Extensively Drug-Resistant Tuberculosis

Research achievements enabled by a combination of advanced AI platforms, research capabilities, and drug discovery technologies SEOUL, South Korea, April 4, 2023 /PRNewswire/ -- Standigm, a company using artificial intelligence (AI) technology for drug discovery and development, and Korean non profit research institute Institut Pasteur Korea announced that they have jointly developed new lead compounds effective in treating resistant tuberculosis (TB). The two organizations conducted a technology acceleration grant project supported by the Right Foundation from 2021 to 2022. They achieved encouraging results by combining their core competencies of artificial intelligence (AI) platforms, infectious disease research capabilities and drug discovery technologies. This breakthrough demonstrates that AI technology can effectively address unmet medical needs for low and middle-income countries that tend to have higher than normal rates of resistant TB. Standigm, the project's lead organization, utilized its drug design artificial intelligence platform, Standigm BEST™, with a scaffold-based molecular generation model and a deep learning prediction model that learned the features of three-dimensional molecular structures. The collaborating institute, Institut Pasteur Korea, utilized its drug discovery platform in a biosafety level 3 laboratory to evaluate the efficacy of new compounds against drug-sensitive and multi-drug-resistant TB (MDR-TB)/extensively drug-resistant TB (XDR-TB) and incorporated the compound information and efficacy evaluation results into Standigm BEST™. In particular, the researchers designed and synthesized various new compounds based on the compounds' structure-activity relationship (SAR) analysis and continuously provided high-quality anti-TB efficacy evaluation results, which Standigm utilized to enhance its AI platform. The two organizations have successfully identified lead compounds for resistant TB through this AI-based drug discovery research collaboration. Standigm and Institut Pasteur Korea have been collaborating on TB drug discovery since 2020. On September 29, 2021, they signed a memorandum of understanding to develop AI-based infectious disease drugs to accelerate their joint research. "There is no vaccination that can guarantee complete protection against TB," said Dr. Sangok Song, co-founder and chief research officer of Standigm. "The BCG vaccination is the only vaccination against TB, and even if antibodies are developed, the lifetime protection rate is only 19% to 27%. We believe that artificial intelligence technology will play an important role in discovering new, low-cost, and effective treatments for TB and other diseases in low- and middle-income countries." TB often spreads in enclosed, poorly ventilated, multi-use facilities where many people stay for long periods, but it is one of the most urgently needed vaccines and treatments in medically underserved countries because of its high prevalence in socio-economically disadvantaged populations and the resistance issues from prolonged use of currently available TB drugs. "Through this collaboration with Standigm, we have presented a complementary and advanced drug discovery research model that combines the accumulated know-how of our researchers with cutting-edge technologies and next-generation artificial intelligence, said Dr. Byung-Kwon Lim, director of the Institut Pasteur Korea." We will accelerate the subsequent development of new drug candidates derived from this research collaboration and contribute to the global effort to end TB." About Institut Pasteur Korea Institut Pasteur Korea is a non-profit research organization that focuses on infectious disease research and development with the goal of improving global public health, and was founded in 2004 based on Korea-France science and technology cooperation. Utilizing its core research capabilities, including innovative screening platforms, the institute is leading the way in understanding the mechanisms of development and accelerating the development of new drugs for emerging infectious diseases such as MERS, Zika, and COVID-19, as well as diseases that threaten humanity today, such as viral hepatitis, tuberculosis, antibiotic-resistant bacterial infections, neglected diseases, and cancers. As a member of the Pasteur Network of 33 laboratories in 25 countries across five continents, the institute plays a key role in leading early drug discovery research within the network. By providing original technologies and promoting multidisciplinary global projects that link Korean and international biomedical sciences, the institute contributes to Korea's scientific, knowledge, and technological resources and helps prepare for and respond to global infectious diseases. () About Standigm Standigm was founded in 2015 to revolutionize drug discovery with artificial intelligence (AI) technology. It's AI technologies cover the entire drug discovery lifecycle (target discovery, hit identification, hit-to-lead, and lead optimization) to continuously develop first-in-class and best-in-class drug discovery