Raloxifene Hydrochloride

- A team of US and European researchers have released new findings in Science Advances showing how the SARS-CoV-2 Spike (S)-protein interacts with human Estrogen Receptor Alpha (ERα) in lung tissue - Data released as pre-print on bioRxiv reveals the interaction of SARS-CoV-2 (S) Spike proteins with ERα may increase the pro-coagulation activity of endothelial cells, enhancing the risk of thrombosis and shedding new light on the pathogenic mechanisms underlying SARS-CoV-2 infection and on its sex-specific differences - Additional data by the same research groups highlights the mechanism underlying some rare vaccine-associated coagulopathies, which may be prevented by small changes in the Spike sequence used to produce currently available vaccines MILAN and SAN MATEO, Calif., Nov. 30, 2022 /PRNewswire/ -- Dompé farmaceutici announced new data revealing a novel function of the SARS-CoV-2 Spike (S) protein interaction with the human Estrogen Receptor Alpha (ERα) that may lead to the severe coagulopathy observed in patients with COVID-19 and a minority of subjects receiving the SARS-CoV-2 vaccine. The data published today in Science Advances[1] is a collaboration between researchers from Dompé farmaceutici, the National Institute on Drug Abuse, part of the U.S. National Institutes of Health, Johns Hopkins University, The Scripps Institute, Stanford School of Medicine, and the University of L'Aquila, in Italy. Continue Reading A virtual working environment: Exscalate platform is capable of evaluating more than three million molecules per second drawing on a “chemical library” of trillion molecules. Related Documents View PDF Science Advances It is well understood that the SARS-CoV-2 virus can cause severe vasculopathy, which may, in turn, result in fatal thrombosis. The team's findings are consistent with the sex-specific differences in thrombosis observed in hospitalized patients with COVID-19, and in a minority of subjects receiving the SARS-CoV-2 vaccine, as reported earlier this year in the American Journal of Cardiology[2] by an unrelated team. The initial finding leading to the study emerged from the results of the Exscalate4CoV[3] (E4C) project, a group composed of 30 public and private institutions from seven countries and funded by EU Commission's in the frame of its Horizon 2020 Framework Programme[4], aimed at fighting Coronavirus with the latest European supercomputing resources and experimental facilities. The project leveraged the computational power of Exscalate, Dompé's supercomputing platform exploiting a database of 500 billion molecules to find those capable of targeting clinically relevant coronavirus variants. Due to its processing capacity of more than 3 million molecules per second, Exscalate is currently the most powerful intelligent supercomputing drug design platform running on Leonardo[5], the 4th most powerful supercomputer in the world. This processing power allowed the E4C researchers to rapidly select and repurpose a generic molecule (raloxifene) with known efficacy and tolerability as an estrogen modulator for treating osteoporosis. Using the Exscalate platform to identify Spike protein binding partners beyond the canonical ACE2 receptor, researchers identified prominent interactions between two human estrogen receptors (ERα, ERβ) and SARS-CoV-2 Spike protein. After an unbiased primary screen to profile the binding of full-length Spike protein against more than 9,000 human proteins, researchers found a consistent interaction with the human estrogen receptor alpha (ERα). Similarly, high ERα levels were measured in the damaged lungs of infected hamsters, as well as in human postmortem lung samples. The researchers suggest that, given the role of ERα in the coagulation cascade, S-protein could increase the pro-coagulation activity of endothelial cells leading to an enhanced risk of thrombosis. While circulating estrogens play a protective role by regulating the immune response to infection, it may be possible that the modulation of ER signaling in SARS-CoV-2-infected lung tissue can stimulate proinflammatory signals leading to hypertrophy, vasoconstriction, and vessel obstruction. This concept has been validated by a further set of experimental findings, which are currently released in a pre-print[6] and submitted to a peer-reviewed publication, demonstrating that the interaction between the Spike protein and ERα leads to an increase in tissue factor (TF) and overall pro-coagulation activity in a human endothelial cell line, a result further confirmed by overexpressing S-protein in mice. These findings are consistent with the researchers' demonstration