GlaxoSmithKline's RIPK1 inhibitor dead on arrival

GSK CSO Hal Barron
GlaxoSmithKline's chief scientific officer Hal Barron (pictured) and CEO Emma Walmsley have been refocusing the company's pipeline. (GSK)

Just one year ago, encouraging preclinical data saw GlaxoSmithKline kick-start a new clinical test of its investigational RIPK1 inhibitor GSK095. Now, the drug’s test in a tough-to-beat cancer has been axed.

A brief line from its third-quarter financials posted this morning read: “GSK095 for pancreatic cancer was terminated as part of ongoing portfolio prioritisation.”

The drug had been designed to work in tandem with checkpoint-inhibiting medicines such as Keytruda and Opdivo in the hopes of empowering the immune system to launch a more aggressive attack against tumors than it does with checkpoint inhibitors alone.

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Early results from a preclinical trial of a related GSK drug suggested the combo could have promise in treating pancreatic cancer—so much so that the company last November launched a phase 1 study of the drug in combination with Merck’s blockbuster Keytruda.

GSK095 works by blocking the enzyme receptor-interacting serine/threonine-protein kinase 1 (RIP1), which is a key regulator of immune cells known as macrophages. These cells travel to tumors, but then they transform into cells that suppress the immune response rather than enhance it.

Pancreatic cancer is notoriously tough to beat and is associated with poor mortality and a growing pile of failed drugs to treat it. GSK did not offer any results on efficacy or safety from its press release nor on ClinicalTrials.gov. It simply reiterates: “The study was terminated following an internal review of the company's current research and development portfolio.” There was a little more detail from Hal Barron, GSK's CSO, on this: He said the drug wasn't completely dead yet on a call with analysts and journalists on Wednesday, and was headed back to the research phase to figure out where it may work.

RIP1 kinase inhibitors have already generated some excitement in biotech, particularly in central nervous system and inflammatory disease research. Last fall, Sanofi laid out $125 million for two RIP1 inhibitors being developed by Denali Therapeutics, including DNL747, which is in a phase 1 study in amyotrophic lateral sclerosis. In that case, Denali’s scientists believe that inhibiting RIP1 stops the production of inflammatory molecules in the body.

In GSK's phase 1 trial, GSK095 was slated to be given to pancreatic cancer patients as an oral drug twice a day. The company was recruiting 220 patients for the trial over two years and tested as both a monotherapy and in combination with Keytruda.

GSK also added in a pipeline update that it had “removed from phase 2” another drug, GSK2982772, also a RIP1k inhibitor, saying only that it had been “moved back to research.” It had been looked at in chronic inflammatory diseases.

On top of this, it has also confirmed the cuts of two other programs: A midstage Ebola drug that has now been “transferred to Sabin Vaccine Institute,” (which we knew about in August) and GSK2292767 (a PI3kd inhibitor), being tested in phase 1 for respiratory diseases.

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