LDHA

Chinook Therapeutics, Inc. (Nasdaq: KDNY), a biopharmaceutical company focused on the discovery, development and commercialization of precision medicines for kidney diseases, today announced that the first patient with IgA nephropathy (IgAN) has been enrolled in the BEYOND study, a pivotal phase 3 clinical trial evaluating the safety and efficacy of zigakibart (BION-1301), a potentially disease-modifying anti-APRIL monoclonal antibody. “Initiation of the phase 3 BEYOND study is an important step towards our goal of providing an innovative treatment option for patients with IgAN, a disease with high unmet need and limited treatment options,” said Eric Dobmeier, president and chief executive officer of Chinook Therapeutics. “The data from our ongoing phase 1/2 trial of zigakibart supports our belief that binding and neutralizing APRIL in patients with IgAN plays a key role in depleting pathogenic galactose deficient-IgA1, reducing proteinuria and preserving kidney function for IgAN patients.” “I am pleased to see Chinook enroll the first patient in the phase 3 BEYOND study of zigakibart in IgAN and look forward to the study’s continued enrollment,” said Vlado Perkovic, MBBS, PhD, FASN, FRACP, dean of medicine and health and Scientia professor at University of New South Wales and co-chair of the BEYOND study steering committee. “IgAN is the most common primary glomerular disease worldwide with limited treatment options currently available, causing many patients to progress to end-stage kidney disease, requiring dialysis or kidney transplant. With the potential to be disease-modifying based on the encouraging results observed in the phase 1/2 study, I believe zigakibart could be an important new therapeutic treatment option for patients with IgAN.” About the BEYOND Study The BEYOND study (see www.clinicaltrials.gov, identifier NCT05852938) is a global, randomized, multicenter, double-blind, placebo-controlled phase 3 clinical trial comparing the safety and efficacy of zigakibart versus placebo in patients with IgAN at risk of progressive loss of kidney function. Approximately 272 patients with biopsy-proven IgAN and eGFR ≥ 30 mL/min/1.73m2 will be randomized to receive 600 mg of zigakibart or a matched placebo subcutaneously every two weeks for 104 weeks. An additional exploratory cohort, not included in the primary analysis, will be comprised of approximately 20 subjects (10 subjects per arm) with biopsy-confirmed IgAN and eGFR of ≥ 20 to 2. The primary efficacy endpoint of the BEYOND study is to evaluate the effect of zigakibart versus placebo on proteinuria as measured by change in urine protein to creatinine ratio (UPCR) from baseline to 40 weeks. Secondary and exploratory objectives include evaluating change in eGFR from baseline to week 104; composite clinical outcome of 30% or 40% reduction in eGFR, eGFR 2 or dialysis, kidney transplantation or all-cause mortality; safety and tolerability; impact of zigakibart on disease biomarkers and health-related quality of life, as well as analysis of zigakibart pharmacokinetics and immunogenicity. About Chinook Therapeutics, Inc. Chinook Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing precision medicines for kidney diseases. Chinook’s product candidates are being investigated in rare, severe chronic kidney disorders with opportunities for well-defined clinical pathways. Chinook’s lead program is atrasentan, a phase 3 endothelin receptor antagonist for the treatment of IgA nephropathy and proteinuric glomerular diseases. Zigakibart (BION-1301), an anti-APRIL monoclonal antibody, is being evaluated in a phase 3 trial for IgA nephropathy. CHK-336, an oral small molecule LDHA inhibitor for the treatment of hyperoxalurias, is in phase 1 development. In addition, Chinook’s research and discovery efforts are focused on building a pipeline of precision medicines for rare, severe chronic kidney diseases with defined genetic and molecular drivers. Chinook is leveraging insights from kidney single cell RNA sequencing and large CKD patient cohorts that have been comprehensively panomically phenotyped, with retained biosamples and prospective clinical follow-up, to discover and develop therapeutic candidates with mechanisms of action targeted against key kidney disease pathways. To learn more, visit www.chinooktx.com. The content above comes from the network. if any infringement, please contact us to modify.

