IGF-2

Potential to more than double the addressable patient population living with hypoglycemia resulting from insulin receptor over-activation (tumor hyperinsulinism)REDWOOD CITY, Calif., March 06, 2024 (GLOBE NEWSWIRE) -- Rezolute, Inc. (Nasdaq: RZLT) (“Rezolute” or the “Company”), a clinical-stage biopharmaceutical company committed to developing novel, transformative therapies for serious metabolic and rare diseases, today announced results from a preclinical pharmacology study that validate the potential for its lead clinical compound, RZ358, to treat individuals with non-islet cell tumors (NICTs) that have uncontrolled hypoglycemia. Tumor hyperinsulinism (HI) may be caused by a variety of different tumor types, resulting in islet cell tumor hypoglycemia (ICTH) and NICTH. The Company previously reported on the successful use of RZ358 under its Expanded Access Program (EAP) to treat patients with insulin-producing pancreatic islet cell tumors (ICTs), or insulinomas, causing severe and uncontrolled hypoglycemia. The therapeutic potential of RZ358 in this setting was anticipated given that ICTH is mediated by insulin and that RZ358 is known to work at the insulin receptor to decrease excess insulin binding and activity. However, it was unknown if RZ358 would have utility in NICTH where hyperinsulinism is mediated by hormones such as insulin-like growth factor-2 (IGF-2) or its variants, which likewise cause hypoglycemia by binding to and activating the insulin receptor. To test this, the Company recently completed in vitro pharmacology studies to evaluate the impact of clinically relevant concentrations of RZ358 on insulin receptor activation by IGF-2, compared to insulin. This was tested at the relative concentrations of each ligand that activate the insulin receptor and are physiologically relevant in tumor HI caused by ICTH and NICTH, respectively. These experiments successfully demonstrated the ability of RZ358 to similarly blunt both IGF-2 and insulin-mediated insulin-receptor signaling, at levels of these ligands that are disease-relevant in humans. “These data demonstrate proof of the ligand-agnostic mechanism of action of RZ358 and therefore validate its broad utility in treating hypoglycemia resulting from any form of hyperinsulinism, including expanded tumor indications,” said Dr. Brian Roberts, Chief Medical Officer of Rezolute. “Coupled with known outcomes from our clinical trials in congenital HI and the positive outcomes seen with ICTH in our expanded access program, we are excited by the potential for RZ358 to provide dramatic therapeutic benefit to cancer patients who often have limited treatment options for managing serious and uncontrolled hypoglycemia, which can accompany their cancer and disrupt treatment plans.” The Company recently reported on its successful interaction with the U.S. Food and Drug Administration (FDA) in January 2024 regarding the potential to initiate a single registrational study in patients with hypoglycemia due to tumor HI. The Company will continue to evaluate the feasibility of a development program in this indication, with the possibility of including both ICTH and NICTH patients. The inclusion of NICTH patients in a potential addressable market for RZ358 in tumor HI would more than double the population. The Company is also currently evaluating RZ358 in a Phase 3 clinical trial in congenital HI, which is a rare pediatric condition where, similar to ICTH, children overproduce insulin creating a dangerous hypoglycemic state. About Tumor Hyperinsulinism (HI)Tumor HI may be the result of two distinct types of tumors: islet cell tumors (ICTs) and non-islet cell tumors (NICTs), both of which lead to hypoglycemia due to excessive activation of the insulin receptor. Insulinomas are the most common type of functional ICT and cause hypoglycemia because of over production of insulin. NICTs can cause hypoglycemia by producing and secreting insulin-like paraneoplastic substances such as IGF-2 or related variants that bind to and activate the insulin receptor. This form of hypoglycemia can occur in more than 15 different tumor types, 60 percent of which are malignant, including hepatocellular carcinoma. The total addressable market for the combined indications causing tumor HI is estimated to be approximately 4,500 patients in the U.S. alone, including approximately 1,500 with ICTH and 3,000 with NICTH. The unique mechanism of action of RZ358 to attenuate excess insulin receptor activation mediated by insulin and related substances makes the therapy a potential universal treatment for hypoglycemia resulting from any form of hyperinsulinism. About RZ358RZ358 is a fully human monoclonal antibody that works downstream from the pancreas and other sources of insulin or related paraneoplastic substances, and instead binds to a unique allosteric site on insulin receptors in the liver, fat, and muscle. The antibody counteracts excess insulin receptor activation by insulin and other effector substances (such as IGF-2), thereby improving hypoglycemia. Because RZ358 acts downstream from the pancreas at the insulin receptor, it has the potential to be universally effective at treating hypoglycemia due to congenital HI, regardless of the causative genetic defect, as well as acquired forms of HI such as those mediated by insulinomas (ICTs) and other tumor types (NICTs). RZ358 received Orphan Drug Designation in the United States and European Union for the treatment of congenital HI, as well as Orphan Drug Designation and Pediatric Rare Disease Designation in the U.S. In the Phase 2 RIZE study, participants with congenital HI ages two and older nearly universally achieved significant improvements in hypoglycemia across multiple endpoints, including the primary and key secondary endpoints planned for the sunRIZE study. At doses and exposures that are planned for the Phase 3 study, RZ358 was generally safe and well-tolerated, and resulted in median improvements in hypoglycemia exceeding 80%. Based on the RIZE clinical trial outcomes and