Persistent Infection

A new test diagnoses patients with melioidosis within hours, rather than days, meaning they can receive the correct antibiotics faster. Globally, more than half of patients die after infection with the neglected tropical disease, melioidosis, often before they are diagnosed. A new rapid test could save lives by diagnosing patients in hours, rather than several days taken by current bacterial culture methods, meaning they receive the correct antibiotics faster. The test uses CRISPR to detect a genetic target that is specific to Burkholderia pseudomallei, the bacterium that causes melioidosis, with 93 per cent sensitivity. It was developed by researchers at the Mahidol-Oxford Tropical Medicine Research Unit (MORU), Chiang Mai University, Vidyasirimedhi Institute of Science and Technology (VISTEC) in Thailand, and the Wellcome Sanger Institute in the UK. The results, published today (14 March) in Lancet Microbe, mean more lives could be saved from melioidosis, with a rapid, easy-to-use diagnostic test that could be rolled out globally. Melioidosis is a neglected tropical disease that is estimated to affect 165,000 people worldwide each year, of whom 89,000 die from the disease. It is caused by the bacterium, Burkholderia pseudomallei, which lives in soil and water in tropical and subtropical regions, and enters human bodies via inoculation through skin abrasions, ingestion or inhalation. It is difficult to diagnose melioidosis as symptoms vary from localised abscess or pneumonia to acute septicaemia, or may present as a chronic infection. As a result of this, and the locations of isolated communities in rural areas that it mostly affects, the disease remains hugely underreported. Currently, melioidosis is diagnosed in patients after bacterial samples are cultured, which takes three to four days. In Thailand, approximately 40 per cent of patients with melioidosis die, many of whom die within the first one to two days following admission to hospital, while waiting for a diagnosis. There is no licensed vaccine for melioidosis, but patients can be effectively treated with intravenous antibiotics -- ceftazidime or carbapenem -- during the first intensive phase of treatment. However, current practices often involve initially treating patients with a range of unnecessary antibiotics to target the various symptoms the disease produces, which can waste time and resources. In a new study, the team set out to develop a new rapid test to reduce the time taken to correctly diagnose and treat patients with melioidosis. The researchers identified a genetic target specific to B. pseudomallei byanalysing over 3,000 B. pseudomallei genomes, most of which were sequenced at the Sanger Institute. They searched for conserved regions of the genome and screened the targets against other pathogens and human host genomes, to ensure their chosen target was specific to B. pseudomallei. Their test, called CRISPR-BP34, involves rupturing bacterial cells and using a recombinase polymerase amplification reaction to amplify the bacterial target DNA for increased sensitivity. Additionally, a CRISPR reaction is used to provide specificity, and a simple lateral flow 'dipstick' read-out is employed to confirm cases of melioidosis. To assess the efficacy of the test, the team collected clinical samples from 114 patients with melioidosis and 216 patients without the disease at Sunpasitthiprasong Hospital, a hospital in northeast Thailand where melioidosis is endemic. The CRISPR-BP34 test was then applied to these samples. The new test showed enhanced sensitivity at 93 per cent, compared to 66.7 per cent in bacterial culture methods. It also delivered results in less than four hours for urine, pus, and sputum samples, and within one day for blood samples. This is a significant improvement over the current bacterial culture diagnostic method, which typically takes three to four days. This new rapid diagnostic test will enable health professionals to prescribe the correct antibiotics faster, meaning fewer patients will die while waiting for a diagnosis. While saving precious time, the new test will also save resources and money, with fewer unnecessary antibiotics prescribed and less time for patients in hospital. In next steps for the team, they are currently designing randomised clinical trials to show the effectiveness of these tests in hospital settings. Plus, members of the team will begin investigating the role of human genetics in susceptibility and immune response to melioidosis infection. Dr ClaireChewapreecha, co-lead author at the Mahidol-Oxford Tropical Medicine Research Unit (MORU), Thailand, and Wellcome Sanger Institute International Fellow, said: "Working in rural Thailand has many limitations. But we have shown that limitations breed innovation, and what succeeds here can succeed anywhere. I am so proud of the team behind this new, robust rapid diagnostic test for melioidosis, and hope that it can potentially be used anywhere in the world to get the right treatments to patients faster, ultimately saving lives." Dr Somsakul Wongpalee, co-lead author at Chiang Mai University, Thailand, said: "We carefully designed the rapid diagnostic test based on CRISPR-BP34, with a robust algorithm, and tested its performance in vitro. We are thrilled that the CRISPR-BP34 test demonstrates outstanding diagnostic efficacy when tested on clinical samples, showcasing its potential to significantly impact patient outcomes and potentially save lives in the near future." Professor Nick Thomson, senior author and Head of Parasites and Microbes at the Wellcome Sanger Institute, said: "This research is a testament to international collaboration and how the application of genomics at scale leads to clinical intervention. Using a genetic target mined from a bank of thousands of bacterial genomes, the team was able to produce an incredibly sensitive test that is specific to the bacterium behind melioidosis. I look forward to seeing the clinical impacts of this research." Professor Nick Day, senior author and Director of the Mahidol-Oxford Tropical Medicine Research Unit (MORU), Thailand, and the Wellcome Trust Thailand Asia and Africa Programme, said: "Melioidosis has been neglected despite its high mortality rate and high incidence in many parts of Asia. Early diagnosis is essential so that the specific treatment required can be started as soon as possible. The new rapid diagnostic tool developed through this collaboration has the potential to be a game-changer."

Findings from a new study reflect the important role that the gut microbiome (communities of bacteria) plays in the airway health of persons with cystic fibrosis. Findings from a new study conducted by a team of researchers at Dartmouth's Geisel School of Medicine and published in the journal mBio, reflect the important role that the gut microbiome (communities of bacteria) plays in the airway health of persons with cystic fibrosis. Cystic fibrosis is an inherited disease that causes sticky, thick mucus to build up in the lungs and other organs, causing persistent infections that can be deadly. Until relatively recently, CF microbiology research has largely been focused on microorganisms in the lungs since most CF-related deaths have been due to respiratory complications. But interest in the CF gut microbiome and its influence on the health of organs like the lungs has grown as the role of the gut microbiome in broader health outcomes has become more apparent. For George O'Toole, PhD, and his colleagues at the Dartmouth Cystic Fibrosis Research Center(DartCF), the journey to better understand the gut-lung connection began more than 10 years ago, as part of a collaboration with physician-scientist Juliette Madan, MD, MS, who studies children with CF at Dartmouth Hitchcock Medical Center (DHMC). "One of the key observations that Dr. Madan made early on was that, surprisingly, the best predictor of how a kid's airway would function actually turned out to be the microbes in their gut rather than the microbes in their airway," explains O'Toole, the Elmer R. Pfefferkorn, PhD, Professor of Microbiology and Immunology at Geisel and anchor author on the study. "We also had noticed that kids with CF were depleted for Bacteroides, a microbe known to be important in programming gut function and the immune system early in life." The findings prompted them to do some experiments in which they were able to show that secreted products from these Bacteroides strains could reduce inflammation in gut-derived cell lines grown in the lab. In further experiments, they were able to narrow down the molecule that was important for that process -- a short-chain fatty acid known as propionate. To reinforce their hypothesis, the team did experiments in mice with the same CF mutation as humans which showed that those mice that had Bacteroides introduced into their guts had less inflammation in their blood and airways after being exposed to Pseudomonas aeruginosa -- a common bacterium in CF infections -- than other similar mice that were not given Bacteroides. Importantly, a Bacteroides variant that could not make propionate could not reduce inflammation. "We think this establishes the idea that changes in the gut are causing a reprogramming of the immune system in such a way that the body isn't as sensitive to subsequent airway infections, so you don't have as much disease burden," says O'Toole. "The other exciting finding is that this actually provides, we think, a proof of concept that probiotics could be beneficial to kids with CF, so it could have important implications for treatments." O'Toole is quick to credit his colleagues at Geisel and at DHMC for their contributions to the study, which in addition to Madan's clinic involved three labs in the CF Center and utilized microbiology experiments, tissue culture work, and animal studies. The Bliska, Cramer, and Ross groups at Geisel contributed to this study. "There were a lot of moving parts to this project, so we needed a lot of help to get it all done," he says. "We're grateful, not only for the expertise that people provided but also for their willingness to participate. The culture of collaboration is core at DartCF, I think, to the success of our group and this is just a nice example of that."