Aerobic glycolysis, the process by which cells transform glucose into lactate, is key for eye development in mammals, according to a new study. Aerobic glycolysis, the process by which cells transform glucose into lactate, is key for eye development in mammals, according to a new Northwestern Medicine study published in Nature Communications. While it has been well known that retinal cells use lactate during cell differentiation, the exact role that this process plays in early eye development was not previously understood. The findings further the field's understanding of the metabolic pathways underlying organ development, according to Guillermo Oliver, PhD, the Thomas D. Spies Professor of Lymphatic Metabolism, Director of the Feinberg Cardiovascular and Renal Research Institute Center for Vascular and Developmental Biology, and senior author of the study. "For a long time, my lab has been interested in developmental biology. In particular, to characterize the molecular and cellular steps regulating early eye morphogenesis," Oliver said. "For us, the question was: 'How do these remarkable and critical sensory organs we have in our face start to form?'" Nozomu Takata, PhD, a postdoctoral fellow in the Oliver lab and first author of the paper, initially approached this question by developing embryonic stem cell-derived eye organoids, which are organ-like tissues engineered in a petri dish. Intriguingly, he observed that early mouse eye progenitors display elevated glycolytic activity and production of lactate. After introducing a glycolysis inhibitor to the cultured organoids, normal optic vesicle development halted, according to the study, but adding back lactate allowed the organoids to resume normal eye morphogenesis, or development. Takata and his collaborators then compared those organoids to controls using genome-wide transcriptome and epigenetic analysis using RNA and ChIP sequencing. They found that inhibiting glycolysis and adding lactate to the organoids regulated the expression of certain critical and evolutionary conserved genes required for early eye development. To validate these findings, Takata deleted Glut1 and Ldha, genes known for regulating glucose transport and lactate production from developing retinas in mouse embryos. The deletion of these genes arrested normal glucose transport specifically in the eye-forming region, according to the study. "What we found was an ATP-independent role of the glycolytic pathway," Takata said. "Lactate, which is a metabolite known as a waste product before, is really doing something cool in eye morphogenesis. That really tells us that this metabolite is a key player in organ morphogenesis and in particular, eye morphogenesis. I see this discovery as having broader implications, as likely also being required in other organs and maybe in regeneration and disease as well." Following this discovery, Takata said he plans to continue to take advantage of traditional and emerging developmental biology's tools such as mouse genetics and stem cells-derived organoids to study the role of the glycolytic pathway and metabolism in the development of other organs. The findings could also be useful in better understanding the direct effect that metabolites could have in regulating gene expression during organ regeneration and tumor development, Oliver said. "Both regeneration and tumorigenesis involve developmental pathways that go awry in some occasions, or you need to reactivate," Oliver said. "For many developmental processes, you need very strict transcriptional regulation. A gene is on or off at certain times, and when that goes wrong, that could lead to developmental defects or promote tumorigenesis. Now that we know that there are specific metabolites responsible for normal or abnormal gene regulation, this can broaden our thinking on approaches to therapeutic treatments." Additional Feinberg faculty co-authors include Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics and director of the Simpson Querrey Institute for Epigenetics, Alexander Misharin, MD, PhD, associate professor of Medicine in the Division of Pulmonary and Critical Care, Jason M. Miska, PhD, assistant professor of Neurological Surgery and Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics. The study was supported by an Illumina Next Generation Sequencing award

CHK-336 was generally well tolerated in healthy volunteers (HV) who received single doses up to 500 mg and multiple doses up to 60 mg for 14 daysPharmacokinetics (PK) was well characterized with dose-proportional exposures and a half-life that supports once-daily dosingSuccessful implementation of a novel 13C2-glycolate tracer established proof-of-mechanism of CHK-336 to block hepatic oxalate production in HVsOne serious adverse event (SAE) of anaphylaxis occurred in a multiple ascending dose HV who received one 125 mg dose CHK-336, resulting in voluntary study pauseAdditional research presented on the impact of maladaptive tubular epithelial cells on progression of chronic kidney disease SEATTLE, June 17, 2023 (GLOBE NEWSWIRE) -- Chinook Therapeutics, Inc. (Nasdaq: KDNY), a biopharmaceutical company focused on the discovery, development and commercialization of precision medicines for kidney diseases, announced a free communication presentation on CHK-336 presented today at the 60th ERA Congress being held virtually and live in Milan, Italy. “The data presented from the phase 1 study of CHK-336 at this year’s ERA Congress successfully demonstrates hepatic LDH target engagement in healthy volunteers and establishes proof-of-mechanism for CHK-336 to decrease hepatic oxalate production,” said Andrew King, chief scientific officer of Chinook Therapeutics. “As we continue to investigate the SAE observed in the 125 mg MAD cohort and consider next steps, the CHK-336 program will remain paused.” CHK-336, A First-in-Class Orally Administered LDH Inhibitor: Safety, PK and Target Engagement in a First-in-Human Phase 1 Healthy