Kidney Cortex Necrosis

CAMBRIDGE, Mass., Dec. 20, 2022 /PRNewswire/ -- Kira Pharmaceuticals, a global biotechnology company pioneering transformational complement therapies to treat immune-mediated diseases, announced today that the Chinese National Medical Products Administration (NMPA) and the Australian Therapeutic Goods Administration (TGA) have approved initiation of Phase 2 studies for evaluation of KP104, a first-in-class bifunctional biologic that selectively targets the alternative and terminal complement pathways, in a renal basket study including IgA nephropathy (IgAN) and complement 3 glomerulopathy (C3G). "These clearances add to the multiple INDs Kira has secured this year for KP104 and mark our first in IgAN and C3G, serious immune-mediated conditions that cause kidney damage and often result in kidney failure," said Frederick Beddingfield, M.D., Ph.D., CEO of Kira. "We believe that KP104's ability to simultaneously and synergistically block two key complement targets makes it a unique therapeutic option with the potential to make a profound impact on the lives of patients living with these kidney diseases around the world." IgAN is an autoimmune disease that damages the kidneys, impacting organ function and often resulting in end-stage kidney disease. Though the exact pathogenesis of IgAN remains unknown, immune complex deposition in the kidneys is characteristic of the disease, causing inflammation and glomerular damage. Recent studies have implicated complement activation across multiple complement pathways as a major contributor to kidney injury and disease progression in IgAN. Drugs that selectively inhibit either the alternative or terminal pathway have shown partial efficacy in recent human studies. KP104 is a potent inhibitor of both the alternative and terminal complement pathways. Thus KP104 may have the unique potential to address IgAN more effectively, where multiple pathways are involved. In C3G, a hyperactivated alternative complement pathway causes excessive cleavage and activation of complement protein 3 (C3) and complement protein 5 (C5), resulting in harmful C3 fragments getting lodged in the kidney and C5 split products contributing to further glomerular inflammation and damage. There are currently no approved therapies for the condition, making KP104 a novel therapeutic option with the potential for transformative patient impact. The Phase 2 studies will evaluate the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KP104 in participants with IgAN and C3G in China and Australia. Phase 1 data from the SYNERGY-1 first-in-human (FIH) study of KP104 demonstrated clinical proof-of-mechanism (PoM) for the biologic, which received Orphan Drug Designation for treatment of paroxysmal nocturnal hemoglobinuria (PNH) from the US Food and Drug Administration (FDA) earlier this year. KP104 is currently undergoing Phase 2 evaluation in PNH and will additionally be evaluated in other hematology and nephrology indications in upcoming clinical trials. About IgA Nephropathy IgA Nephropathy (IgAN) is an autoimmune disease that damages the kidneys, impacting organ function and often resulting in end-stage kidney disease. IgAN is the most common form of glomerulonephritis, with a global population incidence of roughly 2.5 per 100,000 per year, though the exact pathogenesis of the disease remains unknown. In IgAN, the body produces abnormal immunoglobulin A (IgA) antibodies that stimulate an immune response and result in formation of immune complexes that become trapped in the kidney. The immune complexes in the kidney cause inflammation and tissue damage, potentially leading to renal failure. There remains significant unmet need for therapeutics that effectively address IgAN, with current treatment approaches for serious cases largely reliant on corticosteroids to manage inflammation. Recent studies have implicated aberrant complement activity as a major contributor to glomerular inflammation and disease progression of IgAN. KP104 is a potent inhibitor of the alternative and terminal complement pathways that offers unique potential to address IgAN through selective modulation of complement activity. About Complement 3 Glomerulopathy Complement 3 Glomerulopathy (C3G) encompasses dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), two conditions that result in inflammation and damage of the glomeruli in the kidney. In C3G, abnormal complement system activation results in breakdown of C3, a complement protein. The products of this breakdown become lodged in the kidney, triggering inflammation and immune activity that injure the glomeruli. C3 breakdown also leads to C5 and terminal complement activation, causing further glomerular inflammation and damage. C3G has a global prevalence of 2-3 people out of every million, and roughly half of those living with C3G develop end-stage renal disease within 10 years of diagnosis. There are currently no approved therapies for the condition, making KP104 a novel therapeutic option with potential for transformative patient impact. About KP104 KP104 is a first-in-class bifunctional biologic designed to simultaneously and selectively block both the alternative and terminal complement pathways, providing a powerful and synergistic method of targeting validated drivers of complement-mediated disease. This dual-target mechanism of action uniquely positions KP104 to address complement-mediated diseases and potentially provide greater benefits than single-target complement agents. Engineered to have an extended half-life and potency, KP104 has a formulation suitable for both intravenous and subcutaneous administrations. KP104 is entering Phase 2 POC trials across multiple renal disease and hematologic indications and has been granted Orphan Drug Designation by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Phase 2 trials will be conducted globally, including in the U.S., China, and Australia. KP104 is an investigational agent not yet approved for any indication by any health authority. About Kira Pharmaceuticals Kira Pharmaceuticals is a clinical-stage biotechnology company pioneering complement-targeted therapies to treat immune-mediated diseases. Enabled by its LOGIC platform, the company has developed a robust pipeline of novel assets against validated complement targets. Headquartered in Cambridge, Massachusetts and with facilities in China and Australia, Kira Pharmaceuticals has established a global team committed to advancing life-changing therapies to patients around the world. More information on Kira can be found at and on LinkedIn. SOURCE Kira Pharmaceuticals

