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Novartis Trial Validates Inflammasome As Chronic Disease Driver

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Novartis Trial Validates Inflammasome As Chronic Disease Driver NEWS Novartis trial validates inflammasome as chronic disease driver The dramatic finding that an antibody that the monoclonal antibody drug in 2009 for inhibits interleukin-1b (IL-1b) can reduce treating cryopyrin-associated periodic syn- the risk of heart attack and stroke is the first dromes (CAPS), a group of rare inherited clinical evidence that tackling the inflamma- disorders characterized by high levels of tory component of cardiovascular disease auto-inflammation and excessive IL-1b pro- can benefit patients. Drug maker Novartis duction. Most CAPS cases arise from activat- reported results from a mammoth trial test- ing mutations in one of the genes encoding ing Ilaris (canakinumab) in 10,061 patients NLRP3 inflammasome components. with inflammatory atherosclerosis and a Endogenous or environmental factors can prior history of heart attack at the European also overactivate the inflammasome, with Society of Cardiology Congress in Barcelona, pathological consequences. “Fundamentally, Spain, on August 27. Whether the magnitude the NLRP3 inflammasome is a crystallopathy of the effect observed in the Canakinumab detector. As we age, toxins build up in the Anti-inflammatory Thrombosis Outcomes body and form aggregates that cause chronic IFM Therapeutics Study (CANTOS) is sufficient to influence inflammation,” says Matt Cooper, CEO and clinical care is currently an open question. co-founder of Dublin-based Inflazome. Its Drugmakers are targeting the ‘inflammasome’ But the significance of these results extends triggers include uric acid crystals in the case (pictured), a multi-protein complex involved in low-grade inflammation and programmed cell beyond the immediate findings in cardiovas- of gout, cholesterol deposits in atherosclero- death. cular disease. They provide the first concrete sis, a-synuclein aggregation in Parkinson’s support for the general principle that tackling disease and Lewy body dementia, b-amyloid ‘sterile’—or low-grade, persistent—inflam- deposition in Alzheimer’s disease, and the vascular event” (defined as a composite of mation may improve outcomes in a range accumulation of drusen (sub-retinal fatty non-fatal heart attack, non-fatal stroke and of chronic diseases such as type 2 diabetes, deposits) in age-related macular degenera- cardiovascular death) by 15%, compared gout, osteoarthritis, Parkinson’s disease, tion. with placebo, in patients who were already Alzheimer’s disease, liver fibrosis and can- But so far, most IL-1b inhibitors have on cholesterol-lowering therapy, although cer. Because IL-1b production depends on gained approval only in niche indications it failed to provide a statistically significant the inflammasome, a series of multi-protein (Table 1). In conditions that affect larger survival benefit (New Engl. J. Med. http:// complexes involved in an inflammatory form populations, drug developers have struggled dx.doi.org/10.1056/NEJMoa1707914, 2017). of programmed cell death known as pyrop- to make headway. Six years ago, Novartis The drug’s cardiovascular effect was most tosis, some drugmakers are looking to target failed to convince a US Food and Drug pronounced in patients who also exhibited it directly. In light of the CANTOS results, Administration (FDA) advisory committee the sharpest drop in hsCRP. “The magni- this area of biomedical research has taken on that the risk–benefit profile of canakinumab tude of effect of Ilaris is in proportion to a new urgency. was favorable in gout. Around the same my own expectation of the contribution of Several biotech startups are already devel- time, Berkeley, California–based Xoma and inflammation to atherosclerosis,” says Jay oping molecules that target the inflamma- Suresnes, France–based Servier failed to Bradner, president of Novartis Institutes some, and they are focusing on the NOD-like achieve efficacy in a phase 2b trial of another for Biomedical Research (NIBR). Basel, receptor family pyrin-domain-containing IL-1b inhibitor, gevokizumab (Xoma 052), Switzerland–based Novartis plans to file for protein 3 (NLRP3) inflammasome in partic- in type 2 diabetes. CANTOS succeeded by FDA approval in cardiovascular disease in ular. New York–based Bristol-Myers Squibb including only patients with clinically sig- the current quarter. recently entered the field by acquiring one nificant inflammation—defined as a mini- Intriguingly, canakinumab also had dose- of these young companies, IFM Therapeutics mum of 2 mg/L high-sensitivity C-reactive dependent effects on lung cancer in the (Box 1). protein (hsCRP), an established biomarker individuals treated in CANTOS. Compared Interest in tackling chronic