17β-HSD13

Data to be presented at the EASL Congress 2024 demonstrate target coverage and a half-life suitable for once daily oral dosing Nonclinical data demonstrate lipidomic changes in rats consistent with features seen in humans carrying protective forms of the HSD17B13 gene BELLEVUE, Wash. & SAN DIEGO--(BUSINESS WIRE)-- Inipharm, a biopharmaceutical company focused on developing therapies for fibrotic liver diseases, today announced upcoming presentations of clinical and preclinical data from INI-822, the company’s Phase 1 small molecule inhibitor of HSD17B13, currently in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), also known as NASH. The data will be presented at the European Association for the Study of the Liver’s EASL Congress 2024, taking place June 5-8, 2024. Clinical data to be presented demonstrate that doses of INI-822 tested in healthy volunteers achieved plasma exposures that are anticipated to inhibit HSD17B13, a protein whose inactive variant is associated with protection from advanced forms of liver diseases such as MASH. In addition, exposures occurred with a half-life that will enable once daily oral dosing in future clinical studies of participants with MASH. “We are encouraged by the findings to date in healthy volunteers in our Phase 1 study as we move forward to the next portion of our trial, which will evaluate safety and pharmacokinetics in a cohort of MASH patients,” said Chuhan Chung, MD, chief medical officer of Inipharm. “While we have seen promising improvements in the MASH field, the opportunity to target HSD17B13 with an orally delivered small molecule drug remains highly relevant given the improved clinical outcomes associated with the HSD17B13 inactive variant.” Inipharm will also present data showing that that INI-822 treatment led to decreased levels of alanine transaminase (ALT), a biomarker indicative of liver damage, in rats fed CDAA-HFD, a diet known to rapidly induce MASH signs including increased liver enzyme levels. In addition, rats on CDAA-HFD diet treated with INI-822 demonstrated a dose-dependent increase in hepatic phosphatidylcholines (PCs), the major species of phospholipids that play a key role in cell membrane stability. These included PCs that have been shown to be elevated in liver biopsies from individuals with the inactive form of the HSD17B13 protein. Poster details: Abstract Title: Clinical pharmacokinetics of INI-822, a small molecule inhibitor of HSD17B13 Abstract Number: 1310 Abstract Title: Inhibition of HSD17B13 by INI-822 phenocopies the hepatic lipidomic pro humans with the protective allele Abstract Number: 932 About HSD17B13 and INI-822 Multiple human genetic association studies have confirmed that enzymatically inactive variants of the HSD17B13 protein are associated with a reduced risk of developing more advanced fibrotic disease in metabolic, alcoholic, and viral liver diseases. INI-822, a small molecule inhibitor of HSD17B13, is Inipharm’s first development candidate. About Inipharm Inipharm is a biopharmaceutical company focused on discovering and developing therapies for severe liver diseases. Inipharm’s lead programs are focused on the highly genetically validated target, HSD17B13. Extensive, consistent evidence that genetic variants in expression of HSD17B13 are associated with significantly lower rates and severity of multiple liver diseases. Building on these novel insights into the biologic activity of HSD17B13, Inipharm is advancing a pipeline of small-molecule therapies that target the activity of this protein.

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.