Late-breaking platform presentation showed that BIMZELX® (bimekizumab-bkzx) rapidly achieved and maintained high rates of clinical and health-related quality-of-life responses through four years; six out of ten patients achieved complete skin clearance at Year 4 Responder-analyses demonstrated that approximately nine out of ten patients treated with BIMZELX who achieved PASI90 at Week 16, and over seven out of ten patients who achieved complete skin clearance (PASI100) maintained their response to Year 4 Four-year safety data showed that treatment-emergent adverse events were consistent or decreased with longer BIMZELX exposure, with no new safety signals ATLANTA, March 9, 2024 /PRNewswire/ -- UCB, a global biopharmaceutical company, today announced that the first presentations of BIMZELX® (bimekizumab-bkzx) four-year efficacy and safety data in the treatment of adults with moderate-to-severe plaque psoriasis are being shared this week at the 2024 American Academy of Dermatology (AAD) Annual Meeting in San Diego, California, March 8–12. "We are proud to debut the BIMZELX® four-year psoriasis data at the world's largest dermatology meeting, showing that the majority of adult patients treated with BIMZELX achieved deep and durable clinical response through four years, with a consistent tolerability profile. These results, from the largest pool of Phase 3 data, closely follow the U.S. launch, and reinforce our belief that BIMZELX has the potential to transform the lives of people with moderate-to-severe plaque psoriasis," said Emmanuel Caeymaex, Executive Vice President, Immunology Solutions and Head of U.S., UCB. "Moderate-to-severe plaque psoriasis is a chronic condition with physical skin manifestations that can place a significant burden on a patient's health-related quality-of-life. Analysis shows that through four years of bimekizumab treatment, over six out of ten patients achieved and maintained complete skin clearance, a clinically meaningful endpoint and outcome for patients. These long-term data will be highly welcomed by the dermatology community since they provide important considerations for clinical practice," said Dr. Bruce Strober, Clinical Professor of Dermatology at Yale University, and Central Connecticut Dermatology, Connecticut, U.S. The late-breaking platform presentation shared BIMZELX pooled data from treatment initiation through four years, showing that high rates of clinical and health-related quality-of-life responses were rapidly achieved and were maintained in the long-term.¹ Responder-analyses showed that approximately nine out of ten patients treated with BIMZELX who achieved ≥90 percent improvement from baseline in the Psoriasis Area Severity Index (PASI90) and over seven out of ten patients who achieved complete skin clearance (PASI100) at Week 16 maintained their responses to Year 4.² Pooled analysis from five Phase 3/3b studies showed that BIMZELX demonstrated good tolerability and a consistent safety profile with no new safety findings identified up to four years in patients with moderate-to-severe plaque psoriasis.³ Highlights from the four-year BIMZELX data in moderate-to-severe plaque psoriasis presented at the 2024 AAD: Treatment initiation through four years: Data were pooled across the 52-week BE VIVID study, the 56-week BE READY and BE SURE studies and their open-label extension (OLE Week 144) BE BRIGHT.¹ Analyzed patients were randomized to BIMZELX 320 mg every four weeks (Q4W) to Week 16, then BIMZELX Q4W or Q8W until OLE entry.¹ Clinical and health-related quality of life (PASI90 and PASI100, body surface area [BSA] ≤1 percent and Dermatology Life Quality Index [DLQI]0/1) responses were assessed through to Year 4 (OLE Week 144).¹ Data are presented below for all patients who received BIMZELX continuously from baseline and entered the OLE (n=771):¹ 90.9 percent achieved PASI90 at Week 16, and 86.1 percent through to Year 4.1¥ 65.8 percent achieved PASI100 at Week 16, and 64.7 percent through to Year 4.1¥ 78.5 percent achieved BSA≤1 percent at Week 16, and 79.8 percent through to Year 4.1¥ 71.5 percent achieved DLQI0/1 at Week 16, and 78.7 percent through to Year 4.1 ¥ Responder analysis to Year 4: Patients who completed the BE VIVID, BE SURE, and BE READY Phase 3 studies could enter the BE BRIGHT OLE.