequences of treatment-related laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests. Dosage modifications may be required. Neutropenia: Treatment with tocilizumab products was associated with a higher incidence of neutropenia. It is not recommended to initiate TYENNE treatment in RA, GCA, PJIA, and SJIA patients with a low neutrophil count i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an ANC less than 500 per mm3 treatment is not recommended. Thrombocytopenia: Treatment with tocilizumab products was associated with a reduction in platelet counts. It is not recommended to initiate TYENNE in RA, GCA, PJIA, and SJIA patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3, treatment is not recommended. Elevated Liver Enzymes: It is not recommended to initiate TYENNE treatment in patients with elevated transaminases ALT or AST >1.5x ULN. In patients who develop elevated ALT or AST >5x ULN, treatment is not recommended. Lipid Abnormalities: Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterols, and/or HDL cholesterol. Immunosuppression The impact of treatment with tocilizumab products on the development of malignancies is not known, but malignancies were observed in clinical studies with tocilizumab. TYENNE is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. TYENNE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For TYENNE subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of TYENNE immediately and discontinue TYENNE permanently. Do not administer TYENNE to patients with known hypersensitivity to tocilizumab products. Demyelinating Disorders The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies. Monitor patients for signs and symptoms of demyelinating disorders. Prescribers should exercise caution in considering the use of TYENNE in patients with preexisting or recent onset demyelinating disorders. Active Hepatic Disease and Hepatic Impairment Treatment with TYENNE is not recommended in patients with active hepatic disease or hepatic impairment. Vaccinations Avoid use of live vaccines concurrently with TYENNE. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving TYENNE or on the effectiveness of vaccination in patients receiving TYENNE. Patients should be brought up to date on all recommended vaccinations prior to initiation of TYENNE therapy, if possible. ADVERSE REACTIONS Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. DRUG INTERACTIONS In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. Exercise caution when coadministering TYENNE with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. USE IN PREGNANCY The limited available data with tocilizumab products in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. You may report side effects to the FDA at (800) FDA-1088 or . You may also report side effects to Fresenius Kabi at (800) 551-7176. Please see additional Important Safety Information in full Prescribing Information, including Boxed Warning. INDICATIONS TYENNE is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). TYENNE is indicated for the treatment of giant cell arteritis (GCA) in adult patients. TYENNE is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) in patients 2 years of age and older. TYENNE is indicated for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older. Tyenne® demonstrates Fresenius Kabi’s commitment to providing access to affordable and cost-effective biosimilars to more patients living with autoimmune diseases around the world while enabling savings for health care systems. KabiCare, Fresenius Kabi’s comprehensive patient support program, will be available to patients and health care providers in the U.S. from launch. About Fresenius SE Fresenius SE & Co. KGaA (Frankfurt/Xetra: FRE) is a global healthcare company headquartered in Bad Homburg v. d. Höhe, Germany. In the 2023 fiscal year, Fresenius generated €22.3 billion in annual revenue with its more than 190,000 employees. Fresenius offers solutions to the social challenges posed by a growing and ageing population and the resulting need for affordable, high-quality healthcare. The Fresenius Group comprises the operating companies Fresenius Kabi and Fresenius Helios as well as the investment companies Fresenius Vamed and Fresenius Medical Care. With 140 hospitals and countless outpatient facilities, Fresenius Helios is the leading private hospital operator in Germany and Spain, treating around 26 million patients every year. Fresenius Kabi’s product portfolio includes a range of highly complex biopharmaceuticals, clinical nutrition, medical technology, and