Volunteer Study CHK-336 is an oral small molecule LDHA inhibitor with liver-targeted tissue distribution in development for the treatment of patients with primary hyperoxaluria (PH) and other kidney stone disorders driven by endogenous overproduction of oxalate. The phase 1 single-center trial (see www.clinicaltrials.gov, identifier NCT05367661) was designed to evaluate the safety, tolerability, pharmacokinetic profile of CHK-336 in 104 healthy volunteers in randomized, placebo-controlled, double-blinded, single-ascending dose (SAD) and multiple-ascending dose (MAD) settings. Healthy volunteers in the SAD portion of the study received placebo or a single dose of CHK-336 ranging from 15 mg to 500 mg on day 1. Healthy volunteers in the MAD portion of the study were to receive placebo or multiple doses of CHK-336 ranging from 30 mg to 500 mg given daily for 14 days. Key highlights from the presentation include the following: CHK-336 was generally well tolerated in HVs who received single doses up to 500 mg and multiple doses (14 days) up to 60 mg. There were no dose-related trends in adverse events, vital signs or EKG findings.The most common treatment emergent adverse event was headache in six subjects receiving CHK-336 (8.8%) and no placebo subjects, with no dose-related trend. There was one serious adverse event (SAE) of anaphylaxis that occurred in a single HV following the first dose in the 125 mg MAD group. The SAE had a rapid onset within one hour following the first dose and rapidly resolved after treatment with an antihistamine, without requiring epinephrine administration. The HV had clinically significant elevations in serum tryptase levels during the event, confirming anaphylaxis. This SAE resulted in voluntary pausing of the trial to enable further investigation.PK was well characterized with dose proportional exposures, a plasma half-life consistent with once daily oral dosing and no exposure accumulation following repeat dosing.The successful utilization of a novel 13C2-glycolate tracer in the trial establishes proof-of-mechanism for CHK-336 as an orally administered small molecule inhibitor of hepatic LDH. CHK-336 effectively blocked conversion of the 13C2-glycolate tracer to 13C2-oxalate with maximal inhibition observed following a single dose of CHK-336 at 60-125 mg. Accumulation of Maladaptive Tubular Epithelial Cells (TECs) is Ubiquitous in Chronic Kidney Diseases and Represents a Common Initiating Mechanism of Disease Progression Disease-associated maladaptive TECs have been described in rodent models and are characterized by a failed repair phenotype that contributes to tubulointerstitial inflammation and fibrosis. This study explores the significance of maladaptive TECs in the NURTuRE chronic kidney disease (CKD) cohort by integrating clinical, histological, transcriptomic and proteomic data from blood and urine to gain insights into mechanisms of CKD progression. The NURTuRE consortium biobank comprises patient samples from a broad range of CKD diagnoses and kidney functional states with rich clinical data from over 3,500 subjects. Human gene signatures for two maladaptive tubule subtypes were identified in human CKD scRNA-Seq datasets. Based on unbiased analysis, maladaptive tubule signatures were found to be among the most highly associated with CKD progression in the NURTuRE cohort and a high maladaptive tubule gene signature score at time of biopsy was significantly associated with shorter renal event-free survival in the NURTuRE cohort (304 patients across 12 disease etiologies). The emergence of maladaptive tubules is associated with disease progression across multiple CKDs and targeting these cells may potentially be an effective strategy to preserve kidney function broadly in CKD. About Chinook Therapeutics, Inc.Chinook Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing precision medicines for kidney diseases. Chinook’s product candidates are being investigated in rare, severe chronic kidney disorders with opportunities for well-defined clinical pathways. Chinook’s lead program is atrasentan, a phase 3 endothelin receptor antagonist for the treatment of IgA nephropathy and proteinuric glomerular diseases. Zigakibart (BION-1301), an anti-APRIL monoclonal antibody, is being evaluated in a phase 1/2 trial for IgA nephropathy. CHK-336, an oral small molecule LDHA inhibitor for the treatment of hyperoxalurias, is in phase 1 development. In addition, Chinook’s research and discovery efforts are focused on building a pipeline of precision medicines for rare, severe chronic kidney diseases with defined genetic and molecular drivers. Chinook is leveraging insights from kidney single cell RNA sequencing and large CKD patient cohorts that have been comprehensively panomically phenotyped, with retained biosamples and prospective clinical follow-up, to discover and develop therapeutic candidates with mechanisms of action targeted against key kidney disease pathways. To learn more, visit www.chinooktx.com. Forward-Looking Statements In addition to historical information, this communication contains forward-looking statements within the meaning of applicable securities law, including statements regarding the advancement of its product candidates and product pipeline, and the clinical development of its product candidates, including expectations regarding the results of clinical trials. In addition, when used in this communication, the words “will,” “expects,” “could,” “would,” “may,” “anticipates,” “intends,” “plans,” “believes,” “seeks,” “targets,” “estimates,” “looks for,” “looks to,” “continues” and similar expressions, as well as statements regarding our focus for the future, are generally intended to identify forward-looking statements. Each of the forward-looking statements we make in this communication involves risks and uncertainties that could cause actual results to differ materially from these forward-looking statements. Factors that might cause or contribute to