NOX x NOX4

In recent years, the treatment of primary biliary cholangitis (PBC) has seen remarkable progress, with the continuous introduction of new drugs bringing good news to PBC patients worldwide. According to reports from authoritative institutions, the global PBC treatment market is thriving and is expected to experience explosive growth in the coming years. However, despite the fact that three PBC treatment drugs have already been approved, the market still has a significant unmet need, and the industry's expectations for new therapeutic drugs are becoming increasingly urgent.   First, let's understand the three PBC treatment drugs currently on the market. Ursodeoxycholic acid (UDCA) is the recognized first-line treatment drug and has been widely used in clinical practice for many years. However, it is regrettable that about 40% of patients do not respond well to this treatment, leaving them in urgent need of more effective treatment options. Against this backdrop, Ocaliva and Elafibranor emerged, being approved as second-line treatment options for PBC in 2016 and 2021, respectively. The introduction of these two drugs has undoubtedly brought new hope to PBC patients.   However, market competition has not stopped. Industry insiders generally believe that Seladelpar has the potential to become the fourth novel PBC drug approved globally. Seladelpar is an oral, potent, and selective PPARδ agonist, and its unique mechanism of action gives it significant advantages in regulating bile acid synthesis, inflammation, fibrosis, and lipid metabolism. Based on preclinical and clinical data, Seladelpar has demonstrated good efficacy and safety in the treatment of PBC. Currently, the drug is undergoing priority review in the United States and is expected to receive approval for marketing in August 2024. At that time, it is expected to bring a safer and more effective treatment option to PBC patients worldwide.   In addition to Seladelpar, the industry is also paying attention to other PBC drug candidates in development. For example, Setanaxib is a new drug that targets NOX4 and NOX1, and it has unique potential in the field of PBC treatment. Furthermore, domestic pharmaceutical companies are also actively engaged in the development of PBC drug research, such as the dual-target peptide drug TB001 developed by a well-known pharmaceutical company. The successive launch of these candidate drugs will bring new development opportunities to the PBC treatment market.   It is worth mentioning that with the advancement of technology and the depth of research, the PBC treatment field is facing unprecedented development opportunities. More and more new drugs and new technologies are emerging, bringing more treatment options to PBC patients. At the same time, as global medical standards improve and medical resources are optimized, the treatment experience of PBC patients will also be significantly improved. We have reason to believe that in the near future, PBC patients will be able to enjoy safer, more effective, and more convenient treatment services.

Calliditas Therapeutics’ stock rose initially before falling back toward its opening price. Calliditas Therapeutics had a typical to-do list for its midphase head and neck cancer study. Step one, show the molecule shrinks tumors. Step two, look for early evidence of effect on survival. The Swedish biotech fell at the first obstacle on that timeworn path, seeing no change in tumor size, but bounced back up with early evidence of an effect on progression-free (PFS) and overall survival (OS). The double-blind, randomized phase 2 trial compared the effect of adding setanaxib or placebo to Merck & Co.’s PD-1 checkpoint inhibitor Keytruda. Setanaxib is designed to inhibit NOX1 and NOX4, enzymes expressed by cancer-associated fibroblasts (CAFs) in solid tumors. Researchers have linked high levels of CAFs to poor survival and resistance to immunotherapy. Calliditas identified setanaxib as a way to improve the penetration of immune cells into tumors and make checkpoint inhibitors effective in more patients. The biotech put that idea to the test in a phase 2 trial of 55 people with recurrent or metastatic head and neck cancer. Setanaxib was no better than placebo on the primary endpoint of best percentage change from baseline in tumor size. Calliditas is yet to share the response rates, a typical midphase endpoint, but did disclose that 70% of patients on setanaxib had at least stable disease, compared to 52% of people on placebo.  The biotech focused on the PFS and OS results. Median PFS was five months in the setanaxib arm and 2.9 months in the placebo cohort. Similarly, the OS rate at nine months was 88% on setanaxib and 58% on the control. The biotech reported a similar divergence in OS rates after six months.  Calliditas brushed over the failure to hit the primary endpoint—relegating the finding to a single line almost 300 words into its press release—but Chief Medical Officer Richard Philipson was clear about the importance of showing a reduction in tumor size on an earnings call in February. “We think this is an important endpoint in a study at this stage of development. It’s a little bit more sensitive than just looking at response rates,” Philipson said. “Clearly, what we want to see is a significant reduction in tumor size in patients who are receiving setanaxib on top of pembrolizumab versus patients who are receiving placebo on top of pembrolizumab.” Calliditas’ statement lacks an explanation for why patients may live longer on setanaxib if it has no effect on tumor size. The biotech plans to host an R&D day later this month to share more information on the phase 2 trial and other data supporting the mechanism of action of setanaxib.  Investors appeared unsure what to make of the data, with Calliditas’ stock initially rising before falling back toward its opening price.

Why some people remain relatively healthy with fatty liver disease and some go onto potentially life-threatening illness has been a mystery. Until now. The global rise in obesity and diabetes is leading to an epidemic in fatty liver disease affecting 20-30 per cent of the world's population. Almost a third of people with fatty liver disease go on to develop an advanced form of the disease, known as non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis and end-stage liver disease, or even liver cancer, and is a major risk factor for cardiovascular disease. Why some people remain relatively healthy with fatty liver disease and some go onto potentially life-threatening illness has been a mystery. Until now. A study published today in The Journal of Clinical Investigation led by Professor Tony Tiganis from Monash University's Biomedicine Discovery Institute, has shown that the levels of the NOX4 protein change as the disease progresses -- rising in the early stages of the disease to protect the liver, but declining as the liver disease gets worse. The researchers found that removing NOX4 in obese mice led to NASH and liver damage. And when NOX4 levels were artificially raised in these mice they were protected from NASH and liver damage. Importantly, the discovery provides evidence for a therapeutic avenue for a disease whose prevalence is predicted to balloon by 63 per cent from 2015 to 2030. According to Professor Tiganis, the precise mechanisms that govern the transition to NASH and liver damage have remained unclear. "It has been perplexing why the majority of patients with fatty liver disease don't progress to more severe disease," he said. The researchers have shown that this is because NOX4 is induced when the liver first starts to accumulate fat and activates a complex adaptive program that protects the liver. It is only when NOX4 levels decline and this adaptive program is abrogated that obese patients with fatty liver progress to NASH and liver damage. Importantly, previous studies by Professor Tiganis and others have shown that the raising of NOX4 levels in skeletal muscle or in the heart after exercise protects against damage and promote muscle and cardiac function and prevent the metabolic decline otherwise associated with ageing. "Compounds that bolster the activity of NOX4, or the adaptive program that NOX4 instigates, may be highly beneficial, countering not only the development of NASH, but also improving skeletal and cardiac function, as well as metabolic health," Professor Tiganis said. Such compounds are found naturally in cruciferous vegetables, such as broccoli or cauliflower.