² Analyzed patients were randomized to BIMZELX 320 mg Q4W to Week 16, then BIMZELX Q4W or Q8W until OLE entry, then BIMZELX Q4W or Q8W dependent on PASI response/prior dose.² Maintenance of PASI90 and PASI100 was assessed in Week 16 responders to Year 4 (OLE Week 144) and is presented below for all patients:² 87.7 percent who achieved PASI90 at Week 16 (n=693) maintained their response to Year 4.2¥ 73.3 percent who achieved PASI100 at Week 16 (n=503) maintained their response to Year 4.2¥ Safety and tolerability through four years: Data were pooled across the 52-week BE VIVID study, the 56-week BE READY and BE SURE studies, and the OLE studies BE BRIGHT and BE RADIANT.3 The total BIMZELX exposure was 6,324.3 patient-years (PY) across the studies (n=2,186).3 Exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs) remained consistent or decreased with longer BIMZELX exposure. Overall, TEAEs occurred at an EAIR of 170.5/100 PY and serious TEAEs at 5.5/100 PY.3 The most common TEAEs were nasopharyngitis (12.7/100 PY), oral candidiasis (8.9/100 PY), and upper respiratory tract infections (5.7/100 PY). Oral candidiasis decreased from 18.9/100 PY at Year 1 to 5.4/100 PY at Year 4.3 Throughout, fewer TEAEs occurred with BIMZELX every 8 weeks (Q8W) (115.4/100 PY) vs. every 4 weeks (Q4W) (224.4/100 PY).3 ¥ Modified non-responder imputation analyses Notes to Editors: About BIMZELX (bimekizumab-bkzx) Bimekizumab is a humanized IgG1 monoclonal antibody that selectively binds to IL-17A, IL-17F and IL-17AF cytokines, blocking their interaction with the IL-17RA/IL-17RC receptor complex.4 Elevated levels of IL-17A and IL-17F are found in lesional psoriatic skin.4 BIMZELX is not approved in the U.S. for the treatment of psoriatic arthritis or axial spondyloarthritis and these are investigational indications only. Please see Important Safety Information below and full U.S. prescribing information at . BIMZELX U.S. IMPORTANT SAFETY INFORMATION4 Suicidal Ideation and Behavior BIMZELX® (bimekizumab-bkzx) may increase the risk of suicidal ideation and behavior (SI/B). A causal association between treatment with BIMZELX and increased risk of SI/B has not been established. Prescribers should weigh the potential risks and benefits before using BIMZELX in patients with a history of severe depression or SI/B. Advise monitoring for the emergence or worsening of depression, suicidal ideation, or other mood changes. If such changes occur, advise to promptly seek medical attention, refer to a mental health professional as appropriate, and re-evaluate the risks and benefits of continuing treatment. Infections BIMZELX may increase the risk of infections. Do not initiate treatment with BIMZELX in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing BIMZELX. Instruct patients to seek medical advice if signs or symptoms suggestive of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and do not administer BIMZELX until the infection resolves. Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with BIMZELX. Avoid the use of BIMZELX in patients with active TB infection. Initiate treatment of latent TB prior to administering BIMZELX. Consider anti-TB therapy prior to initiation of BIMZELX in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients for signs and symptoms of active TB during and after treatment. Liver Biochemical Abnormalities Elevated serum transaminases were reported in clinical trials with BIMZELX. Test liver enzymes, alkaline phosphatase and bilirubin at baseline, periodically during treatment with BIMZELX and according to routine patient management. If treatment-related increases in liver enzymes occur and drug-induced liver injury is suspected, interrupt BIMZELX until a diagnosis of liver injury is excluded. Permanently discontinue