Switching off chronic inflammation

Two drug candidates designed to turn off a key molecular mechanism that promotes inflammation are in human clinical trials. The two treatments are being developed at Inflazome, a startup based on intellectual property discovered at The University of Queensland (UQ) and Trinity College Dublin.

Professor Kate Schroder, one of the inventors on the patents licensed to Inflazome by UniQuest, UQ's technology transfer company, has been working toward these treatments since she first helped identify the molecule that led to their development. Schroder is director of the Centre for Inflammation and Disease Research at UQ’s Institute for Molecular Bioscience, and she says she’s excited by the potential of the new drug candidates. “It’s not often that your research contributes to a drug development programme that progresses from the discovery of a promising molecule all the way to clinical development,” she says.

The two treatments being developed by Inflazome are aimed at different groups of conditions. According to Inflazome, Inzomelid has been developed to reach the brain and treat neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease. Somalix is peripherally restricted and intended for the treatment of inflammatory conditions such as cardiovascular disease and arthritis. Inflazome is also developing tissue-specific inhibitors for inflammatory bowel disease (IBD) and dermatological diseases.

Initial results from the trials evaluating the drugs’ safety are expected by March 2020. Positive results will lead to the progression of the drug candidates into multiple Phase II studies focusing on specific diseases.

The potential to treat a number of important diseases is significant, says Schroder. Swelling, heat and pain are the three most common signs of acute inflammation, as immune cells try to fix an injury or infection. But, if the response doesn’t switch off once a health threat has been resolved, chronic inflammation can contribute to a huge number of common diseases, including cancer, asthma, diabetes and neurodegeneration.

A key driver of inflammation is the inflammasome, a protein complex that assembles within cells when a pathogen or cellular disruption is detected. Inflammasomes activate the protein-cleaving enzyme caspase 1, which leads to the release of two strong pro-inflammatory molecules, interleukin-1β (IL-1β) and IL-18. Caspase 1 also cleaves the protein gasdermin-D, which then forms pores in a cell’s membrane, often causing a type of cell death known as pyroptosis.

In 2015, in collaboration with The University of Queensland’s Professor Matt Cooper, Professor Avril Robertson and Dr Rebecca Coll, as well as Trinity College Dublin’s Professor Luke O’Neill, Schroder examined an inhibitor of interleukin-1 release. It turned out that the compound, MCC950 (also known as CP-456,773 and CRID-3) is a potent inhibitor of a type of inflammasome called NLRP3.

The team showed that MCC950 prevented the assembly of the NLRP3 inflammasome in mouse cells exposed to a bacterial toxin and blocked IL-1β secretion and cell death by pyroptosis. In mice, MCC950 was also shown to ameliorate the symptoms of Muckle–Wells syndrome, a rare auto-inflammatory condition caused by the overactivation of NLRP3 and characterised by episodes of rash, fever, and joint pain, as well as hearing loss and kidney damage. MCC950 also blocks NLRP3 responses in blood cells from individuals with the disease.

“These results generated a lot of excitement in the field,” says Schroder. “MCC950 was the most potent NLRP3 inhibitor that had been published at the time.”

Since then, MCC950 has been shown to have a positive effect on chronic liver disease and Parkinson’s disease in mouse models, without causing major side effects. Yet, until recently, little was known about its specific mechanism of action. In the first half of 2019, Schroder and her colleagues identified that MCC950 directly binds to NLRP3 and blocks its enzymatic activity, essentially locking NLRP3 in an inactive form.

“While MCC950 isn’t ideal for clinical trials, understanding how MCC950 works has resulted in a flurry of activity to generate NLRP3 inhibitors for clinical development, with a number of pharmaceutical companies initiating or acquiring NLRP3 inhibitor programmes,” says Schroder.

She is optimistic about the potential of NLRP3 inhibitors. While several biologic agents that block IL-1β are currently approved for therapeutic use, blocking IL-1β alone only addresses one of the pathways important for NLRP3-driven diseases. In contrast, compounds that target the NLRP3 inflammasome pathway, such as Inflazome’s clinical compounds, should be more efficacious.

“By targeting the particular signalling pathway that is driving harmful inflammation, NLRP3 inhibitors offer a new way to control inflammation,” says Schroder.