that deletion of the appropriate point mutations in the Spike sequence abolished the binding of ERα and its effects without compromising its immunogenicity and pointing at a way to mitigate the rare side effects observed with the currently available vaccines. "Supercomputing has already demonstrated its capacity to find answers to questions we could not answer only a few years ago," underscored Roberto Viola, Director-General of the European Commission's Directorate-General for Communications Networks, Content and Technology (DG CONNECT) who last week inaugurated Leonardo supercomputer in Bologna, Italy. "And it will increasingly help us find solutions in all kinds of areas: from climate change with extreme weather forecasts and urban planning to understanding human brain and body. Medicine is the field where supercomputing is already giving concrete fruits. I am very proud of the support which the European Commission gave to the Exscalate4Cov consortium to discover promising leads for fighting COVID-19 more effectively." "Eventually, the overall evidence provides a solid rationale for some previously published results[7] obtained by our team," said Dompé farmaceutici's Chief Scientific Officer, Marcello Allegretti, "namely the beneficial role of Estrogen Receptor modulators, especially raloxifene, in preventing some of the infection side-effects and support raloxifene use for both therapy and vaccine side-effects mitigation." About Dompé Dompé is a private, rapidly scaling international biopharmaceutical company founded in Milan, Italy, with a 130-year legacy of medical innovation. The R&D department of the company is anchored by EXSCALATE, a structure-based virtual screening platform developed in-house that leverages one of the most powerful supercomputing and artificial intelligence platforms in the world. Today, Dompé employs more than 800 employees worldwide and maintains a US commercial operations hub in the San Francisco Bay Area as well as an R&D presence in Boston. Forward Looking Statements This press release refers to certain information that may not coincide with expected future results. Dompé firmly believes in the soundness and reasonableness of the concepts expressed. However, some of the information is subject to a certain degree of indetermination in relation to its research and development activities and the necessary verifications to be performed by regulatory bodies. Therefore, as of today, Dompé cannot guarantee that the expected results will be consistent with the information provided above. 1. Science Advances - The SARS-CoV-2 spike protein binds and modulates estrogen receptors - eadd4150 (2022) 30 November 2022 - . 2. Wilcox et al. Sex Differences in Thrombosis and Mortality in Patients Hospitalized for COVID-19, Am J Cardiol. 2022 May 1; 170: 112–117, . 3. The Exscalate4Cov () consortium, supported by the the EU's Horizon 2020 programme for research and innovation, was coordinated by Dompé farmaceutici, and composed by 18 member institutions from seven European countries: Politecnico di Milano (Dept. of Electronics, Information and Bioengineering), Consorzio Interuniversitario CINECA(Supercomputing Innovation and Applications), Università degli Studi di Milano (Department of Pharmaceutical Sciences), International Institute of Molecular and Cell Biology in Warsaw (Warsaw, Poland), KU Leuven, Elettra Sincrotrone Trieste, Fraunhofer Institute for Molecular Biology and Applied Ecology, BSC Barcelona Supercomputing Centre, Forschungszentrum Jülich, Università Federico II di Napoli, Università degli Studi di Cagliari, SIB Swiss Institute of Bioinformatics, KTH Royal Institute of Technology (Department of Applied Physics), Associazione Big Data, Istituto Nazionale di Fisica Nucleare (INFN), Istituto nazionale per le malattie infettive Lazzaro Spallanzani and Chelonia Applied Science. Part of E4C League were: ENI, SAS, Alfasigma, CFEL Center for Free-Electron Laser Science, MMV Medicines for Malaria Ventures, Esteve Pharmaceutical, University of Basel Biozentrum, University of Basel Innovation Office, University of Basel Department of Pharmaceutical Sciences, D-wave, Pierre fabre, Greenpharma, University of Sheffield - Sheffield Institute for Translational Neuroscience – SITraN, Dassault Systemes- Biovia, Institute of Food Science Research, CECAM Centre Européen de Calcul Atomique et Moleculaire, Nanome, Esteco, IT4Innovation, Università degli Studi della Tuscia, Sofia University "St. Kl. Ohridski," Faculty of Physics, Institut Cochin. 4. EXaSCale smArt pLatform Against paThogEns for Corona Virus / Grant agreement ID: 101003551 . 5. . 6. Silvia Barbieri et al. - Relevance of the viral Spike protein/cellular Estrogen Receptor-a interaction for endothelial-based coagulopathy induced by SARS-CoV-2; BioRxiv . 7. Allegretti, M. et al. Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 370 infection. Cell Death Differ. 29, 156-166 (2022). 371. Photo - PDF - Logo - SOURCE Dompé farmaceutici S.p.A

