Odanacatib

Researchers with Shenzhen Institutes of Advanced Technology in China used a variety of computational techniques to simulate drug-virus interactions. They then screened 1,906 existing drugs to evaluate which ones might inhibit replication of SARS-CoV-2, the virus that causes COVID-19. From this broad screening, they identified four drugs that had potential to prevent replication of the virus, which they then tested in laboratory experiments. Two of the drugs, pralatrexate, a chemotherapy, and azithromycin, an antibiotic, were successful at preventing replication of the virus. More lab experiments demonstrated that pralatrexate had stronger viral inhibition than Gilead Sciences’ remdesivir, which is currently the only approved drug for COVID-19. They published their research in the journal PLOS Computational Biology. Pralatrexate is marketed by Acrotech Biopharma under the trade name Folotyn. It is indicated for relapsed or refractory peripheral T-cell lymphoma. Like many chemotherapeutics, it comes with a wide range of serious side effects, including low blood cell counts—platelets, white blood cells, and red blood cells—mucositis, which is inflamed mucous membranes, severe skin reactions, tumor lysis syndrome (TLS), increased risk of serious reactions in kidney patients, fever, dehydration, nausea, as well as significant risk for pregnant and nursing women. As a result, the authors note that immediate use of the drug for COVID-19 patients is not guaranteed, but believe their approach was useful in identifying drugs that can be repurposed. “We have demonstrated the value of our novel hybrid approach that combines deep-learning technologies with more traditional simulations of molecular dynamics,” said Haiping Zhang, study author. The research team is working to develop more computational methods for creating novel molecular structures that could be developed into new drugs to treat COVID-19. The screening method focused on viral RNA-dependent RNA polymerase (RdRp), a promising therapeutic target. The authors write that other computational drug screening methods are based on molecular docking, deep learning or Molecular Dynamics. Most of these typically depend upon a single technique or lack experimental validation. “Each computation method,” they write, “with its underlying philosophy, often has its own strong and weak points, while a proper combination and modification of such methods could provide a better solution. Previously, we have developed two deep learning-based models to estimate protein-ligand interactions: DFCNN and DeepBindBC. DFCNN uses molecular vector data of protein pocket and ligand, instead of spatial information at interaction site, to estimate the protein-ligand pair as binding or non-binding with a probability value between 0 and 1. DeepBindBc estimates the binding possibility from atom contact information at interaction surface of a modelled 3D protein-ligand complex. The input of DeepBindBC contains spatial information of the protein-ligand interface, thus it strongly complements DFCNN.” Their hybrid screening procedure was made up of DFCNN, DeepBindBC, Autodoc Vina, pocket localized molecular dynamics simulation, metadynamics, and their own inhouse-developed tools. They screened potential drugs from the TargetMol-Approved_Drug_Library, which contains 1,906 currently marketed drugs. One of the findings, less focused on COVID-19, but of particular interest to validation of the screening approach, was that DFCNN, DeepBindBC and Autodock Vina predicted different drug compounds as top hits. For example, amenamevir and azithromycin had better scores on Autodock Vina, while odanacatib and nitisinone had higher DFCNN scores. Azithromycin, with hydroxychloroquine, an anti-malarial, had demonstrated efficacy in treating COVID-19 earlier in the pandemic, but subsequent studies have failed to show that either drug is effective in treating COVID-19. For that matter, a large World Health Organization (WHO) study failed to prove remdesivir’s effectiveness in hospitalized patients, resulting in the organization issuing a conditional recommendation against its use.

September 16, 2014 By Riley McDermid , BioSpace.com Breaking News Sr. Editor Drug giant Merck & Co. is facing increasing concern about the cardio safety of its osteoporosis drug odanacatib, which would could muddy its way as its seeks U.S. Food and Drug Administration approval, an analyst with ISI Group said today. The company just announced its Phase III data for odanacatib at the American Society for Bone and Mineral Research conference earlier this week. The info showed that the drug will build bone mineral density in patients, while demonstrating a significant reduction in fractures. It found a 47 percent relative risk reduction of clinical hip fractures; a 54 percent relative risk reduction of new and worsening morphometricvertebral fractures; and a 23 percent relative risk reduction of clinical nonvertebral fractures. Most surprisingly, it could reduce clinical vertebral fractures by as much as 72 percent. But Mark Schoenebaum, a biotech and pharmaceuticals analyst for ISI Group, cautioned that the drug still shows signs of being hard on the cardiovascular system, “But on cardiovascular safety (recall, we learned at the analyst day even in May ’14 that there were imbalance in atrial fibrillation and stroke events), we learned today there were numerical imbalances in afibrilliation, stroke, major adverse cardiac events and deaths,” he wrote in a note to investors. Schoenebaum said that while none were statistically significant, with confidence intervals of the hazard ratios crossed one, many still trended the same way, which would have most data readers preferring a placebo over odanacatib. “While not statistically significant, these safety issues will be analyzed closely by the FDA,” he wrote. “Merck reports that it continues to collect data from the blinded extension study and plans additional analyses including a re-adjudication of MACE events.” As a result, the company told the conference it does not plan to the FDA until 2015.“Bottom line: The fracture data reported for odanacatib (an oral drug with a novel mechanism of action) are generally in line with bisphosphonates, the current standard of care,” wrote Schoenebaum. While odanacatib did not result in osteonecrosis of the jaw and had a low rate of atypical femoral shaft fractures, the numerical imbalances of cardiovascular events will be analyzed closely by the FDA and “commercially could make detailing the drug to doctors more difficult.” “Despite these concerns, as expectations for odanacatib had already come down meaningfully on the Street (we saw this more as an upside opportunity for MRK), we expect a modest impact to MRK’s stock,” he concluded. var switchTo5x=true; stLight.options({publisher: "0341611e-38a4-415d-9e18-75e093ff27e0", doNotHash: false, doNotCopy: false, hashAddressBar: false});