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. The Difference in Immune Responses in Asymptomatic Versus Severe COVID-19 Patients One of the mysteries of COVID-19 is why people have such different responses to the disease, with some being asymptomatic, some with mild syndromes, and others who get severe disease. Researchers with the Wellcome Trust Sanger Institute and several other universities culled data from the Human Cell Atlas to analyze cells in COVID-19 patients. The Human Cell Atlas initiative is an attempt to map every cell type in the human body. They analyzed blood from 130 people with COVID-19. The researchers also included investigators from Newcastle University, University College London, University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI) and collaborators within the Human Cell Atlas initiative. They performed single-cell sequencing from approximately 800,000 individual immune cells, as well as detailed analysis of cell surface proteins and antigen receptors on immune cells in the blood. They found differences in several types of immune cells involved in the response to COVID-19 infection. They published their research in the journal Nature Medicine. In people who were asymptomatic, they found increased levels of B-cells that produced antibodies found in mucus membranes, such as the nose. They are believed to be the first line of defense against COVID-19. But they found that these B-cells were missing in patients with serious symptoms. They also found that people with mild to moderate symptoms had high levels of B-cells and helper T-cells, which fight infection. People with serious symptoms had also lost many of these immune cells. This suggests that in people with severe COVID-19, part of the immune system had failed. Also, they found that people with severe disease that led to hospitalization had an uncontrolled increase in monocytes and killer T-cells. High levels of these immune cells can lead to lung inflammation. Patients with severe COVID-19 also had increased levels of platelet-producing cells, which increase blood clotting. “This is one of the most detailed studies of immune responses in COVID-19 to date, and it begins to help us understand why some people get really sick while others fight off the virus without even knowing they have it,” said Menna Clatworthy, senior author and professor of Translational Immunology at the University of Cambridge and Wellcome Sanger Institute Associate Faculty. “This new knowledge will help identify specific targets for patients that get sick with COVID-19.” Diabetic Drug Metformin Seems to Slow Chronic Kidney Disease Metformin is a common drug to treat type 2 diabetes and pre-diabetic syndromes. A recent study out of Kumamoto University shows that metformin significantly extends the survival of mice in a model of non-diabetic chronic kidney disease (ND-CKD). The drug appears to do this by decreasing conditions like reduced kidney function, glomerular damage, inflammation and fibrosis. They note that metformin’s mechanism of action is different from existing drugs that only treat symptoms, such as the blood pressure drug losartan. Metformin is used for type 2 diabetes because it improves insulin sensitivity. It is also both inexpensive and safe. It has been shown to be protective against other disease involving inflammation and fibrosis, including improving the renal pathology of diabetic kidney disease. New Type of Cell Linked to ALS The causes of amyotrophic lateral sclerosis (ALS) are not well understood. Researchers at Karolinska Institute and KTH Royal Institute of Technology have identified a new type of cell in the brain blood vessels that might help better understand the disease. ALS is a neurodegenerative disease of the motor neurons that eventually results in muscular atrophy, paralysis and death. About 5% to 10% have inherited disease, which is reasonably well understood. Researchers at KI, KTH and SciLifeLab, London’s Imperial College and Umea University have found that perivascular fibroblast cells may be linked to the disease. In mice with ALS, genes for perivascular fibroblasts were already active in an early asymptomatic stage of the disease and months before damage to nerve cells were observed. Their analysis of the blood of 574 patients with ALS and 504 healthy controls suggested a correlation between increased levels of the protein marker SPP1 for perivascular fibroblasts and aggressive disease progression. Some Alzheimer’s Plaques May Be Protective One of the hallmarks of Alzheimer’s disease is the buildup of amyloid-beta plaques in the brain. Numerous clinical trials that successfully cleared or prevented the continued buildup of amyloid-beta, however, failed to improve cognition and memory, which has cast a lot of doubt on the amyloid theory of the disease. Many researchers believe amyloid-beta is only part of the issue, perhaps triggering inflammation that causes damage to the brain. New research out of the Salk Institute has added a new twist, suggesting that some of the plaques may actually be protective. A type of immune cells in the brain, microglia, were long believed to inhibit the growth of plaques by “eating” them. Their research, however, demonstrated that microglia promote the formation of what are being dubbed dense-core plaques, which transports the “wispy” plaque away from neurons. They published their research in the journal Nature Immunology. “We show that dense-core plaques don’t form spontaneously,” said Greg Lemke, a professor in Salk’s Molecular Neurobiology Laboratory. “We believe they’re built by microglia as a defense mechanism, so they may be best left alone. There are various efforts to get the FDA to approve antibodies whose main clinical effect is reducing dense-core plaque formation, but we make the argument that breaking up the plaque may be doing more damage.” Although there are several forms of plaque, the two most common are “diffuse” and “dense-core.” Diffuse plaques are wispy, like clouds, and loosely organized. Dense-core, as the name suggests, have a dense center that is surrounded by a halo. Up to this point, researchers thought both types formed spontaneously from excessive production of amyloid precursor protein (APP). But the Salk research finds that the dense-core plaques are formed by microglia from diffuse amyloid-beta fibrils as part of their cellular cleanup duties. They found that after a microglial cell ate a diffuse plaque, it moved it to a highly acidic compartment and converted it into a highly compacted aggregate, that was then transported to a dense-core plaque. “Our research seems to show that when there are fewer dense-core plaques, there seem to be more detrimental effects,” said Youtong Huang, first author of the study. “With more-diffuse plaques, there’s an abundance of dystrophic neurites, a proxy for neuronal damage. I don’t think there’s a distinct clinical decision on which form of plaque is more or less detrimental, but through our research, we seem to find that dense-core plaques are a bit more benign.” If the research holds up, it suggests that although amyloid-beta is still a bad thing and behind much of the Alzheimer’s symptoms, dense-core plaques may not be as bad a thing. And if there are ways of boosting expression of TAM receptors on microglia that accelerate dense-core plaque formation, or therapies that only clear the wispy plaques, there may be a way to better treat or prevent the disease.