EPO receptor

Hitting targets embedded within the cell membrane has long been difficult for drug developers due to the membrane's challenging biochemical properties. Now, chemists have demonstrated new custom-designed proteins that can efficiently reach these 'intramembrane' targets. Hitting targets embedded within the cell membrane has long been difficult for drug developers due to the membrane's challenging biochemical properties. Now, Scripps Research chemists have demonstrated new custom-designed proteins that can efficiently reach these "intramembrane" targets. In their study, published March 13, 2024, in Nature Chemical Biology, the researchers used a unique computer-based approach to design novel proteins targeting the membrane-spanning region of the erythropoietin (EPO) receptor, which controls red blood cell production and can go awry in cancers. In addition to these new EPO-targeting molecules, the study yielded a general computational process, or "workflow," for streamlining the flexible custom design of proteins aimed at intramembrane targets. The researchers are now using their approach to develop potential new intramembrane-targeting treatments across a wide range of diseases. "This work opens up many new possibilities for the modulation of targets within the cell membrane, including for therapeutic applications and understanding signaling mechanisms across cell biology," says study co-corresponding author Marco Mravic, PhD, an assistant professor in the Department of Integrative Structural and Computational Biology at Scripps Research. The study's other co-corresponding authors were Daniel DiMaio, MD, PhD, of the Yale School of Medicine; and William DeGrado, PhD, of the University of California, San Francisco School of Pharmacy, where Mravic was previously a PhD student. "A major goal of synthetic biology is to design proteins with biological activity -- here, we report the design and testing of a small protein that specifically perturbs the activity of a much larger protein receptor involved in blood cell growth and differentiation," says DiMaio, who is a professor of Genetics and of Molecular Biophysics and Biochemistry, and deputy director of Yale Cancer Center. "We accomplished this by targeting the segment of the receptor that crosses the cell membrane. Because many cell proteins contain structurally conserved membrane-spanning segments, this general approach may be applicable to many other protein targets and provides a new tool to modulate the behavior of cells." Hitting intramembrane targets has long been an important goal in biomedicine since many proteins in cells -- especially receptor proteins -- have functionally important domains inside the membrane. Such proteins have prominent roles in almost every area of health and disease. Yet intramembrane targets are not ordinary targets. Cell membranes generally are made of two layers of tightly spaced, fat-related "lipid" molecules, which are water-repellent and have other unique and complex properties. This makes the intramembrane space a much harder target for drug designers, compared to the watery zones of cell surfaces or interiors. "There have been very few successful examples of drugs that target this space inside the membrane," Mravic says. Those few successes, which include treatments for low-blood-platelet disorders and cystic fibrosis, have come from blind screenings of large compound libraries or from close mimicry of proteins known to interact with partner proteins within the cell membrane. By contrast, Mravic and colleagues set out to design completely novel proteins -- small ones called peptides -- to hit intramembrane protein targets in new and diverse ways. To do that, they had to extend the frontier of computational methods, combining "data mining" of known protein-to-protein interactions in membranes with traditional physics-based predictions of protein interactions. Ultimately, Mravic and his colleagues designed the first proteins that bind the EPO receptor's membrane-spanning portion in a new way -- not seen in nature. The team showed that these proteins very specifically and potently block the receptor's function, in contrast to prior approaches. The results may be of most immediate interest to researchers seeking new ways to inhibit the EPO receptor, which is often abnormally activated by tumor cells to maintain their growth and survival. But for Mravic and his colleagues, the study above all represents a proof of principle of a new and more flexible approach to intramembrane targeting. "We intend to use this approach to target membrane proteins across multiple biological processes and disease areas, including cancers, immune disorders, and pain," Mravic says. He also expects the computational workflow he designed for the project to be a general accelerator of membrane-targeting drug design. "Before, the process basically involved two people in a dark room looking at a computer screen and saying, 'Yeah, I think this looks better than that,'" Mravic says. "Now, we've automated a lot of that molecule design process and decision making in the computer. Being more modular, flexible and streamlined allows the method to be more accessible for a broader range of scientists."