generic intravenous drugs. Fresenius was established in 1912 by the Frankfurt pharmacist Dr. Eduard Fresenius. After his death, Else Kröner took over management of the company in 1952. She laid the foundations for a global enterprise that today pursues the goal of improving people’s health. The largest shareholder is the non-profit Else Kröner-Fresenius Foundation, which is dedicated to advancing medical research and supporting humanitarian projects. For more information visit the company website at . Follow us on social media: . About Fresenius Kabi Fresenius Kabi is a global healthcare company that specializes in lifesaving medicines and technologies for infusion, transfusion and clinical nutrition. The company’s products and services are used for the therapy and care of critically and chronically ill patients. Its product portfolio comprises a range of highly complex biopharmaceuticals, clinical nutrition, medical technologies, and I.V. generic drugs. Within biopharmaceuticals, Fresenius Kabi offers, among others, biosimilar drugs with a focus on autoimmune diseases and oncology. The company’s clinical nutrition offering includes a wide selection of enteral and parenteral nutrition products. In the segment of medical technologies, its offering includes vital disposables, infusions pumps, apheresis machines, cell therapy devices, and more. Fresenius Kabi puts essential medicines and technologies in the hands of people who help patients and finds the best answers to the challenges they face. Following its strategy “Vision 2026”, which is a key part of the #FutureFresenius program of the Fresenius healthcare group, the company is furthermore committed to increase efficiencies in the therapy and care of patients and improve access to high-quality healthcare around the globe. Fresenius Kabi aspires to be leading globally in its product segments – all for the benefit of patients, its customers, and its stakeholders. Actemra® is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group. Tyenne® is a registered trademark of Fresenius Kabi Deutschland GmbH. Idacio® and Stimufend® are registered trademarks of Fresenius Kabi Deutschland GmbH in selected countries. View source version on businesswire.com: Contacts Matt Kuhn (847) 220-3033 matt.kuhn@fresenius-kabi.com Source: Fresenius Kabi Smart Multimedia Gallery Photo Fresenius Kabi announced that Tyenne® (tocilizumab-aazg), a biosimilar of Actemra® (tocilizumab) is now available in the U.S. in an IV presentation. Tyenne tocilizumab-aazg) is for use in the treatment of chronic autoimmune diseases. (Photo: Business Wire) Logo View this news release and multimedia online at:

On March 18th, Cell published online a research paper about a new mechanism involving the gut in regulating cholesterol metabolism. The researchers discovered a gut-derived hormone called Cholesin, which is triggered by cholesterol intake and produced within intestinal cells. Cholesin achieves inhibition of the PKA-ERK1/2 signaling pathway in the liver by binding to the GPR146 receptor there, thereby downregulating the cholesterol synthesis process regulated by SREBP2. This means that when the gut absorbs cholesterol, the Cholesin-GPR146 axis acts to suppress cholesterol production in the liver, helping to maintain stable blood cholesterol levels and combat hypercholesterolemia and atherosclerosis.  DOI: 10.1016/j.cell.2024.02.024To investigate the interaction between intestinal cholesterol absorption and hepatic cholesterol synthesis, the researchers designed experiments to induce mice to consume diets with varying cholesterol content (regular diet and high-cholesterol Western diet) and observed changes in cholesterol levels in the intestine and liver. Under a high-cholesterol diet, intestinal cholesterol content increased, accompanied by downregulated expression of the cholesterol biosynthesis marker HMGCR in the intestine, suggesting a negative feedback mechanism where absorbed cholesterol can influence its own synthesis. Against this backdrop, the researchers identified a new gut-derived hormone induced by cholesterol – Cholesin. Cholesin is triggered by cholesterol absorption mediated by NPC1L1, with its gene encoded in humans as C7orf50 and in mice as 3110082I17Rik. After secretion by intestinal cells, Cholesin binds to a specific orphan GPCR member, GPR146, and suppresses the PKA-ERK1/2 signaling pathway, reducing the hepatic cholesterol synthesis activity regulated by SREBP2. To further confirm the relationship between Cholesin and its receptor GPR146, researchers employed a variety