use of BIMZELX in patients with causally associated combined elevations of transaminases and bilirubin. Avoid use of BIMZELX in patients with acute liver disease or cirrhosis. Inflammatory Bowel Disease Cases of inflammatory bowel disease (IBD) have been reported in patients treated with IL-17 inhibitors, including BIMZELX. Avoid use of BIMZELX in patients with active IBD. During BIMZELX treatment, monitor patients for signs and symptoms of IBD and discontinue treatment if new onset or worsening of signs and symptoms occurs. Immunizations Prior to initiating therapy with BIMZELX, complete all age-appropriate vaccinations according to current immunization guidelines. Avoid the use of live vaccines in patients treated with BIMZELX. Most Common Adverse Reactions Most common adverse reactions (≥1 percent) are upper respiratory infections, oral candidiasis, headache, injection site reactions, tinea infections, gastroenteritis, Herpes Simplex Infections, acne, folliculitis, other Candida infections, and fatigue. For further information, contact UCB: Investor Relations Antje Witte T +32.2.559.94.14 email [email protected] U.S. Communications Erica Puntel T +1.770.970.8465 email [email protected] About UCB UCB, Brussels, Belgium () is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With approximately 9,000 people in approximately 40 countries, the company generated revenue of €5.3 billion in 2023. UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCBUSA. Forward looking statements This press release may contain forward-looking statements including, without limitation, statements containing the words "believes", "anticipates", "expects", "intends", "plans", "seeks", "estimates", "may", "will", "continue" and similar expressions. These forward-looking statements are based on current plans, estimates and beliefs of management. All statements, other than statements of historical facts, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial information, expected legal, arbitration, political, regulatory or clinical results or practices and other such estimates and results. 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Finally, a breakdown, cyberattack or information security breach could compromise the confidentiality, integrity and availability of UCB's data and systems. Given these uncertainties, you should not place undue reliance on any of such forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labelling in any market, or at any particular time, nor can there be any guarantee that such products will be or will continue to be commercially successful in the future. UCB is providing this information, including forward-looking statements, only as of the date of this press release. UCB expressly disclaims any duty to update any information contained in this press release, either to confirm the actual results or to report or reflect any change in its forward-looking statements with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless such statement is required pursuant to applicable laws and regulations. Additionally, information contained in this document shall not constitute an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any offer, solicitation or sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such jurisdiction. References 1. Strober B. 2024 AAD. Oral Presentation. 2. Blauvelt A, Foley P, Langley RG, et al. Bimekizumab 4-year maintenance of responses in Week 16 responders with moderate to severe plaque psoriasis: Results from the BE BRIGHT open label extension phase 3 trial. Abstract at the 2024 American Academy of Dermatology Annual Meeting, San Diego, CA, U.S., March 8–12, 2024. 3. Gordon KB, Thaçi D, Gooderham M, et al. Bimekizumab safety and tolerability in moderate to severe plaque psoriasis: Pooled analysis from up to 4 years of treatment in 5 phase 3/3b clinical trials. Abstract at the 2024 American Academy of Dermatology Annual Meeting, San Diego, CA, U.S., March 8–12, 2024. 4. BIMZELX [prescribing information]. Smyrna, GA: UCB, Inc. SOURCE UCB