LOX-1

AstraZeneca kicked MEDI6570 out alongside two partnered phase 1 programs. AstraZeneca’s first-quarter results (PDF) put a twist on a fairy tale, telling the lesser-known story of GOLDILOX and the porcupine. The drugmaker axed a cardiovascular disease prospect after wrapping up the phase 2 GOLDILOX trial while stopping work on early-stage assets bought in from Ionis Pharmaceuticals and Redx Pharma. The drugmaker is locking the three assets away in its tower as part of a strategic portfolio prioritization. MEDI6570, an antibody that blocks ligands to the LOX-1 scavenger receptor, is the most advanced asset affected by the quarterly cull. AstraZeneca took the molecule into a phase 2 trial in 2020 to assess whether it improves outcomes in patients with a history of heart attacks. Having wrapped the study up in November, AstraZeneca removed the asset from its pipeline Thursday. Earlier studies implicated LOX-1 in all the main stages of the buildup of plaque in arteries, but the clinical data have failed to persuade AstraZeneca that the molecule is a good use of its money. Aradhana Sarin, chief financial officer at AstraZeneca, discussed the termination on a media conference call, explaining that the action was based on the company’s “internal evaluation” and was “just part of our normal prioritization process.” AstraZeneca kicked MEDI6570 out alongside two partnered phase 1 programs. The drugmaker picked up the rights to RXC006, a porcupine inhibitor, for fibrotic diseases from Redx for $17 million in near-term payments in 2020. Porcupine is a key enzyme in the Wnt signaling pathway that is implicated in diseases such as idiopathic pulmonary fibrosis. In theory, targeting porcupine could address lung scarring. To test that theory, AstraZeneca ran four phase 1 clinical trials between 2021 and 2023. The drugmaker has said little publicly about what it learned in the studies but has decided it has seen enough and cut the program from its pipeline.  The third asset to land on the discard pile is AZD7503, an antisense oligonucleotide AstraZeneca was developing with Ionis. AstraZeneca took the molecule through a series of early-phase trials, culminating in the initiation of a study in people with suspected non-cirrhotic nonalcoholic steatohepatitis in 2023. The liver condition is now known as metabolic dysfunction-associated steatohepatitis (MASH). Ionis designed AZD7503, also known as ION455, to treat MASH by inhibiting production of a protein that is associated with the progression of the condition in mice and humans. Genetic changes in the gene encoding for the protein, HSD17B13, correlate to the occurrence and severity of MASH, but the molecule failed to survive AstraZeneca’s portfolio prioritization.

Pictured: Exterior of Sanofi's U.S. headquarters in Bridgewater, N.J./ iStock/JHVEPhoto On Thursday, European drugmakers Sanofi and AstraZeneca announced several pipeline cuts in their respective first-quarter 2024 financial results, including assets to treat Sjögren’s syndrome and cardiovascular disease. According to Sanofi’s first-quarter results, the development of the CD40L antibody frexalimab in Sjögren’s syndrome was halted due to unfavorable Phase II study data. While Sanofi touted the safety and “pharmacologic activity” of the drug, the candidate did not reach the “necessary efficacy outcomes” to move forward. However, frexalimab will continue on in Phase III trials in multiple sclerosis (RMS) and secondary-progressive multiple sclerosis (SPMS) as well as Phase II trials in type 1 diabetes and systemic lupus erythematosus. In February 2024, frexalimab secured positive mid-stage results in RMS demonstrating a slowing in disease activity. The drug is also one of Sanofi’s “pipeline-in-a-product” assets that the company contends can potentially generate annual sales of €5 billion ($5.3 billion). Sanofi is also halting a Phase II study of the molecule venglustat to treat the rare genetic disorder GM2 gangliosidosis. The company said there was an “absence of positive trends” for its clinical endpoints in the trial. The molecule aims to slow disease progress by inhibiting the abnormal accumulation of glycosphingolipids. In 2021, Sanofi stopped a Phase II/III trial of venglustat in kidney disease as it did not reach the futility criteria. In neurology, Sanofi discontinued a Phase II study of the RIPK1 inhibitor oditrasertib in amyotrophic lateral sclerosis (ALS) as the trial failed to reach the primary endpoint of improvement based on the ALS Functional Rating Scale-Revised. Sanofi said it will share the complete safety and efficacy data at an upcoming medical meeting and continue the Phase II study of oditrasertib in MS patients. Sanofi’s pipeline cuts come amid announced layoffs last week as part of the company’s restructuring of its U.S. vaccine operations. Thursday’s Q1 earnings also saw AstraZeneca putting the kibosh on several early-stage medicines, including MEDI6570, designed to block multiple ligands to the LOX-1 receptor. The asset was in a Phase IIb trial, called GOLDILOX, for post-myocardial infarction but was stopped due to a “strategic portfolio prioritization.” Other AstraZeneca assets nixed for portfolio prioritization include the metabolic dysfunction-associated steatohepatitis (MASH) candidate AZD7503. The ligand-conjugated antisense (LICA) drug originally belonged to Ionis Pharmaceuticals and is designed to inhibit the production of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13). The other asset to get axed is the oral porcupine inhibitor AZD5055, which was in Phase I trials for Idiopathic pulmonary fibrosis (IPF) and other Interstitial lung diseases (ILDs) with progressive fibrosis. The candidate was picked up from Redx Pharma in 2020 for $17 million and $360 million, respectively, in potential milestone payments. For Sanofi’s Q1 results, the pharma reported over €10.4 billion ($11.2 billion) in sales, driven by its blockbuster drug Dupixent which increased 24.9% compared to the same period. AstraZeneca meanwhile pulled in $12.1 billion in sales for the quarter, a 15% boost from Q1 of 2023, with its oncology products bringing in more than $5.1 billion, a 23% bump from the previous quarter. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