Two papers, published in The Lancet and Nature, indicate that treatment with oral raloxifene, a selective estrogen receptor modulator (SERM) with a proven safety profile, may be efficacious against SARS-CoV-2 clinically relevant variants. Raloxifene was identified as a potential COVID-19 treatment by Exscalate4CoV consortium, a multidisciplinary European center of excellence created with the aim to fighting coronavirus by combining the best supercomputing resources and artificial intelligence with state of the art experimental facilities up through clinical validation. New digital open tools for researches are now being developed with the support of the European High Performance Computing Joint Undertaking to further accelerate the drug discovery process. MILAN, July 26, 2022 /PRNewswire/ -- Dompé farmaceutici S.p.A ("Dompé") today announced positive results from two studies demonstrating that treatment with oral raloxifene, a selective estrogen receptor modulator (SERM) with a proven safety profile, may be effective against SARS-CoV-2, including its clinically relevant variants. The two studies were conducted in collaboration with the Italian National Institute for the Infectious Diseases "Lazzaro Spallanzani" in Rome and other important clinical and preclinical research groups highly committed to COVID-19 research. "The clinical results on raloxifene published on Lancet's eClinical Medicine[1] show a significant virological impact in term of negative nasopharyngeal swab at day 7 in COVID-19 patients treated at home with raloxifene compared to standard of care. This randomized clinical trial confirm the in vitro data published in Nature's Cell Death and Disease[2], on the efficacy of Raloxifene on cellular lines experimentally infected by SARS-CoV-2" said Emanuele Nicastri, author of both studies and Director of the Infectious and Tropical Diseases Unit of the Spallanzani Institute in Rome, where Italy's very first Covid-19 patients were hospitalized. A virtual working environment: Exscalate platform is capable of evaluating more than three million molecules per second drawing on a “chemical library” of trillion molecules. Raloxifene was identified by the Exscalate4CoV[3] (E4C) project, a group composed of 30 public and private institutions from seven countries and funded by EU Commission's in the frame of its Horizon 2020 Framework Programme[4], aimed at fighting Coronavirus with the latest European supercomputing resources and experimental facilities. Results were driven by the use of Exscalate, Dompé's supercomputing platform which leveraged a database of 500 billion molecules to find those capable of targeting clinically relevant coronavirus variants. Due to its processing capacity of more than 3 million molecules per second, Exscalate is currently the most powerful intelligent supercomputing drug design platform. This processing power allowed the E4C researchers to rapidly select and repurpose a generic molecule with known efficacy and tolerability to make it available to the global community. As raloxifene is a generic molecule already tested and approved for the treatment of osteoporosis, this was a not for profit effort aimed at providing a globally available low cost treatment. The first study on raloxifene, published in The Lancet's eClinical Medicine, demonstrated that after seven days of treatment, patients taking raloxifene showed an improvement in symptoms compared to patients receiving placebo (please refer to for additional clinical trial details). The second study, published in Cell Death and Disease), indicates raloxifene as a potential agent to treat mild-to-moderate COVID-19 caused by the most common SARS-CoV-2 variants. Mechanistic studies[5] confirmed the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies. Researchers concluded that raloxifene is efficacious against the main SARS-CoV-2 variants and could represent a useful addition to the therapeutic arm for the management of Covid-19. "Supercomputing is already demonstrating its potential for finding new solutions at previously unprecedented speeds in many domains, including medicine. I am very pleased that the Commission has supported the Exscalate4Cov consortium to discover promising treatments for COVID-19, and we now look forward to seeing the results of the consortium's successor LIGATE project[6], which is developing a new drug discovery platform with the support of the European High Performance Computing Joint Undertaking" commented Thomas Skordas, Deputy Director-General of the European Commission's Directorate-General for Communications Networks, Content and Technology (DG CONNECT). "All of us at Dompé are incredibly proud of our contribution to the identification of new solutions to reduce the impact of COVID-19 on patients, healthcare systems, and their communities" said Marcello Allegretti, Chief Scientific Officer at Dompé. "The huge power of our unique supercomputing platform has been a gamechanger, but we want to thank all patients and researchers around the world who participated in these two studies. These results show the importance of combining pharmacological knowledge and breakthrough technologies as AI tools, to exploit the potential of repurposed drugs, and to elevate understanding of yet to be revealed mechanisms of action to address critically unmet medical needs". About Raloxifene Raloxifene is currently on the market for the treatment of osteoporosis and is well-tolerated with a known safety profile. The compound is a marketed drug and has been approved by the EMA for clinical use. About Dompé Dompé is a private, rapidly scaling international biopharmaceutical company founded in Milan, Italy, with a 130-year legacy of medical innovation. The R&D department of the company is leveraging EXSCALATE, a structure-based virtual screening platform developed in-house and presently one of the most powerful supercomputing and artificial intelligence platforms. Today, Dompé employs more than 800 employees worldwide and maintains a U.S. commercial operations hub in the San Francisco Bay Area as well as an R&D presence in Boston. Forward Looking Statements This press release refers to certain information that may not coincide with expected future results. Dompé firmly believes in the soundness and reasonableness of the concepts expressed. However, some of the information is subject to a certain degree of indetermination in relation to its research and development activities and the necessary verifications to be performed by regulatory bodies. Therefore, as of today, Dompé cannot guarantee that the expected results will be consistent with the information provided above. [1] A phase 2 randomized, double-blinded, placebocontrolled, multicenter trial evaluating the efficacy and safety of raloxifene for patients with mild to moderate COVID-19 - (22)00180-8/fulltext [2] "Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants" in Nature Cell Death and Disease (). [3] The Exscalate4Cov () consortium, supported by the the EU's Horizon 2020 programme for research and innovation, was coordinated by Dompé farmaceutici, and composed by 18 member institutions from seven European countries: Politecnico di Milano (Dept. of Electronics, Information and Bioengineering), Consorzio Interuniversitario CINECA(Supercomputing Innovation and Applications), Università degli Studi di Milano (Department of Pharmaceutical Sciences), International Institute of Molecular and Cell Biology in Warsaw (Warsaw, Poland), KU Leuven, Elettra Sincrotrone Trieste, Fraunhofer Institute for Molecular Biology and Applied Ecology, BSC Barcelona Supercomputing Centre, Forschungszentrum Jülich, Università Federico II di Napoli, Università degli Studi di Cagliari, SIB Swiss Institute of Bioinformatics, KTH Royal Institute of Technology (Department of Applied Physics), Associazione Big Data, Istituto Nazionale di Fisica Nucleare (INFN), Istituto nazionale per le malattie infettive Lazzaro Spallanzani and Chelonia Applied Science. Part of E4C League were: ENI, SAS, Alfasigma, CFEL Center for Free-Electron Laser Science, MMV Medicines for Malaria Ventures, Esteve Pharmaceutical, University of Basel Biozentrum, University of Basel Innovation Office, University of Basel Department of Pharmaceutical Sciences, D-wave, Pierre fabre, Greenpharma, University of Sheffield - Sheffield Institute for Translational Neuroscience – SITraN, Dassault Systemes- Biovia, Institute of Food Science Research, CECAM Centre Européen de Calcul Atomique et Moleculaire, Nanome, Esteco, IT4Innovation, Università degli Studi della Tuscia, Sofia University "St. Kl. Ohridski", Faculty of Physics, Institut Cochin. [4] EXaSCale smArt pLatform Against paThogEns for Corona Virus / Grant agreement ID: 101003551 [5] "Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection" in Nature Cell Death & Differentiation journal () and "Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants" in Nature Cell Death and Disease (). [6] Photo - Logo - SOURCE Dompé Farmaceutici S.p.A