NRG4

None The confetti is still flying from Eli Lilly’s party celebrating the approval of Alzheimer’s disease therapy donanemab, but the company is yet again facing the harsh reality of the neurodegenerative disease with the failure of an early tau-targeting med.Lilly Chief Scientific Officer and President, Lilly Research Laboratories Daniel Skovronsky, M.D., Ph.D., said the O-GlcNAcase Inhibitor called LY3372689 failed on the primary endpoint of a phase 2 clinical trial recently. The therapy, which targets the OGA enzyme, did not spur a change in baseline to endpoint time in a rating scale of Alzheimer’s severity in either dose tested.“While this negative outcome was disappointing, we remain committed to tap as a high conviction target in Alzheimer's disease and plan to continue studying tau biology,” Skovronsky said, speaking on a second-quarter earnings call Thursday. The executive said the company is currently reviewing the data for presentation at an upcoming medical conference.LY3372689 was a key part of Lilly’s next wave of Alzheimer’s efforts. After getting donanemab approved in July, to be marketed as Kisunla, the company was hoping that tau would be the next front in the fight against the memory-robbing disease. Behind Kisunla, Lilly has remternetug in phase 3 development, which targets amyloid plaques in the brain. Positive allosteric modulator mevidalen is in phase 2 testing. The company also has two undisclosed neurodegeneration medicines in phase 1.Lilly also trimmed around the edges of other programs after getting some early data on a few candidates.They include LOXO-783, a highly mutant-selective, brain-penetrant, allosteric small molecule PI3Kα H1047R inhibitor that was acquired as part of the acquisition of Loxo Oncology. The drug was being investigated in a phase 1 study in patients with PIK3CA H1047R-mutant advanced breast cancer and other solid tumors.Lilly had taken LOXO-783 into the clinic on the basis of preclinical data showing activity without on-target wild-type PI3Kα mediated toxicity.“We evaluated the ongoing clinical data for the program and compared the molecule to next-generation candidates that we have progressed from our discovery efforts,” Skovronsky said on the call. “We believe our next molecules have greater potential benefits to patients.”Also on the discard pile is an unnamed NRG4 agonist. Neuregulin 4 acts locally on brown and white adipose tissue and works to protect against obesity-related inflammatory and hypoxic events. The Big Pharma had halted work on the asset as “the profile is insufficient for further clinical development,” Skovronsky explained. A GITR antagonist has also been removed from the phase 1 immunology pipeline “due to insufficient efficacy,” Skovronsky said. At the time of publication, Lilly had not confirmed to Fierce whether this was LY3461767, a GITR antagonist that was being evaluated in a phase 1 trial of the drug in patients with chronic heart failure with reduced ejection fraction.Acadamic researchers have named glucocorticoid-induced tumor necrosis factor receptor (GITR), a co-stimulatory immune checkpoint protein, as playing a pivotal in cardiovascular disease. It’s also been suggested as a potential target to enhance immunotherapy, in particular immune checkpoint inhibitors.

In this week’s research news, a fat hormone that slows liver tumor growth, a genetic map to track tumorigenesis, study that shows we inherit more than expected epigenetic information from our mothers, Alzheimer linked APOE gene protects against glaucoma. Fat Hormone Slows Liver Tumor Growth Scientists at the University of Michigan Life Sciences Institute found that a hormone secreted by fat cells could slow the growth of liver tumors in mice. The research team previously used single-cell RNA sequencing to construct a liver cell atlas and map intercellular signaling in healthy and NASH mouse livers. NASH stands for nonalcoholic steatohepatitis, a type of fatty liver disease. Working to identify specific molecular changes in the NASH state of the liver cell types, they found changes in two types of immune cells that seemed to lead to the development of hepatocellular carcinoma (HCC), the most common type of liver cancer. This seemed to occur in T cells and macrophages, showing signs of acquired molecular features associated with cancer. They also identified a hormone, NRG4, secreted by fat cells that appears to protect mouse livers against NASH and HCC. By boosting NRG4 levels in the mice, they suppressed NASH liver cancer progression. Do We Inherit More Epigenetic Information than We Think? Researchers from the Walter and Eliza Hall Institute in Melbourne, Australia, found that more epigenetic information is carried from mother to offspring than was previously understood. They published their research in Nature Communications. Epigenetics is how expression of genes are switched on and off. One way this occurs, is through addition of methyl groups (a carbon atom with three hydrogen atoms attached) to the genes. Under certain situations and environments, these genes are switched on or off. These changes could be diet, trauma, whether the genes or gene alterations are inherited from the mother or the father, or other factors. But the genes were generally believed to be reset when they are passed on to offspring. Part of the team's research found that a specific protein in the mother's egg can affect the genes behind the skeletal patterning of offspring. SMCHD1 is an epigenetic regulator discovered in 2008. Hox genes, which are essential for normal skeletal development control the identity of each vertebra during embryonic development. SMCHD1 prevents the Hox genes from activating too soon. They found that the amount of SMCHD1 in the mother's egg affects Hox gene activity and influences the patterning of the embryos. Without maternal SMCHD1 in the egg, offspring were born with altered skeletons. "It took us a while to process because our discovery was unexpected," Marnie Blewitt, Ph.D., chief investigator and Joint Head of the Epigenetics and Development Division at WEHI, said. "Knowing that epigenetic information from the mother can have effects with life-long consequences for body patterning is exciting, as it suggests this is happening far more than we ever thought. It could open a Pandora's box as to what other epigenetic information is being inherited." A Genetic Map of Tumors Show How They Grow Researchers at the University of Oxford used a new technique called spatial transcriptomics to map out the genetic changes of a whole prostate, including both healthy and cancerous cells. The technique grouped cells according to similar genetic identities. Surprisingly, they found that areas of what were thought to be healthy tissue already had genetic characteristics of cancer. What was originally thought to be healthy tissue showed mutations specifically linked to cancer. Researchers also analyzed more than 150,000 regions including prostate, breast cancer, skin, lymph node and brain tissue. They then developed an algorithm to track groups of cells with similar genetic changes in their specific location. Alzheimer's Linked APOE Gene and Glaucoma Protection The most prominent gene associated with the risk of Alzheimer's disease is the APOE4 gene variant. However, this same gene variant decreases the risk of glaucoma, an eye disease. Researchers at Mass Eye and Ear and Brigham and Women's Hospital and Mass General Brigham also prevented the destruction of neurons in the eyes of mice with glaucoma by using a drug that targeted the APOE signaling pathway. Specifically, APOE4 blocks a disease cascade that causes the destruction of retinal ganglion cells in glaucoma. Separately, in a mouse model, they used a drug called Galectin-3, which is regulated by the APOE gene, to prevent the death of retinal ganglion cells, which cause loss of vision in glaucoma. "Our research provides greater understanding of the genetic pathway that leads to irreversible blindness in glaucoma, and importantly, points to a possible treatment to address the root cause of the vision loss," Milica Margeta, M.D., Ph.D., lead author and a glaucoma specialist and scientist at Mass Eye and Ear, and assistant professor of ophthalmology at Harvard Medical School, said. "This study shows that the APOE-mediated disease cascade is clearly harmful in glaucoma, and that when you interfere with it genetically or pharmacologically, you can actually stop the disease

