PORCN

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.

On April 5, 2024, the final results of the first-in-human study of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in patients with advanced solid tumors were reported in 2024 AACR. RXC-004's R&D ProgressRXC-004 is a small molecule drug that targets the protein PORCN. RXC-004 has shown potential in treating various therapeutic areas, including neoplasms, digestive system disorders, endocrinology and metabolic diseases, and hemic and lymphatic diseases. According to the Patsnap Synapse, RXC-004 is currently in Phase 2, which is the highest phase of clinical development globally. And the clinical trial distributions for RXC-004 are primarily in the United States, United Kingdom and Australia. The key indication is Metastatic Microsatellite Stable Colorectal Carcinoma.  Detailed Clinical Result of RXC-004This non-randomized, sequential assignment, open-labeled clinical study (NCT03447470) was aimed to evacuate the efficacy and safety of RXC-004 in patients with advanced solid tumors.   In this study, module 1 investigated continuous monotherapy dosing, Module 2 investigated combination with nivolumab 480mg s.c. Q4W and Module 3 investigated intermittent monotherapy dosing (2 weeks on 1 week off). Patients received denosumab 120 mg s.c Q4W to prevent loss of bone mineral density (BMD), a known effect of Wnt inhibition. The primary objectives were safety and tolerability. Secondary objectives were PK and RECIST response. PD markers included on-treatment changes in: Wnt pathway and fibrosis biomarkers in paired skin biopsies; circulating immune subsets by flow cytometry; cytokine changes by Luminex, and changes in circulating-tumor DNA (ctDNA) levels by ddPCR. The result showed that in module 1, 25 patients (pts) with unselected advanced solid tumors (AST) received RXC004 between 0.5mg and 10mg QD. The RP2D was 2mg QD; at this dose the most common AEs were fatigue, diarrhoea, dysgeusia and decreased appetite; no grade 4/5 AEs or bone fragility events were reported whilst 1 pt had a RXC004-related grade 3 AE, 3 pts (50%) had a dose interruption and 1 had a dose reduction. The median T1/2 of RXC004 was 14.5h. 5 pts with upstream Wnt pathway activated tumors had stable disease (SD), in 1 case for 26 weeks with sustained reduction in ctDNA and no BMD loss. In Module 2, 14 patients with unselected AST received RXC004 at 1mg QD or 1.5mg QD with nivolumab. The AE profile was similar to Module 1. The RP2D was 1.5mg QD; at this dose 3 pts had a RXC004-related grade 3 AE, 6 pts (75%) had a dose interruption and 3 had a dose reduction, and 4 pts had SD. PK was similar to Module 1. In Module 3, 7 patients with upstream Wnt-activated AST received RXC004 2mg QD, 2 weeks on, 1 week off. The AE profile was similar to Modules 1 and 2. There were no RXC004-related Grade 3 AEs, 2 pts (29%) had a dose interruption and there were no dose reductions. PK and PD analyses confirmed time off target. 2 pts had SD; 1 pt with RSPO fusion small intestinal adenocarcinoma remained on treatment for 36 weeks, with sustained reduction in ctDNA and no BMD loss. It can be concluded that in patients with AST, RXC004 was safe and tolerated at doses up to 2mg QD as monotherapy and 1.5mg QD in combination with nivolumab, demonstrating differential disease control in upstream Wnt pathway activated tumours. Denosumab prevented loss of BMD. Intermittent RXC004 dosing was well tolerated with no detrimental impact on efficacy. How to Easily View the Clinical Results Using Synapse Database?If you want to know the other clinical results of popular conferences, please lick on the “Clinical Results” on the homepage of Patsnap Synapse, which provides multi-dimensional screening and filtering of drugs, indications, targets, companies, result evaluation, release date, popular conferences, etc. to help you quickly locate the data you need.  Select the clinical meeting you are interested in, such as ESMO. In the results, you can quickly locate the data you want to view by indication, phase and drug name.  A single result clearly shows important information such as registration number, phase, indication, Sponsor/Collaborator, biomarker, Trial number, dosing regimen and more.  If you would like to view more information about this result, you can go to the result detail page by clicking on the title.  Above the headings, we provide the original source of the outcome data. The basic information is supplemented with more information beyond the list, such as company, study. design, etc.  In the important Outcome Measures section, we provide both list and flowchart forms, which are convenient for you to overview the comparison group information and core indicator data.  Finally, if you need to download these results, you can conveniently check the check boxes on the left side of the list, or directly click the "Export" button to download the data for personalized analysis and file sharing. Click on the image below to embark on a brand new journey of drug discovery!