of experimental approaches, including but not limited to binding assays on frozen tissue sections, genome-wide CRISPR-Cas9 screenings, and immunohistochemistry techniques. Ultimately, it was established that GPR146 is an effective receptor for Cholesin, and the interaction between Cholesin and GPR146 directly influences the regulation of cholesterol metabolism. Through CRISPR screenings, protein expression purification, and a range of experimental validations, Cholesin's mechanism of action was elucidated, and it was demonstrated that both the sole use of Cholesin and its combination with statin drugs significantly reduce total plasma cholesterol levels and alleviate atherosclerotic lesions. Moreover, Cholesin can also decrease body weight gain, lower triglyceride levels, and improve hepatic lipid accumulation and inflammation markers. About AtherosclerosisAtherosclerosis is a chronic inflammatory disease, primarily characterized by the accumulation of substantial amounts of cholesterol and other lipid substances on the vessel walls, forming plaques. These plaques gradually enlarge and can lead to the narrowing of the arterial lumen, impeding blood flow. Additionally, these plaques may become unstable and rupture, causing thrombosis, which in turn can trigger serious events such as myocardial infarction or stroke. Cholesterol is an essential lipid for the human body, involved in the construction of cell membranes, hormone synthesis, and various other physiological functions. However, when cholesterol levels in the blood are too high, especially when low-density lipoprotein cholesterol (LDL-C) concentrations are excessive, the risk for cardiovascular diseases increases, with the most notable being the onset and progression of atherosclerosis. Studies have shown that an excess of cholesterol, particularly oxidized LDL cholesterol, penetrating beneath endothelial cells, can trigger an inflammatory response through a complex series of biochemical processes. This stimulates smooth muscle cell migration and proliferation, causes macrophages to engulf lipids and become foam cells, forming what are called fatty streaks, which then evolve into mature atherosclerotic plaques. In addition to the abnormal accumulation of lipids, the state of imbalance between immune responses and their clearance is also believed to be primarily shaped by the migration and homeostasis of leukocytes, which are regulated by chemokines and their receptors. In recent years, new pro-inflammatory and anti-inflammatory pathways that link lipid biology with inflammation have been discovered, and gene expression profiling studies have revealed various factors involved in human coronary artery disease. Cardiovascular diseases are the leading cause of death globally, with an estimated 17.8 million people dying each year. Inflammation is considered to be one of the main driving forces in the development of atherosclerosis and is recognized as one of the major etiologies of cardiovascular disease. Despite the increasing body of research evidence over the past three decades showing that immune components play an indispensable role in the formation and chronicity of atherosclerosis, through a series of immunotherapeutic targets, the benefits and challenges brought about by targeting inflammation and the immune system in cardiovascular diseases have been demonstrated. DOI: 10.1038/s41569-021-00668-4DOI: 10.1038/nm.2538Using the diagram above as an example, chemokines and their receptors also play an important role in the pathogenesis of atherosclerosis. The process of leukocyte recruitment includes rolling, firm adhesion, lateral migration, and transendothelial migration, which are finely regulated by chemokines. On the one hand, soluble chemokines directly mediate the recruitment of leukocytes; on the other hand, chemokines immobilized by glycosaminoglycans (GAGs) on the surface of activated endothelial cells can trigger the docking of leukocytes through GPCRs and activate leukocyte integrins, thus achieving firm adhesion. The cell-specific and lesion stage-specific utilization of chemokines and their receptors underscores the robustness and complexity of the chemokine system, ensuring the formation of specific chemokine combinations at each stage of the lesion that attract specific subtypes of leukocytes. Synergistic effects among chemokines in the recruitment of leukocytes can lead to cooperative interactions, potentially mediating the process between leukocytes and atherosclerotic lesions. According to statistics from the Synapse database, as of