The Revolution in Inflammation Drug Development


Xconomy Boston — 

Chronic autoimmune and inflammatory diseases are painful and often lifelong conditions. I know this both as a scientist and a father, as my son, Jeremy, was diagnosed 12 years ago with Crohn’s disease, one type of inflammatory bowel disease (IBD). According to the National Institutes of Health, there are more than 80 autoimmune diseases affecting approximately 23.5 million Americans like Jeremy. Chronic inflammation related to other conditions such as non-alcoholic steatohepatitis (NASH), cardiovascular disease, and neurodegeneration including Alzheimer’s, could affect nearly 100 million others. Due to the clinical impact of inflammatory diseases and the shortcomings of existing therapies, now is the time to explore new pathways to treat patients.

Currently available treatments for autoimmune disorders and chronic inflammation have progressed significantly in terms of efficacy; however, these powerful medicines by nature lower the body’s immune response to infections. This, compounded with their high cost, narrows the risk-benefit ratio of this class of medicines. As a result, there is an increased demand for treatments that can precisely target inflammation, without leaving a patient’s immune system too weakened to fight harmful pathogens, which can include bacteria, viruses, and other microbes that can cause disease.

A new opportunity for both researchers and investors alike is drugs that target the innate immune system – our body’s first line of defense and the primary instigator of inflammation. The innate immune response relies on pattern-recognition receptors (PRRs) to detect pathogenic microbes and other harmful substances that may enter our bodies or form during tissue stress. “Inflammasomes” are newly identified PRRs that control the activation and release of powerful inflammation mediators. They are members of the IL-1beta family of cytokines and thus play an integral role in innate immunity.

One inflammasome in particular holds great promise as a target for new drugs – the NLRP3 inflammasome. Sometimes referred to as a “danger sensor,” the NLRP3 inflammasome detects damage to tissues and thereby protects against pathogenic threats. However, inappropriate activation of the NLRP3 inflammasome can also contribute to the onset and progression of various diseases such as cardiovascular disease, NASH, IBD, neurodegeneration and gout, as well as certain autoimmune and auto-inflammatory diseases.

Inappropriate activation of NLRP3 in the absence of a pathogenic threat can be caused by a host of triggers that include gain-of-function mutations of NLRP3 itself, an unhealthy environment or lifestyle (Western diet, inhaled particulate matter), substances that accumulate with age (for example, β amyloid aggregates or hyperphosphorylated Tau in the brain), and dysregulated metabolism (uric acid and cholesterol crystals). This process is called sterile inflammation.

Sterile inflammation caused by inappropriate NLRP3 activation has been documented in the brains of Alzheimer’s patients, highlighting NLRP3 as a potential target for neurodegenerative diseases. A 2018 report in BioCentury on Alzheimer’s targets stated that 50 percent of early stage trials and 57 percent of NIH funding is directed to new pathways in Alzheimer’s, including neuroinflammation. In neurodegenerative diseases where β amyloid (Aβ) deposition is a root cause of disease progression, a research study, conducted by IFM Therapeutics clinical advisory board member Michael Heneka and collaborators at the University of Bonn, found that when Aβ is deposited, it causes an innate immune response, subsequent activation of the NLRP3 inflammasome, which in turn leads to a feed-forward seeding of new Aβ plaques.

Recent studies have also shown the NLRP3 inflammasome has a critical role in the progression of NASH, which is projected to overtake hepatitis C as the leading cause of liver transplants in the U.S. by 2020.

The involvement of the NLRP3 inflammasome in such a range of diseases makes it a highly attractive drug target, providing the opportunity for a surgical strike at the underlying cause. At my company, IFM Therapeutics, we are developing small-molecule NLRP3 inflammasome antagonists that we plan to bring into the clinic beginning in 2019 for gout, NASH, Crohn’s disease, metabolic disease and Cryopyrin-associated periodic syndromes (CAPS), and in 2020 for Alzheimer’s disease. Unlike biologics, these orally available drugs may offer patients improved safety and efficacy, while being easier for patients to take and less costly to health systems than current therapies.

We are not alone in our excitement about this target: big pharma has taken notice, several biotech companies have formed around this concept, and academic research on NLRP3 has exploded. Searching PubMed using the term “NLRP3” shows just two papers published in the year 2002, ramping up to 870 in 2017. Based on April numbers, 2018 is on pace to have over 1,300 papers, and it seems that not a week goes by that a paper isn’t published linking NLRP3 activation to disease.

Beyond NLRP3, the pace of discovery in the immunology field is dizzying, and this is an exciting time to be a part of a new era of drug development in inflammation. Treatments for autoimmune diseases and chronic inflammation are a highly recognized area of opportunity and investment, and the discovery of the NLRP3 inflammasome and its potential as a therapeutic target have upped the ante. Over the next few years, we are likely to see revolutionary advances in this space.

Gary Glick is the CEO and co-founder of IFM Therapeutics, LLC, a Boston-based biopharmaceutical company developing a portfolio of first-in-class small molecules targeting the innate immune system for the treatment of inflammatory diseases. Follow @ifmthera

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