Plitidepsin

Now that the researchers have a clear idea of the proteins at play in the virus's evolution, the next step will be to try to develop new treatments that target them from multiple angles. The spike protein on the surface of SARS-CoV-2, the virus that causes COVID-19, has basked in the spotlight since the pandemic began. And for good reason: After all, that spike is what enables it to enter human cells. But despite its notoriety, the protein is just one of several that make SARS-CoV-2 a tricky foe, as scientists from the University of California, San Francisco’s Quantitative Biosciences Institute (QBI), Icahn School of Medicine at Mount Sinai and University College London show in an article published online Sept. 21 in Cell. The findings shed light on how the virus is evolving and support a combination approach that tackles the proteins that help it suppress the immune system, study lead and QBI founder Nevan Krogan, Ph.D., told Fierce Biotech Research. “We’ve figured out how this virus is going to behave as it goes forward, or at least a big part of it,” he said. “And what we need to do, just like we do with HIV, is fight it with a cocktail of therapies.” The new findings build on the 50-plus studies published over the course of the pandemic by the QBI Coronavirus Research Group, a network of scientists founded by Krogan that has been tracking COVID’s evolution and identifying potential therapies since the virus emerged in 2020. Besides a plethora of papers, the collaboration has also led to two clinical trials, including one with Spanish pharma PharmaMar assessing the use of cancer drug plitidepsin as a treatment for immunocompromised patients with COVID. “We now have a deep mechanistic understanding of how this virus works,” Krogan said. That now includes an explanation for the convergent evolution of different strains of the virus—that is, the way it mutates via different mechanisms but seemingly ends with the same result: suppression of the innate immune response. “It’s converging on the same kind of final output, but it’s doing so through different kinds of evolutionary trajectories through different mutations,” Krogan said. “It’s almost like if you try to force it to go one way, it’ll go another way and do what it wants.” To map this out, the researchers took healthy lung cells and cultured sets of them with major strains of the virus, from alpha through omicron BA.1. Then they used various computational tools to examine how protein and gene expression changed between strains as well as how the virus affected genes within the host cells. While the way the virus evolved to outsmart the immune system changed depending on the strain, as expected, there was a common mechanism involving a handful of select proteins. One of them, ORF9b, stood out as being especially complicit in enabling pre-omicron variants of the virus to suppress the innate immune response, the body’s first line of defense against pathogens, and invade cells. Interestingly, the original strain of omicron was less effective than alpha or delta in getting around that defense system, the researchers noted—potential evidence for the theory that it arose from a chronically ill, immunocompromised patient. Future offshoots, including BA.5, made up for that by expressing higher levels of another protein, ORF6, which once again bumped up the virus’s ability to suppress innate immunity. (The researchers went into more detail on ORF6 in a second paper, also published Sept. 18, in Cell Host & Microbe.) Now that the researchers have a clear idea of the proteins at play, the next step will be to try to develop new treatments that target them from multiple angles. Work is ongoing now to develop therapies that would target the SARS-CoV-2 proteins that manipulate the immune response. “Ultimately, these drugs could effectively be used in a ‘cocktail’ with therapies that target viral entry involving the spike protein,” Krogan said in an email. Meanwhile, his COVID research efforts will be helped along by a $200,000 award he received Sept. 20 as the first-ever recipient of Research!America’s Discovery | Innovation | Health prize, sponsored by Pfizer. 

YONDELIS® (trabectedin) now PBS listed for Australian patients Listing described as "wonderful news" for patients living with rare lipo and leiomyo sarcomas YONDELISÒ (trabectedin) demonstrates 45% reduction in risk of disease progression or death versus dacarbazine1 SINGAPORE, July 31, 2023 /PRNewswire/ -- AUSTRALIAN cancer patients who have been diagnosed with rare soft tissue sarcomas will now have affordable access to a global therapy shown to improve survival, following its listing on the Pharmaceutical Benefits Scheme (PBS). The therapy YONDELIS (trabectedin) is a novel anti-tumour agent originally derived from the sea squirt and will be available to eligible patients on the PBS from August 1. It is used extensively around the world and has been shown to improve progression-free survival for patients with liposarcoma and leiomyosarcoma when used after anthracycline-based therapy.1 Until today, some patients have paid up to $50,000 to access YONDELIS treatment. News of the PBS listing is being welcomed by oncologists and the Australian sarcoma community, who say it will alleviate cost of treatment pressures for those patients whose disease has progressed. Medical oncologist and Scientific Advisory Committee member and Lead of the ANZSA National Sarcoma Database Dr Susie Bae, said YONDELIS has been available in Europe since 2007 for patients with advanced soft tissue sarcoma, and Australian patients had waited many years for reimbursed access. "This milestone means patients don't need to worry about not being able to afford or miss out on an active drug that can potentially buy precious time with their loved ones, by providing disease control and keeping symptoms at bay for longer," Dr Bae said. Melbourne patient advocate and mother of two Karen Lurati – herself diagnosed with liposarcoma six years ago – said this listing provided new hope for other patients. "A PBS listing for YONDELIS is so exciting for those people who may not have been able to afford the treatment before," she said. "Rare cancers don't often get (Government) funding