the evidence of benefit in this serious condition with substantial unmet medical need, RZ358 was subsequently granted a priority medicines (PRIME) designation by the European Medicines Agency (EMA) and an Innovation Passport designation by the U.K. Innovative Licensing and Access Pathway (ILAP) Steering Group for the treatment of congenital HI. RZ358 also received Orphan Drug Designation status in the European Union for the treatment of Insulinoma, the primary cause of ICTH. About Rezolute, Inc. Rezolute strives to disrupt current treatment paradigms by developing transformative therapies for devastating rare and chronic metabolic diseases. Its novel therapies hold the potential to both significantly improve outcomes and reduce the treatment burden for patients, treating physicians, and the healthcare system. Rezolute is steadfast in its mission to create profound, positive, and lasting impacts on patients’ lives. Patient, clinician, and advocate voices are integrated in the Company’s drug development process. Rezolute places an emphasis on understanding the patient’s lived experiences, enabling the Company to boldly address a range of severe conditions. For more information, visit www.rezolutebio.com. Forward-Looking Statements This release, like many written and oral communications presented by Rezolute and our authorized officers, may contain certain forward-looking statements regarding our prospective performance and strategies within the meaning of Section 27A of the Securities Act and Section 21E of the Securities Exchange Act of 1934, as amended. We intend such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and are including this statement for purposes of said safe harbor provisions. Forward-looking statements, which are based on certain assumptions and describe future plans, strategies, and expectations of Rezolute, are generally identified by use of words such as "anticipate," "believe," "estimate," "expect," "intend," "plan," "project," "seek," "strive," "try," or future or conditional verbs such as "could," "may," "should," "will," "would," or similar expressions. These forward-looking statements include, but are not limited to statements regarding the Innovation Passport designation, the RZ358 Expanded Access Program, the ability of RZ358 to become an effective treatment for congenital hyperinsulinism, the effectiveness or future effectiveness of RZ358 for the treatment of congenital hyperinsulinism, and statements regarding clinical trial timelines for RZ358. Our ability to predict results or the actual effects of our plans or strategies is inherently uncertain. Accordingly, actual results may differ materially from anticipated results. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. Except as required by applicable law or regulation, Rezolute undertakes no obligation to update these forward-looking statements to reflect events or circumstances that occur after the date on which such statements were made. Important factors that may cause such a difference include any other factors discussed in our filings with the SEC, including the Risk Factors contained in the Rezolute’s Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, which are available at the SEC’s website at www.sec.gov. You are urged to consider these factors carefully in evaluating the forward-looking statements in this release and are cautioned not to place undue reliance on such forward-looking statements, which are qualified in their entirety by this cautionary statement. Investors & Media:Christen BaglaneasRezolute, Inc.cbaglaneas@rezolutebio.com (508)272-6717 A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/165f8dbc-1fce-47b8-ac3f-0cf6fb4170cb

A new study reveals the crucial role of vascular system cells -- known as pericytes -- in the formation of long-term memories of life events -- memories that are lost in diseases such as Alzheimer's disease. Research on long-term memories has largely focused on the role of neurons -- the brain's nerve cells. However, in recent years, scientists are discovering that other cell types are also vital in memory formation and storage. A new study, published in the journal Neuron, reveals the crucial role of vascular system cells -- known as pericytes -- in the formation of long-term memories of life events -- memories that are lost in diseases such as Alzheimer's disease. The research, conducted by New York University neuroscientists, shows that pericytes, which wrap around the capillaries -- the body's small blood vessels -- work in concert with neurons to help ensure that long-term memories are formed. "We now have a firmer understanding of the cellular mechanisms that allow memories to be both formed and stored," says Cristina Alberini, a professor in New York University's Center for Neural Science and the paper's senior author. "It's important because understanding the cooperation among different cell types will help us advance therapeutics aimed at addressing memory-related afflictions." "This work connects important dots between the newly discovered function of pericytes in memory and previous studies showing that pericytes are either lost or malfunction in several neurodegenerative diseases, including Alzheimer's disease and other dementia," explains author Benjamin Bessières, a postdoctoral researcher in NYU's Center for Neural Science. Pericytes help maintain the structural integrity of the capillaries. Specifically, they control the amount of blood flowing in the brain and play a key role in maintaining the barrier that stops pathogens and toxic substances from leaking out of the capillaries and into brain tissue. The discovery, reported in the new Neuron article, of the pericytes' significance in long-term memory emerged because Alberini, Bessières, Kiran Pandey, and their colleagues examined the role of insulin-like growth factor 2 (IGF2) -- a protein that was known to increase following learning in brain regions, such as the hippocampus, and to play a critical role in the formation and storage of memories. They