now, there are more than 500 therapeutic drug pipelines globally, originating from over 400 institutions, encompassing over 200 targets, and involving 4095 clinical trials. The therapeutic drugs for this disease have a diverse range of Mechanisms of Action (MOA). At present, the primary therapeutic drugs for the treatment of atherosclerosis include statins, which function primarily by inhibiting the key enzyme in cholesterol biosynthesis—hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Examples include Lovastatin (Merck, approved in 1987), Fluvastatin (Novartis, approved in 1993), Atorvastatin (Pfizer, approved in 1996), Rosuvastatin (AstraZeneca, approved in 2002). P2Y12 receptor antagonists are another class of therapeutic drugs for atherosclerosis, acting by selectively blocking the function of the P2Y12 receptor to inhibit excessive activation and aggregation of platelets. This is crucial because platelets play a key role in the development of atherosclerosis and thrombosis, especially in the progression of cardiovascular diseases. Common drugs in this category include Clopidogrel (Sanofi, approved in 1997), Ticagrelor (AstraZeneca, approved in 2010), Cangrelor (CHIESI, approved in 2015). Additionally, in recent years, PCSK9 has emerged as a therapeutic candidate for the treatment of hypercholesterolemia and atherosclerosis-related diseases. The primary function of PCSK9 is to regulate the number of low-density lipoprotein cholesterol (LDL-C) receptors on the membrane of liver cells. When PCSK9 binds to LDL receptors, it leads to their degradation within lysosomes, thereby reducing the uptake and clearance of circulating LDL-C by the liver, resulting in elevated levels of LDL-C in the blood. Therapeutic drugs related to this mechanism include Evolocumab (Amgen, approved in 2015), Alirocumab (Sanofi, approved in 2015), Inclisiran (Novartis, approved in 2020). Factor Xa inhibitors are a class of drugs that specifically inhibit the activity of coagulation factor Xa (FXa). FXa plays a crucial role in the blood coagulation process, as it acts as a key enzyme in the coagulation cascade, facilitating the conversion of prothrombin to thrombin, which in turn catalyzes the transformation of fibrinogen into fibrin, leading to the formation of a stable clot. By binding to FXa and preventing its activity, Factor Xa inhibitors can effectively suppress the formation of thrombi and are widely used in clinical practice to prevent and treat various thrombotic diseases, such as deep vein thrombosis, pulmonary embolism, and stroke prevention in patients with atrial fibrillation. Therapeutic candidates in this category include Rivaroxaban (Bayer, approved in 2008), Edoxaban Tosylate (Daiichi Sankyo, approved in 2012), Apixaban (Bristol-Myers Squibb, approved in 2011). Additionally, SGLT2 inhibitors were initially developed for the treatment of type 2 diabetes by inhibiting the SGLT2 transporter protein in the renal proximal convoluted tubules, reducing the reabsorption of glucose and thereby promoting the excretion of glucose in the urine, leading to decreased blood glucose levels. In recent years, multiple large-scale clinical trials have revealed the significant therapeutic effect of SGLT2 inhibitors in reducing the risk of cardiovascular events, especially in patients with type 2 diabetes who have atherosclerotic cardiovascular diseases. Therapeutic candidates related to this include Tofogliflozin (Kowa, approved in 2014) and Ertugliflozin (Pfizer, approved in 2017). Besides the classical P2Y12 receptor, potential therapeutic targets within the GPCR family include AT1R, PAR-1R, CXCR4, CCR2, NIACR1, TBXA2R, PGI2R, ADRA1, and EP3. However, the progress in the drug pipeline related to these targets is not promising. Only Vorapaxar, a tricyclic compound derived from camptothecin that acts as a selective inhibitor on thrombin-activated receptor (PAR-1), has been approved for reducing the incidence of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD). The first antibody drug candidate developed targeting an immunomodulatory factor associated with GPCRs for treating atherosclerosis is the humanized monoclonal antibody Plozalizumab, an antagonistic monoclonal antibody targeting CCR2 developed by Takeda Pharmaceutical in Japan. CCR2 plays a critical role in the migration of monocytes and macrophages to sites of inflammation. The recruitment of macrophages to the arterial wall is considered a key step in the development of atherosclerosis. The first nanobody drug candidate is BI-655088, targeting the CX3CR1 receptor.