or attention. To now have this therapy on the PBS is great progress. "Patients often feel that they have to go overseas and spend enormous amounts of money on treatments that may not be available in Australia. This can be frustrating and financially crippling. So, for patients to have access to a global therapy in their own country is wonderful news." And Rare Cancers Australia (RCA) Chief Executive Richard Vines said he was "delighted with this outcome", describing the listing as "great news" for patients living with an L-sarcoma. "For too long, sarcoma patients have been unable to access all therapies which may provide benefit," he said. Today's announcement means they can access a PBS funded medicine instead of having to try and find tens of thousands of dollars – if not more – to self-fund a treatment that may give them more time." YONDELIS is marketed in Australia by independent pharmaceutical company Specialised Therapeutics, under an exclusive license arrangement with international partner PharmaMar. ST Chief Executive Officer Carlo Montagner said the PBS listing was a significant milestone for the company. He commented: "We acquired the YONDELIS rights in 2019 following requests from key oncology groups and doctors, who had been importing the product at great cost and with complex logistics for those patients diagnosed with these rare cancers. "This PBS listing is the culmination of a substantive effort by our team together with the oncology community to achieve full regulatory approval and a PBS listing. "We look forward to continuing our work with the sarcoma community." Ends. About Specialised Therapeutics Asia Headquartered in Singapore, Specialised Therapeutics (ST) is an international biopharmaceutical company established to commercialise new therapies and technologies to patients in Australia, New Zealand and across South-East Asia. ST and its regional affiliates collaborate with leading global pharmaceutical and diagnostic companies to bring novel, innovative and life-changing healthcare solutions to patients affected by a range of diseases. Our mission is to provide therapies that would otherwise not be available to communities in our regions. The company's broad therapeutic portfolio currently includes novel agents in oncology, haematology, neurology, ophthalmology and supportive care. Additional information can be found at About YONDELIS® (trabectedin) YONDELIS® (trabectedin) is a novel, multimodal, synthetically produced antitumor agent, originally derived from the sea squirt, Ecteinascidia turbinata. The anti-cancer medicine works by preventing tumor cells from multiplying and is approved in 76 countries in North America, Europe, South America and Asia for the treatment of advanced soft-tissue sarcomas as a single-agent, and in 69 countries for relapsed ovarian in combination with doxorubicin HCl liposome injection. The approval was based on the results of a pivotal phase 3, randomised, open-label controlled study which evaluated YONDELIS versus dacarbazine in over 500 patients with unresectable or metastatic liposarcoma (LPS) or leiomyosarcoma (LMS) previously treated with an anthracycline and at least one additional chemotherapy regimen. LPS and LMS are subtypes of soft tissue sarcoma (STS) and represent more than 35% of all STS cases.3 The median progression-free survival (PFS) among the YONDELIS treatment group was 4.2 months compared to 1.5 months in the dacarbazine treatment group, representing a 45% reduction in the risk of disease progression or death with YONDELIS (HR=0.55; 95% CI: 0.44 - 0.70; p<0.001).1 Among the 340 patients who received YONDELIS and were included in the safety analysis in the randomised trial, the most common (≥20%) adverse reactions were nausea (73%), fatigue (67%), vomiting (44%), constipation (36%), decreased appetite (34%), diarrhoea (34%), dyspnoea (25%), peripheral oedema (24%) and headache (23%). The most common (≥20%) laboratory abnormalities were neutropenia (49%), increased alanine transaminase (ALT) (45%), anaemia (39%), increased aspartate aminotransferase (AST) (35%), thrombocytopaenia (30%) and increased blood alkaline phosphatase (20%).1 About Soft Tissue Sarcoma Soft tissue sarcoma is a rare type of cancer that forms as a painless lump (tumour) in any one of the soft tissues connecting all the organs and body structures – including fat, muscle, nerves, deep skin tissue, blood vessels and the tissue surrounding joints (synovial tissue). Soft tissue sarcomas commonly develop in the thigh, shoulder and pelvis and may sometimes develop in the abdomen or chest.6 Metastatic or locally advanced STS is generally considered incurable, with the mainstay of treatment being systemic chemotherapy. For some patients with limited disease burden however, long-term remission can be achieved through a multimodality approach involving medical, surgical and radiation therapy.4 About PharmaMar PharmaMar is a biopharmaceutical company focused on the research and development of new oncology treatments, whose mission is to improve the healthcare outcomes of patients afflicted by serious diseases with our innovative medicines. The Company is inspired by the sea, driven by science, and motivated by patients with serious diseases to improve their lives by delivering novel medicines to them. PharmaMar intends to continue to be the world leader in marine medicinal discovery, development and innovation. PharmaMar has developed and now commercializes Yondelis® in Europe by itself, as well as Zepzelca® (lurbinectedin), in the US; and Aplidin® (plitidepsin), in Australia, with different partners. In addition, it has a pipeline of drug candidates and a robust R&D oncology program. PharmaMar has other clinical-stage programs under development for several types of solid cancers: lurbinectedin, ecubectedin, PM534 and PM54. It also has a preclinical and clinical program in virology. Headquartered in Madrid (Spain), PharmaMar has subsidiaries in Germany, France, Italy, Belgium, Austria, Switzerland and The United States. PharmaMar also wholly owns Sylentis, a company dedicated to researching therapeutic applications of gene silencing (RNAi). To learn more about PharmaMar, please visit us at . SOURCE Specialised Therapeutics