Mesalamine

Study finds that mesalamine, a common anti-inflammatory drug, can fight the fungus Candida albicans in the gut, potentially preventing the risk of invasive candidiasis in patients with blood cancers. A team of UC Davis Health researchers discovered that a common anti-inflammatory drug, mesalamine, can replace the work of good bacteria in fighting the nasty fungus Candida albicans in the gut. C. albicans, or candida, is known to cause yeast infections. In some cases, it develops into invasive candidiasis, a potentially fatal infection occurring mostly in patients with compromised immunity. The researchers found that this fungus can't grow without an oxygen supply. Their study in mice showed that the drug can maintain a low oxygen (hypoxia) environment that prevents fungal bloom in the gut. Their study appears today in Cell Host & Microbe. Antibiotic use may lead to fungal bloom in the gut The team studied how C. albicans colonizes the gut. The fungus, best known for causing vaginal yeast infections, is usually treated with a topical or oral antifungal without serious side effects. It also harmlessly lives in the gut of around 60% of people. Yet, when the body's immunity goes down due to cancer or chemotherapy, the fungus may grow beyond the colon and spread throughout the body. In such cases, the patient develops invasive candidiasis. "Invasive candidiasis is a potentially deadly infection with a mortality rate of around 50%. That's even with the best available treatment," explained the study's lead author Andreas Bäumler. Bäumler is a distinguished professor in the Department of Medical Microbiology and Immunology. Patients with leukemia and other blood cancers may need to take antibiotics. This use may cause an imbalance in the gut's microbial community. It reduces Clostridia, a group of bacteria that promotes resistance to fungi colonization in the gut. With less Clostridia, C. albicans grows and colonizes in the tract. "A bloom of C. albicansin the gut during antibiotic therapy is the most common cause of candidemia in people treated for blood cancers," Bäumler explained. Candidemia is the presence of fungi or yeast in the blood. Bäumler and his team wanted to understand the factors involved in antibiotic-induced colonization of C. albicans in the gut. Candida loves simple sugars and oxygen They first colonized germ-free mice with Candida to see what the fungus consumed to bloom. They realized that Candida really liked simple sugars, similar to those found in high-sugar diets. Then, they tested its growth in a petri dish. They placed Candida with simple sugars in an aerobic (with oxygen) setting, and the fungi bloomed. "A healthy gut has low oxygen. So, we repeated the test in a hypoxia setting," Bäumler said. The fungi didn't grow despite the presence of sugars. This meant oxygen is a necessary condition for Candida growth. The role of probiotics in preventing fungal growth The team did a series of experiments that showed antibiotic use reduced Clostridiain the gut. Giving mice probiotics, such as Clostridia, prevented C. albicans from growing in the gut. Yet, probiotics can be killed by antibiotics and cancer therapy. For this reason, probiotics would not help patients with leukemia or other blood cancers. "Probiotics are often not safe in patients at the highest risk for invasive candidiasis," Bäumler said. "Finding a therapy that can function like probiotics but can endure the impact of cancer treatment and antibiotics was important." Anti-inflammatory drugs as faux-biotics The team explored 5-aminosalicylic acid (5-ASA) as a safer way to control C. albicansin the gut. 5-ASA, also known as mesalamine, is an anti-inflammatory drug. It is used to treat inflammatory bowel diseases (IBD) like Crohn's disease and ulcerative colitis. The team tested 5-ASA in mice treated with antibiotics. They found that the drug could replace the work of probiotics by preventing oxygen in the colon and C. albicans from expanding in the gut. "Limiting oxygen in the gut by replacing the function of good bacteria could be a strategy for reducing invasive candidiasis," Bäumler said. "Our study opens a totally new treatment option for fatal fungal infections, especially for patients with cancer. After all, fungi cannot become resistant against hypoxia." The team proposed the term "faux-biotics" to refer to products, such as 5-ASA, that mimic the function of probiotics like Clostridia. The first coauthors of the study are Hannah Savage, Derek Bays and Connor Tiffany. The other co-authors are Mariela Gonzalez, Eli Bejarano, Thaynara Carvalho, Zheng Luo, Hugo Masson, Henry Nguyen, Renato Santos, Krystle Reagan and George Thompson of UC Davis.

The European Commission has approved Pfizer's S1P receptor modulator Velsipity (etrasimod) for patients 16 years and older with moderate-to-severe active ulcerative colitis (UC) who haven't responded well to traditional treatments or biological agents, or who couldn't tolerate them.Séverine Vermeire, an investigator in the ELEVATE registrational programme, suggested the once-daily oral medicine could provide an effective advanced treatment for those who may be apprehensive about using injectable therapies such as biologics.Velsipity recently passed muster with the European Medicines Agency's drug advisory body based on data from the Phase III ELEVATE UC 12 and ELEVATE UC 52 trials, both of which met all primary and key secondary efficacy endpoints. The studies involved UC patients who had previously failed or were intolerant to at least one conventional, biologic or JAK inhibitor therapy.Clinical remission in ELEVATE UC 12 was achieved among 26% of patients receiving Velsipity compared to 15% for placebo. In ELEVATE UC 52, the clinical remission rate was 27% with Pfizer's drug at week 12, and 32% at week 52, compared to 7% at both timepoints for placebo. Key secondary efficacy goals such as endoscopic improvement and mucosal healing were also achieved. Hitting the 'sweet spot' with S1PsVelsipity was approved in the US for the same indication last October, and more recently in Canada. Regulatory applications have also been submitted in several other markets, including Australia, India, Mexico, Russia, Singapore, Switzerland, Turkey and the UK.The EU's Velsipity nod follows the approval of Bristol Myers Squibb's S1P receptor modulator Zeposia (ozanimod) for UC in 2021. In a recent FirstWord interview, a key opinion leader (KOL) suggested the "sweet spot" for S1Ps will likely be in moderate patients who have failed mesalamine and may have required one or two courses of steroids. "It probably does not play a role in those who have failed multiple biologics."The expert also predicted that Velsipity will probably dominate the S1P market within a year or two, although drugs in the class may face some competition from biosimilar versions of Johnson & Johnson's Stelara (ustekinumab) if the price difference is significant enough.Johnson & Johnson is bracing for the first biosimilars of its autoimmune blockbuster to come on the scene this year with Alvotech's contender AVT04 expected to enter the market in Canada, Japan and Europe, while a US launch for the biosimilar rival is planned for early 2025.Johnson & Johnson is bracing for the first biosimilars of its autoimmune blockbuster to come on the scene this year with Alvotech's contender AVT04 expected to enter the market in Canada, Japan and Europe, while a US launch for the rival is planned for early 2025.