inflamma- for inflammation and cardiovascular disease with placebo, those on the highest dose had tion is booming, but Ilaris itself is not new. risk. The trial established that canakinumab a 67% reduction in lung cancer incidence and © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2017 Novartis initially gained the go-ahead for reduced the risk of a “major adverse cardio- a 77% reduction in death from lung cancer Table 1 Approved drugs targeting IL-1 Company Drug Description Approved indications Sales 2016 Novartis Ilaris Human IgG1 antibody targeting IL-1b CAPS; active systemic juvenile idiopathic $283 million arthritis; tumor-necrosis-factor-receptor- associated periodic syndrome; hyperimmu- noglobulin; familial Mediterranean fever Regeneron Arcalyst Fusion protein comprising ligand-binding domains CAPS $15.3 million Pharmaceuticals (rilonacept) of IL-1 receptor and IL-1 receptor accessory protein, (Tarrytown, New York) linked to human IgG1 Fc fragment Swedish Orphan Kineret Recombinant version of the human IL-1 receptor Rheumatoid arthritis; CAPS; neonatal onset SEK 1 billion Biovitrum (Stockholm) (anakinra) antagonist multisystem inflammatory disease ($125.9 million) Sources: FDA, company websites, SEC filings NATURE BIOTECHNOLOGY VOLUME 35 NUMBER 10 OCTOBER 2017 893 NEWS Box 1 BMS targets innate immune pathways through IFM acquisition Bristol-Myers Squibb’s acquisition of Boston-based IFM IFM co-founder and CEO Gary Glick. Their success, although Therapeutics for $300 million upfront, plus about $2 billion spectacular in some cases, is still limited. “Checkpoint more in potential milestones, represents a highly profitable and inhibitors only work for a small number of cancers, and even rapid exit for the company’s investors. IFM, which was formed within those tumors, for a small number of patients,” he says. in 2015, had raised $27 million in first-round funding in June Glick envisages using an NLRP3 agonist as an acute or 2016. The scale of the deal, which followed a highly competitive episodic therapy—its administration would not lead to the bidding process, is evidence of the intense level of interest chronic inflammation associated with ongoing inflammasome that is now being brought to bear on precision modulation activation. “No one else has an NLRP3 agonist program we’re of innate immune pathways. New York–based Bristol-Myers aware of,” he says. BMS has also gained options on earlier- Squibb (BMS) is picking up two preclinical programs at IFM, stage NRLP3 inflammasome antagonist programs in liver based on the development of STING (stimulator of interferon fibrosis, inflammatory bowel disease and gout—the IFM team genes) agonists and NLRP3 agonists. The goal of each is to will continue to develop these for now. IFM’s agonists and improve the response rates of immuno-oncology drug regimens antagonists are chemically distinct and interact with the NLRP3 by marrying an innate response to the adaptive responses that inflammasome in different ways. The company’s ability to drug are already activated by checkpoint inhibitors, such as BMS’s the complex in both directions was helped by its expertise in CTLA4 inhibitor Yervoy (ipilimumab) or its PD-1 inhibitor Opdivo inflammasome biology and structural biology, as well as by some (nivolumab). luck, Glick says. Both approaches are useful for further probing “Up until now we’ve only been working on the adaptive arm its function. “Being able to turn something on and being able to of the immune response with checkpoint inhibitors,” says turn something off is remarkably helpful.” (The Lancet http://dx.doi.org/10.1016/S0140- the structure and function of the NLRP3 of the University of California, San Diego, 6736(17)32247-X, 2017). The effect “is very inflammasome 15 years ago (Mol. Cell 10, is developing small-molecule inhibitors of compelling and is the opposite of a chance 417–426, 2002). It has proven a difficult tar- the NLRP3 inflammasome for treating non- finding,” Bradner says. Novartis will need to get for drug developers, but Cooper, who also alcoholic steatohepatitis (NASH) and liver confirm the result in a prospective trial before holds an academic post at the University of fibrosis. Nodthera, an Edinburgh-based it can seek approval in that indication as well. Queensland, in Brisbane, Australia, and joint venture between the Edinburgh-based Until it does so, some will remain skeptical. Inflazome co-founder and CSO Luke O’Neill, venture capital firm Epidarex Capital and “I don’t think this drug prevents lung can- of Trinity College, Dublin, galvanized the Selvita, a Krakow, Poland–based drug dis- cer,” says Charles Rudin, chief of the thoracic field by reporting that MCC950, a compound covery services company, has yet to reveal its oncology service at Memorial Sloan Kettering originally described by
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