CAMBRIDGE, Mass., April 28, 2021 /PRNewswire/ -- Akebia Therapeutics, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced that the New England Journal of Medicine (NEJM) has published the results of the global Phase 3 clinical program of vadadustat for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis (INNO2VATE) and adult patients not on dialysis (PRO2TECT) in two separate manuscripts. Vadadustat, an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), is Akebia's lead product candidate. In late March 2021, the Company submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for vadadustat for the treatment of anemia due to CKD in both adult patients on dialysis and adult patients not on dialysis. "Having recently submitted our NDA for vadadustat, we are proud to have the results of our global Phase 3 clinical program published in the prestigious New England Journal of Medicine for review by the broader medical community," said Steven K. Burke, M.D., Chief Medical Officer of Akebia Therapeutics. "The publications, authored by members of the independent Executive Steering Committee in collaboration with trial investigators and Akebia, are a testament to the work of these team members who designed this program after extensive dialogue with the FDA and European regulators. We extend our deepest appreciation to everyone involved in this program, including the physicians, investigators, site coordinators, and, most importantly, the nearly 7,500 patients who participated." "The kidney community has been eagerly awaiting peer-reviewed publication of comprehensive and straight-forward analyses of cardiovascular safety and hematological efficacy results of a Phase 3 program evaluating the treatment of anemia associated with CKD with a novel HIF-PHI," said Glenn Chertow, M.D., M.P.H., Professor of Medicine at Stanford University School of Medicine, lead author of one of the manuscripts and Co-Chair of the independent Executive Steering Committee for the vadadustat global Phase 3 program. "We are honored to have vadadustat's global Phase 3 clinical program published in the New England Journal of Medicine. These publications reflect the clinical relevance, scientific rigor and transparency of the vadadustat development program." Kai-Uwe Eckardt, M.D., Professor of Medicine and Head of the Department of Nephrology and Medical Intensive Care at the Charité in Berlin, Germany, and Co-Chair of the independent Executive Steering Committee for the vadadustat global Phase 3 program, is the lead author of the INNO2VATE manuscript titled, "Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis." The manuscript states, "Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and maintenance of hemoglobin concentrations." Dr. Chertow is the lead author of the PRO2TECT manuscript titled, "Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD," which states, "Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety. The New England Journal of Medicine is recognized as the world's leading medical journal and website. Published continuously for over 200 years, NEJM delivers high-quality, peer-reviewed research and interactive clinical content to physicians, educators, researchers, and the global medical community. About Akebia Therapeutics Akebia Therapeutics, Inc. is a fully integrated biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease. The Company was founded in 2007 and is headquartered in Cambridge, Massachusetts. For more information, please visit our website at , which does not form a part of this release. About Vadadustat Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor designed to mimic the physiologic effect of altitude on oxygen availability. At higher altitudes, the body responds to lower oxygen availability with stabilization of hypoxia-inducible factor, which can lead to increased red blood cell production and improved oxygen delivery to tissues. Vadadustat recently completed its global Phase 3 clinical development program for the treatment of anemia due to CKD. Vadadustat is not approved by the U.S. Food and Drug Administration (FDA) or any regulatory authority with the exception of Japan's Ministry of Health, Labour and Welfare (MHLW). In Japan, vadadustat is approved and marketed under the tradename Vafseo™, as a treatment for anemia due to CKD in both dialysis-dependent and non-dialysis dependent adult patients. About Anemia due to Chronic Kidney Disease (CKD) Anemia is a condition in which a person lacks enough healthy red blood cells to carry adequate oxygen to the body's tissues. It commonly occurs in people with CKD because their kidneys do not produce enough erythropoietin (EPO), a hormone that helps regulate production of red blood cells. Anemia due to CKD can have a profound impact on a person's quality of life as it can cause fatigue, dizziness, shortness of breath and cognitive dysfunction. Left untreated, anemia leads to deterioration in health and is associated with increased morbidity and mortality in people with CKD. Investor Contact Kristen K. Sheppard, Esq. Ir@akebia.com Company Codes: NASDAQ-NMS:AKBA