found that IGF2's highest levels in the brain cells of the hippocampus do not come from neurons or glial cells, or other vascular cells, but, rather, from pericytes. IGF2's presence in pericytes, then, raises the following question: How is this linked to memory? The scientists conducted a series of cognitive experiments using mice, comparing behaviors of those with pericytes that produced IGF2 and those that did not. By removing IGF2-producing capacity in some, the researchers could isolate the significance of both pericytes and IGF2 in neurological processes. In these experiments, the mice were subjected to a series of memory tests -- learning to associate a mild foot shock to a specific context or learning to identify objects placed in a new location. Their results showed that production of IGF2 by pericytes in the hippocampus was enhanced by the learning event. More specifically, this increase in pericytic IGF2 took place in response to activity of neurons, revealing a concerted, neuron-pericytic action. In addition, IGF2 produced by pericytes were shown to circle back to influence biological responses of neurons that are critical for memory. "IGF2 produced from pericytes and acting on neurons support the idea that a neurovascular unit regulates neuronal responses as well as functions of the blood barrier and may have repercussions on brain injury and inflammation," notes Pandey, a postdoctoral researcher in NYU's Center for Neural Science. "Cooperation between neurons and pericytes is necessary to assure that long-term memories are formed," observes Alberini. "Our study provides a new view of the biology of memory -- though more research is needed to further understand the roles of pericytes and the vascular system in memory and its diseases." The research of this study also included scientists from Cold Spring Harbor Laboratory and the University of Cambridge. The research was supported by grants from the National Institutes of Health (MH065635), the United Kingdom's Biotechnology and Biological Sciences Research Council (BB/H003312/1) and Medical Research Council (MRC MC_UU_00014/4, MRC_MC_UU_12012/5). Alberini is a founder and equity holder of Ritrova Therapeutics, Inc, a company exploring new treatments for neurodegenerative diseases and neurodevelopmental disorders. The company did not fund this study.

Scientists have identified a key part of a mechanism that annotates genetic information before it is passed from fathers to their offspring. The findings shed new light on genomic imprinting, a fundamental, biological process in which a gene from one parent is switched off while the copy from the other parent remains active. Errors in imprinting are linked to a host of diseases, such as the rare disease Silver-Russell syndrome along with certain cancers and diabetes. Van Andel Institute scientists and collaborators have identified a key part of a mechanism that annotates genetic information before it is passed from fathers to their offspring. The findings, published today in the journal Science Advances, shed new light on genomic imprinting, a fundamental, biological process in which a gene from one parent is switched off while the copy from the other parent remains active. Errors in imprinting are linked to a host of diseases, such as the rare disease Silver-Russell syndrome along with certain cancers and diabetes. "Proper imprinting is crucial for lifelong health but, despite its importance, we still lack a full understanding of the factors that regulate this vital process," said VAI Associate Professor Piroska Szabó, Ph.D., the study's corresponding author. "Our findings reveal an RNA mechanism that governs establishment of imprinting and illuminates why it differs between fathers and mothers." Our genetic information is encoded in DNA, a long, winding molecule that is tightly packed to form 23 pairs of chromosomes, half of which come from one's father and half from one's mother. Sperm and eggs only contain 23 single chromosomes -- half of the genetic material required for life. During fertilization, they each contribute their half, resulting in a zygote with a full set of 23 pairs of chromosomes. But not all instructions in DNA are needed at the same time or in the same places. That's where epigenetics come in. Epigenetic mechanisms annotate DNA with special chemical tags called methyl groups, which tell certain genes when to be active and when to be silent -- all without changing the sequence of DNA itself. Imprinting occurs when methyl groups are added to certain genes during either sperm or egg formation. This, in turn, is important for determining which parental copy of that gene is expressed in the offspring. To better understand the processes that govern imprinting, Szabó and colleagues focused on an imprinting control region in the DNA that regulates the Igf2 gene. Igf2 plays key roles in fetal growth and only is active in the chromosome inherited from the father. Too little methylation in the IGF2 control region in humans can result in Silver-Russell syndrome, which is marked by reduced growth and increased risk of metabolic disease. "If the IGF2 gene's imprinting control region from one's father is not methylated, it can result in disease," Szabó said. Using genetic models and in-depth genetic sequencing, the team found that the methylation of the Igf2 control region in paternally inherited DNA is governed by an underlying RNA-based process in the male germline. "We found earlier that RNA similarly runs through other paternally marked imprinted domains in the male germ cells, suggesting that this same process is generally true for paternal imprinting," Szabó said. "These results suggest a more broadly applicable process, which is exciting and will need to be confirmed in subsequent studies." Other authors include Ji Liao, Ph.D., Zhen Fu, Ph.D., Ivan VanderKolk, Brianna M. Busscher and Kin H. Lau, Ph.D., of VAI; Sangmin Song of City of Hope Cancer Center; and Samuel Gusscott, Ph.D., and Julie Brind'Amour, Ph.D., of Université de Montréal.