projects. Standigm's leading AI platforms include Standigm ASK™, which identifies novel and promising disease targets, and Standigm BEST™, which generates novel chemical structures. By combining the Standigm ASK™ and Standigm BEST™ platforms, Standigm has completed Standigm Magic, a workflow AI that can be completed in an average of seven months from target discovery to lead compound series. Standigm works on various first-in-class and best-in-class drug candidate development projects in collaboration with leading domestic and international pharmaceutical companies and research institutes. For more information about the company, please visit . Press Inquiries Kim Ji-Eun, Head of External Relations, Institut Pasteur Korea [email protected] +82-31-8018-8041 Kyungmoon Kim, Head of Operations at Standigm [email protected] +82-2-501-8118 Gabriella Perez-Silva, PR for Standigm [email protected] 714-875-6424 SOURCE Standigm

GSK plc (LSE/NYSE: GSK) announced positive results from a Phase IIa study demonstrating that GSK3036656, a first-in-class investigational antitubercular agent, was well tolerated and showed early bactericidal activity with a low, once-daily oral dose after 14 days of treatment in participants with drug-susceptible pulmonary tuberculosis. These results demonstrate the potential for GSK3036656 to be a component of simpler treatment regimens in the future which could help address the TB epidemic. A selection of these data was presented in an oral late breaker session at the Union World Conference on Lung Health on 11 November. The TB epidemic is one of the most pressing public health challenges: over the last decade TB was the leading cause of death due to an infectious disease globally, causing approximately 1.5 million deaths annually. Earlier this year, GSK made a commitment to invest 1bn over the next decade to accelerate R&D on infectious diseases, including TB, that disproportionately impact lower-income countries. David Barros-Aguirre, Head of Global Health Medicines R&D, GSK, said: Existing treatments for TB can be complicated, of long duration and have serious side effects which significantly impact the lives of patients with TB around the world. Todays encouraging data provide a good foundation from which to investigate GSK3036656 in different combinations in Phase IIb/c studies, with the aim of contributing to shorter, simpler and better tolerated treatment regimens for patients with TB. Anti-mycobacterial activity was demonstrated both in terms of reducing the number of viable TB cells which are able to multiply (colony forming units - CFU), and an increase in the time to detect bacterial growth in culture (time to positivity - TTP). In addition, PET CT imaging of the lungs showed a reduction in TB disease over 14 days in all participants taking GSK3036656 30mg. Prof. Andreas Diacon, Chief Scientific Officer, TASK, said The data show that GSK3036656 is a potential new antibiotic for tuberculosis that can be used in low, once daily doses. This can help reduce side effects and is an important characteristic of any new TB drug. GSK3036656 is of a completely new class of antibiotics which makes the chance of drug resistance very low. I am looking forward to evaluating GSK3036656 in shorter and better tolerated combinations with other new agents to bring about a new era of tuberculosis treatment. The investigational antitubercular agent will be tested in Phase IIb/c studies in different drug regimens to determine the appropriate partner agents to complement its anti-TB action and the optimal regimen durations. The aim is to identify a GSK3036656-containing regimen with sufficient tolerability, efficacy and short enough duration to progress to Phase III with a high probability of success. These innovative studies will be conducted in collaboration with industry and academic partners and will be co-funded by the European Unions IMI2 programme. GSK works in partnership to develop new TB medicines and vaccines, focusing efforts on research and early development, and partnering with world-leading organisations and funders on late development, manufacturing and access to maximise impact for patients. About the trial Study 201214 was a single centre, Phase IIa, open-label study to investigate the early bactericidal activity (EBA), safety, and tolerability of GSK3036656 in participants with drug-sensitive pulmonary tuberculosis. The study had four cohorts, with 12 to 20 participants in each cohort. The participants were randomized in a 3:1 ratio to receive either GSK3036656 at doses 1 mg, 5 mg, 15 mg, and 30 mg or standard-of-care (SoC) regimen for drug sensitive TB (i.e. Rifafour e-275 or equivalent generic alternative), respectively. The primary endpoint was to determine the rate of change in log10colony forming units (CFU) per mL direct respiratory sputum samples over the period baseline to Day 14 (EBA CFU0-14). A key secondary outcome was the rate of change in time to sputum culture positivity (EBA TTP) over the time period baseline to Day 14 (EBA TTP0-14). GSK3036656 doses of 5 mg to 30 mg showed bactericidal activity as evidenced by both endpoints after 14 days. GSK3036656 30 mg had the highest bactericidal activity: A decline in CFU of -0.138 log10CFU/mL (95% CI: -0.167, -0.109) An increase in TTP of 0.22 log10CFU/mL (95% CI: 0.019, 0.024) GSK3036656 was generally well tolerated with no serious adverse events (SAEs) identified in the study. The percentage of participants reported with adverse events was similar between SoC and GSK3036656 and no large differences between GSK3036656 and SoC or GSK3036656 dose related trends were observed. The trial was conducted as part of the anTBiotic project, a consortium which consists of GSK Global Health Medicines R&D (Spain), the University of Troms (Norway), Forschungszentrum Borstel (Germany), the University of Cape Town (South Africa) and the TASK Foundation (South Africa). The project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 733079. About tuberculosis Tuberculosis is the leading cause of death due to an infectious disease globally, other than COVID-19, causing approximately 1.5 million deaths annually. It is caused by a bacterium called Mycobacterium tuberculosis and mainly affects the lungs, although it can affect any part of the body. Current treatment options are often inadequate for patients with TB: long and complicated courses of treatment with serious side effects mean many people struggle to adhere to the full course. As a result, the bacteria are developing resistance to existing medicines making treatment less effective. New treatments are urgently needed: the ambition is to find shorter, simpler and better tolerated treatments for TB to reduce the burden on patients and increase adherence to treatment thereby preventing further selection of resistant strains. However, developing new TB treatment regimens is challenging as they involve a combination of more than three different compounds often from multiple organisations. A collaborative approach is required to ensure researchers can access the compounds at an early stage of development to understand how they work in combination. About GSK3036656 GSK3036656 is a first-in-class investigational antitubercular agent which is being developed for the treatment of tuberculosis as part of a future combination regimen. It suppresses protein synthesis in Mycobacterium tuberculosis (Mtb) by inhibiting the enzyme leucyl t-RNA synthetase (LeuRS). GSK3036656 has demonstrated activity not only against laboratory strains of Mtb, but also against a selection of Drug Sensitive TB (DS-TB), Multi Drug Resistant TB (MDR-TB) and Extensively Drug Resistant TB (XDR-TB) clinical isolates. Animal models of TB infection have shown that GSK3036656 is potent in vivo. The compound is the result of a collaboration between GSK and Anacor Pharmaceuticals which led to the identification of GSK3036656 as a selective anti-mycobacterial agent that is inactive against other respiratory pathogens. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together.

The number of estimated deaths from tuberculosis (TB) increased between 2020 and 2021 as the COVID-19 pandemic reversed decades of progress in the fight against the disease, according to the World Health Organization’s (WHO) Global TB report 2022 . TB services are among many others disrupted by the COVID-19 pandemic, but its impact on the TB response has been particularly severe, WHO said in a statement. The figures show an estimated 10.6 million were infected with TB in 2021, an increase of 4.5% from 2020, and 1.6 million people died from the disease. WHO also reported that the burden of drug-resistant TB increased by 3% between 2020 and 2021, with 450,000 new cases of rifampicin-resistant TB in 2021. This is the first time in many years an increase has been reported in the number of people falling ill with TB and drug resistant TB. “The report provides important new evidence and makes a strong case on the need to join forces and urgently redouble efforts to get the TB response back-on-track to reach TB targets and save lives,” said Dr Tereza Kasaeva, director of WHO’s Global TB Programme. Continued challenges with providing and accessing essential TB services have meant that many people with TB were not diagnosed and treated, WHO said. The reported number of people newly diagnosed with TB fell from 7.1 million in 2019 to 5.8 million in 2020. There was a partial recovery to 6.4 million in 2021, but this was still well below pre-pandemic levels. These reductions in the reported number of diagnosed TB cases suggest that the number of people with undiagnosed and untreated TB has grown. The report also notes a decline in global spending on essential TB services from $6bn in 2019 to $5.4bn in 2021, which is less than half of the global target of $13bn annually by 2022. Urging the world to apply lessons learnt from the pandemic to tuberculosis, Dr Tedros Adhanom Ghebreyesus, WHO director-general, said: “If the pandemic has taught us anything, it’s that with solidarity, determination, innovation and the equitable use of tools, we can overcome severe health threats. Let’s apply those lessons to tuberculosis. It is time to put a stop to this long-time killer. Working together, we can end TB.”