such differences include, but are not limited to: expected revenues, cost savings, synergies and other benefits from the proposed merger might not be realized within the expected time frames or at all and costs or difficulties relating to integration matters, including but not limited to employee retention, might be greater than expected; the requisite regulatory approvals and clearances for the proposed transaction may be delayed or may not be obtained (or may result in the imposition of conditions that could adversely affect the combined company or the expected benefits of the proposed merger); the requisite approval of Company stockholders may be delayed or may not be obtained, the other closing conditions to the proposed merger may be delayed or may not be obtained, or the merger agreement may be terminated; business disruption may occur following or in connection with the proposed merger; Novartis or Chinook’s businesses may experience disruptions due to transaction-related uncertainty or other factors making it more difficult to maintain relationships with employees, other business partners or governmental entities; the milestones for the proposed CVRs may not be achieved; the possibility that the proposed merger is more expensive to complete than anticipated, including as a result of unexpected factors or events; and diversion of management’s attention from ongoing business operations and opportunities as a result of the proposed merger or otherwise. Additional factors that may affect the future results of Novartis and Chinook are set forth in their respective filings with the U.S. Securities and Exchange Commission (the “SEC”), including in the most recently filed annual report of Novartis on Form 20-F, subsequently filed Current Reports on Form 6-K and other filings with the SEC, which are available on the SEC’s website at www.sec.gov, and Chinook’s most recently filed Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the SEC, which are available on the SEC’s website at www.sec.gov. The risks described in this communication and in Novartis and Chinook’s filings with the SEC should be carefully reviewed. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date they are made. Novartis and Chinook undertake no obligation to publicly release any revisions to the forward-looking statements or reflect events or circumstances after the date of this communication, except as required by law. Additional Information and Where to Find It In connection with the proposed merger between Novartis and Chinook, Novartis and Chinook intend to file relevant materials with the SEC, including a preliminary and definitive proxy statement to be filed by Chinook. The definitive proxy statement and proxy card will be delivered to the stockholders of Chinook in advance of the special meeting relating to the proposed merger. CHINOOK’S STOCKHOLDERS ARE URGED TO READ THE DEFINITIVE PROXY STATEMENT IN ITS ENTIRETY WHEN IT BECOMES AVAILABLE AND ANY OTHER DOCUMENTS FILED BY EACH OF NOVARTIS AND CHINOOK WITH THE SEC IN CONNECTION WITH THE PROPOSED MERGER OR INCORPORATED BY REFERENCE THEREIN BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT THE PROPOSED TRANSACTION AND THE PARTIES TO THE PROPOSED TRANSACTION. Investors and security holders will be able to obtain a free copy of the proxy statement and such other documents containing important information about Novartis and Chinook, once such documents are filed with the SEC, through the website maintained by the SEC at www.sec.gov. Novartis and Chinook make available free of charge at the Novartis website and Chinook’s website, respectively (in the “Investors” section), copies of materials they file with, or furnish to, the SEC. The contents of the websites referenced above are not deemed to be incorporated by reference into the proxy statement. Participants in the Solicitation This document does not constitute a solicitation of proxy, an offer to purchase or a solicitation of an offer to sell any securities. Novartis, Chinook and their respective directors, executive officers and certain employees may be deemed to be participants in the solicitation of proxies from the stockholders of Chinook in connection with the proposed merger. Information regarding the special interests of these directors and executive officers in the proposed merger will be included in the definitive proxy statement referred to above. Security holders may also obtain information regarding the names, affiliations and interests of the Novartis directors and executive officers in the Novartis Annual Report on Form 20-F and Form 20-F/A for the fiscal year ended December 31, 2022, which were filed with the SEC on February 1, 2023, and May 15, 2023, respectively. Security holders may obtain information regarding the names, affiliations and interests of Chinook’s directors and executive officers in Chinook’s Annual Report on Form 10-K for the fiscal year ended December 31, 2022, which was filed with the SEC on February 27, 2023, and its definitive proxy statement for the 2023 annual meeting of stockholders, which was filed with the SEC on April 28, 2023. To the extent the holdings of Chinook’s securities by Chinook’s directors and executive officers have changed since the amounts set forth in Chinook’s definitive proxy statement for its 2023 annual meeting of stockholders, such changes have been or will be reflected on Statements of Change in Ownership on Form 4 filed with the SEC. Additional information regarding the interests of such individuals in the proposed merger will be included in the definitive proxy statement relating to the proposed merger when it is filed with the SEC. These documents (when available) may be obtained free of charge from the SEC’s website at www.sec.gov, the Novartis website at https://www.novartis.com and Chinook’s website at https://www.chinooktx.com. The contents of the websites referenced above are not deemed to be incorporated by reference into the proxy statement.