AUSTIN, Texas, April 14, 2023 /PRNewswire/ -- The main results of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) trial, a National Heart, Lung, and Blood Institute (NHLBI) sponsored trial were presented. Although the results of the trial are not final, they offer valuable information for patients using the generic drug Spironolactone. This drug therapy activates white cells and reduces tissue damage as well as reduces proteins that would normally be considered inflammatory. The results from this study will be presented at the National Kidney Foundation's (NKF) NKF Spring Clinical Meetings during the "late-breaking presentations" at the largest multidisciplinary gathering of kidney care professionals in North America from April 11-15 in Austin, Texas. My message to patients is to consider using Spironolactone as their generic drug choice if they can. QUOTE FROM RESEARCHER "My message to patients is to consider using Spironolactone as their generic drug choice if they can for appropriate indications. We want to consider using this drug in high-risk patients with diabetes and atherosclerosis, because the benefit of the drug might extend not only to preventing heart failure and kidney disease progression but potentially other benefits," explained Sanjay Rajagopalan, MD, FACC, FAHA, Chief of the Division of Cardiovascular Medicine and Chief Academic and Scientific Officer of UH Harrington Heart & Vascular Institute; Herman K. Hellerstein, MD, Chair in Cardiovascular Research and a professor at the Case Western Reserve University School of Medicine. "Having a drug that works on these systems in a connective manner is a big benefit to a patient, and this drug happens to be one of those." Highlights of the interim results include: Results: Seventy-nine patients were randomized at 4 sites in US and Canada to Spironolactone (n=37) vs placebo (n=42) for 12 months, after a 2-week single-blind placebo lead-in period and 4-week dose escalation phase. Mean age was 64±8 years; HbA1c 7.3±1.3%; eGFR 44 ml/min/1.73m2; baseline systolic BP 132 ±19 mmHg. The results demonstrated a marked reduction in thoracic plaque volume (Percent change in wall volume) response to Spironolactone at the end of 12 months compared to placebo. These changes were accompanied by changes in left ventricular mass and fibrosis. Spironolactone treatment did not change clinic systolic blood pressure but did cause a statistically significant change in 24-hour mean systolic and diastolic blood pressures compared to baseline and versus placebo respectively. Spironolactone also reduced LV wall mass and a measure of LV fibrosis (native T1 values). Plasma proteomic analysis revealed significant downregulation of a number of pathways involved in immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. The top 2 molecules downregulated were DDR2, and oxidized LDL receptor-1 (LOX-1) involved in collagen synthesis and inflammation respectively. Additional top downregulated proteins included known Aldosterone targets such as Sodium/potassium-transporting ATPase subunit beta-3 and Adenylyl cyclase-associated protein 1. Data are mean ± SD. Change was defined as the value at 12 months minus the value at baseline. †p < 0.05; †††p < 0.001 Thousands of kidney care professionals will attend the Spring Clinical Meetings in-person and virtually. Hundreds of the latest studies and kidney care advances will be unveiled. NKF Spring Clinical Meetings For the past 31 years, nephrology healthcare professionals from across the country have come to NKF's Spring Clinical Meetings to learn about the newest developments related to all aspects of nephrology practice; network with colleagues; and present their research findings. The NKF Spring Clinical Meetings are designed for meaningful change in the multidisciplinary healthcare teams' skills, performance, and patient health outcomes. It is the only conference of its kind that focuses on translating science into practice for the entire healthcare team. About Kidney Disease In the United States, more than 37 million adults are estimated to have kidney disease, also known as chronic kidney disease (CKD)—and approximately 90 percent don't know they have it. About 1 in 3 adults in the U.S. are at risk for kidney disease. Risk factors for kidney disease include: diabetes, high blood pressure, heart disease, obesity, and family history. People of Black or African American, Hispanic or Latino, American Indian or Alaska Native, Asian American, or Native Hawaiian or Other Pacific Islander descent are at increased risk for developing the disease. Black or African American people are about four times as likely as White people to have kidney failure. Hispanics experience kidney failure at about double the rate of White people. NKF Professional Membership Healthcare professionals can join NKF to receive access to tools and resources for both patients and professionals, discounts on professional education, and access to a network of thousands of individuals who treat patients with kidney disease. Media Contacts: