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.

Phase 2a publication entitled “Combined Regulatory T-Lymphocyte and IL-2 Treatment is Safe, Tolerable, and Biologically Active for One Year in Persons with Amyotrophic Lateral Sclerosis” has been published in peer-reviewed journal Neurology, Neuroimmunology & Neuroinflammation COYA 101 was well tolerated and increased Treg suppressive function The majority (6 out of 8) of patients either slowed or stopped progression (mean change of -2.7 points on ALSFRS-R score) during the open label extension over a 24-week period while 2 out of 8 patients did not benefit from treatment Assessment of biomarkers of inflammation and oxidative stress over the course of the study correlated with ALS disease severity and may serve to prospectively evaluate and/or monitor treatment response HOUSTON, Sept. 01, 2022 (GLOBE NEWSWIRE) -- Coya Therapeutics, Inc. (“Coya”), a clinical-stage biotechnology company developing multiple approaches that aim to enhance regulatory T cells (Tregs) function, including allogeneic Treg-derived exosome therapeutics and novel biologics, today announced the publication of the Phase 2a clinical trial data for its first-in-class Treg cell therapy product candidate, COYA 101. Coya has an exclusive worldwide license from Houston Methodist Hospital to develop, manufacture, and commercialize COYA 101. The article entitled “Combined Regulatory T-Lymphocyte and IL-2 Treatment is Safe, Tolerable, and Biologically Active for One Year in Persons with Amyotrophic Lateral Sclerosis” has been published online in the peer-reviewed journal Neurology, Neuroimmunology, & Neuroinflammation. Subjects enrolled in the Phase 2a trial were initially randomized into a double-blind portion to receive active Treg cells or matching placebo every four weeks over 24 weeks. After completion of the 24-week double-blind (DB) portion, subjects entered an open-label extension (OLE) during which all patients received active Treg cells every four weeks for additional 24 weeks. The DB portion of the trial was curtailed due to COVID-19-related restrictions, and the limited number of patients enrolled made statistical analysis not feasible. However, the eight patients included in the OLE completed the 24-week study, and 75% (n=6) of them exhibited slow to no progression as measured by the ALSFRS-R (mean decline of -2.7 points). A sub-analysis of these six patients showed that four of them (50% of the intention-to-treat [ITT] patient population, n=8) exhibited no decline over the 24-week treatment period. The two remaining patients in the OLE did not experience a treatment benefit. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a validated rating instrument that gauges the progression of disability in patients with amyotrophic lateral sclerosis (ALS) on a 48-point scale. In addition to the benefit experienced by the majority of patients in clinical function, Treg suppressive function was higher following infusions, compared to baseline values at screening. An unbiased proteomics assay of the OLE specimens documented that the two rapidly progressing patients had markedly higher levels of biomarkers of inflammation (IL-17F and IL-17C) and oxidative stress (OLR1 and ox-LDL) compared to the other six patients who exhibited amelioration or halting of disease progression, representing important findings that may provide new tools to identify the most suitable ALS patients for the next well-powered and well controlled trial. Overall, treatment with COYA 101 was well tolerated. No deaths were reported and no patient receiving Treg infusions were discontinued from the study. Howard Berman, Ph.D., Chief Executive Officer of Coya, stated, “We believe this Phase 2a study, with the limitations of a small sample size, supports that COYA 101 was well tolerated and biologically active in ALS patients and may slow or halt disease progression in the right patient population. We believe the findings that high levels of inflammation and oxidative stress may limit the effectiveness of Tregs, resulting in shorter cell half-lives and impacting their downstream suppressive anti-inflammatory effects, may help to better enhance the signal by prospectively identifying the patients with the higher likelihood to respond,” concluded Dr. Berman. “We are encouraged by the results from this study, which are consistent with the positive outcomes of the previous Phase 1 trial in ALS patients. We believe these results are relevant, as they provide information we need to design our next double-blind controlled study to assess the efficacy and safety of COYA 101,” added Adrian Hepner, M.D, Ph.D., President and Chief Medical Officer of Coya. Stanley H. Appel, M.D., the Chair of the Scientific Advisory Board of Coya, stated, “Although the double-blind portion of the Phase 2a study was compromised by COVID-19, we believe the Open Label Extension supports the findings of our Phase 1 study that COYA 101 infusions are well tolerated, may enhance suppressive functions and may have the potential to slow disease progression.” The online publication can be accessed at About Coya Therapeutics, Inc. Headquartered in Houston, TX, Coya Therapeutics, Inc. (Coya) is a clinical-stage biotechnology company developing approaches utilizing Treg modifying therapeutics to target systemic and neuro inflammation. Coya has pioneered the ability to produce Tregs with a highly suppressive phenotype (“Super Tregs”) from a patient’s own dysfunctional Tregs. "Super Tregs” confer their properties through reproducible upregulated proteins in the expanded/post cryopreserved condition that allow for an off-the-shelf like approach for serial infusion. Coya is also developing exosome therapies derived from “Super Tregs” for allogeneic applications, as well as a biologic that works to upregulate Treg function in vivo. Coya is focused on the advancement of disease modifying approaches to address the significant unmet medical needs of patients with Amyotrophic Lateral Sclerosis (ALS), Frontal Temporal Dementia (FTD), Scleroderma, and Hepatic Inflammation and Fibrosis. For more information, please visit . Contacts Investor Contact David Snyder david@coyatherapeutics.com Media Contact Jessica Starman media@coyatherapeutics.com