GSK-3036656

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.

GSK says an experimental tuberculosis drug has delivered positive results in a Phase IIa, paving the way for combination regimens that can be tested in Phase IIb/III trials. The candidate, dubbed GSK3036656, originated from a 11-year collaboration with Anacor Pharma. In the mid-stage study, a low, once-daily oral dose of the drug showed early bactericidal activity after 14 days of treatment. It marks the second antibiotic win for GSK in days, after the pharma giant — one of a few still in this space — claimed success in two large clinical trials on a new antibiotic for uncomplicated urinary tract infections. Wrapping the trials up early, GSK said it will be filing for FDA approval next year. In the Phase IIa tuberculosis trial, investigators tracked samples from patients with drug-susceptible pulmonary tuberculosis and found that GSK3036656 lowered the number of viable tuberculosis cells, meeting the primary endpoint. On a key secondary endpoint, the drug also increased the time it took to detect growth in culture. Both were measured over a period of 14 days. Typically, people with tuberculosis are prescribed six months of treatment. “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,” said David Barros-Aguirre, GSK’s head of global health medicines R&D, in a statement. The hope is that GSK3036656, which targets an enzyme on Mycobacterium tuberculosis known as leucyl-tRNA synthetase, can serve as a component to shorter, simpler and better tolerated treatment regimens. A total of four doses were tested in the trial: 1 mg, 5 mg, 15 mg and 30 mg, alongside a control arm given standard of care antibiotics. For those taking the highest dose (which showed the most bactericidal effect), PET CT imaging of the lungs also showed a reduction in TB disease over 14 days. With the threat of drug resistance — public health experts have warned of doomsday scenarios where even simple infections could become deadly — looming over antibiotics. GSK has emphasized that the drug belongs in a new class, which can mean a lower risk of resistance. Together with industry and academic partners, GSK will now look to identify the appropriate drugs to pair with GSK3036656 and put them into late-stage studies.