In a study that could have important therapeutic implications, researchers found promising connections between the Neuregulin 4 (NRG4) endocrine factor protein and the suppression of specific liver diseases, including non-alcoholic steatohepatitis (NASH). The study, published Monday in the journal Cell Metabolism and spearheaded by Dr. Peng Zhang at the University of Michigan Medical Center demonstrated that the NRG4 endocrine factor protein essentially functions as a tumor suppressor for NASH-associated liver cancer. The researchers suggest that targeting the NRG4 hormonal checkpoint could "pave the way" for therapeutic intervention. Non-alcoholic steatohepatitis (NASH) is a fatty liver disease marked by inflammation and damage to the liver in addition to a buildup of fat. Inflammation in the liver can lead to fibrosis and cirrhosis, leaving the organ permanently damaged and increasing the risk of developing liver cancer. While it is clear that the general cause is a buildup of fat in the liver, it is unclear as to what may cause that buildup.  As far as NASH goes, the researchers found that NRG4 acted as a checkpoint of sorts and restrained the production of a tumor-prone environment in the liver. They also found that NRG4 deficiency worsened the production of a tumor-prone liver environment.  NASH is notoriously difficult to treat, and because so many people are affected by it, there are many companies aiming to be the victor in this race. As of now, there are no FDA-approved treatments, but some market analysts believe the NASH treatment market could be worth up to $35 billion. Pfizer announced in May that it received the FDA’s fast track destination for its drugs ervogastat and clesacostat, both potential treatments for NASH. "Receiving Fast Track designation from the FDA reinforces Pfizer's belief in ervogastat/clesacostat as a potential treatment for NASH, a serious, progressive liver disease with no currently approved therapies," James Rusnak, M.D., Ph.D., SVP and chief development officer of internal medicine at Pfizer said in a press release. These two drugs target diacylglycerol O-acyltransferase 2 (DGAT2) and acetyl-CoA carboxylase (ACC), which are two key enzymes in the regulation of fat metabolism. They are based on previous research showing that inhibiting these enzymes may lower liver fat in patients with non-alcoholic fatty liver diseases.  "We are proud to be advancing this investigational combination as part of our goal to develop innovative medicines to address some of the world's most widespread health challenges that affect millions of people - including diseases like NASH," Rusnak added. There has also recently been research into the CIDEB gene its impacts on liver disease. Regeneron found that people whose genetic material included a loss-of-function mutation in a copy of the CIDEB gene were 53% less likely to develop nonalcoholic liver diseases like NASH. The protein also seemed to offer resilience against type 2 diabetes and obesity.  “The unprecedented protective effect that these CIDEB genetic variants have against liver disease provides us with one of our most exciting targets and potential therapeutic approaches for a notoriously hard-to-treat disease where there are currently no approved treatments, "Aris Baras, M.D., SVP and head of the Regeneron Genetics Center said in a statement. Pharma giants like Pfizer and Regeneron get a lot of attention in the space, but other companies, like Intercept Pharmaceuticals and GENFIT, also have drugs in Phase III trials targeting NASH. As research advances and more information about the disease becomes available, more companies will likely begin vying for their spots in the potentially lucrative market.