CINCINNATI--(BUSINESS WIRE)-- Akebia Therapeutics, Inc., a pharmaceutical discovery and development company focused on anemia and vascular disorders, today announced that it has successfully completed a randomized, double-blinded, placebo-controlled Phase 2 dose-ranging study of AKB-6548 in patients with stage 3 and 4 chronic kidney disease (CKD). AKB-6548 is an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor designed to increase the natural production of erythropoietin (EPO) and cause a controlled, gradual rise in hemoglobin in patients with anemia. The study met its primary endpoint of a dose-responsive increase in hemoglobin from baseline over the 42 days of the study (p "Safe, effective, oral therapies for patients that suffer from anemia associated with chronic kidney disease represents a major unmet need. The results from this Phase 2 study demonstrate AKB-6548’s ability to safely and effectively increase hemoglobin levels in a controlled manner, which recapitulates results seen in our prior pilot dose escalation study. We have also identified an optimal dose to take into a larger Phase 2b study, preparations for which are underway,” said Dr. Robert Shalwitz, SVP and Chief Medical Officer of Akebia. “We believe AKB-6548 could offer patients a treatment option that mimics the body’s natural response to hypoxia, including erythropoietin production in a highly controllable manner and a well-coordinated iron response. These are key attributes that are unavailable with today’s standard of care.” The Phase 2 randomized, double-blind, placebo-controlled dose range finding study was designed to evaluate the safety, tolerability and pharmacokinetics of AKB-6548 in patients with stage 3 and 4 CKD. Subjects were randomized into 5 different dosing groups, and AKB-6548 was administered orally on an outpatient basis once daily for 42 days. The study enrolled 93 subjects at multiple sites in the United States. The results show a highly significant, dose-responsive increase in hemoglobin and overall red blood cell production. Specifically: - On average, patients that received the placebo experienced a small decline, 0.1 g/dL, in hemoglobin by week 6 of treatment - Patients that received AKB-6548 experienced an increase from baseline to day 42 in hemoglobin, ranging from 0.7 to 1.4 g/dL In addition, there was a parallel increase in iron mobilization, with significant dose-related reductions in ferritin and hepcidin, as well as an increase in total iron binding capacity (predominantly transferrin). AKB-6548 was generally well tolerated, with no dose-related changes in adverse events, liver function or renal function as compared to placebo. Of particular note, there were no dose-related changes in vascular endothelial growth factor (VEGF) levels, a HIF responsive gene, at the end of 6 weeks of dosing. Together, these data strongly suggest that AKB-6548 could provide a highly efficacious and well-tolerated oral alternative to currently approved anemia treatments. About HIF-PH Hypoxia-inducible factors (HIFs) are transcription factors that regulate the body’s response to decreases in oxygen, or hypoxia, in the cellular environment. HIF-PH’s are the hypoxia-inducible factor prolyl hydroxylase enzymes that normally regulate the levels of HIF in bodily tissues. By inhibiting HIF-PH enzymes, HIFs can be stabilized or up-regulated, allowing the body to better respond to reduced oxygen, injury and infection. The ability to stabilize HIFs may lead to treatments for many conditions including anemia, fractures, wounds and other conditions where the HIF mechanism is not functioning optimally. About AKB-6548 AKB-6548 is an orally bioavailable HIF-PH inhibitor designed to increase natural production of EPO, a glycoprotein hormone that controls red blood cell production, and causes a controlled rise in hemoglobin levels. Inadequate EPO production by the kidney is a common cause of anemia. Akebia will initially target pre-dialysis patients with chronic kidney disease, a large patient population that is currently undertreated for anemia. AKB-6548 potentially promises to be a safe, cost effective, orally dosed drug that delivers the efficacy of injectable EPO stimulating agents. The market for chronic anemia drugs, which generated over $9 billion in worldwide sales in 2010, is dominated by injectable forms of recombinant EPO. There are currently no approved orally dosed small molecule drugs for the treatment of chronic anemia. About Akebia Therapeutics Akebia Therapeutics is a discovery and development company focused on anemia and vascular disorders. Akebia’s lead program, AKB-6548, an orally bioavailable HIF-prolyl hydroxylase (HIF-PH) inhibitor for patients with anemia, is in Phase 2 clinical trials. AKB-6548 potentially promises to be a safer, less expensive, orally dosed pharmaceutical to stimulate endogenous EPO production. Website: Contact: Akebia Therapeutics, Inc. Bill Daly, 513-985-1928 SVP of Business Development wdaly@akebia.com or MacDougall Biomedical Communications Michelle Avery, 781-235-3060 mavery@macbiocom.com