DUBLIN – Inflazome Ltd. raised €40 million (US$45.3 million) in a series B round that will fund its push into clinical development in several indications in 2019.

The Dublin-based firm, which has led the way in targeting the NLRP3 [NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3)] inflammasome, is not yet disclosing its main clinical priorities, although its first-in-human trial will entail a pilot study of an oral NLRP3 inflammasome inhibitor in patients with cryopyrin-associated autoinflammatory syndrome (CAPS), a group of rare autoinflammatory diseases caused by activating mutations in the NLRP3 inflammasome. Inflazome has already demonstrated ex vivo activity in cells obtained from CAPS patients. It now plans to obtain technical proof of concept in patients, by demonstrating target engagement, while also building an understanding of its drug's pharmacokinetic and pharmacodynamic properties.

The NLRP3 inflammasome is an intracellular, pro-inflammatory molecular complex that undergoes assembly and activation in response to the build-up of toxic aggregates emanating from pathogens, the environment or the host. Its activity results in the maturation of the inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18 and, by a separate pathway, in the induction of pyroptosis, a form of inflammatory cell death. Its over-activation has been linked to a host of chronic diseases involving sterile inflammation, including: metabolic disorders such as type 2 diabetes, obesity and gout; neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease and Lewy body dementia; and sundry other conditions, including atherosclerosis, age-related macular degeneration and inflammatory bowel disease.

Inflazome's co-founders, CEO Matt Cooper and chief scientific officer Luke O'Neill, kick-started the emergence of the field by identifying a tool compound MCC-950 (originally a discarded Pfizer Inc. clinical candidate called CP-446,773) as the first molecule capable of potent NLRP3 inflammasome inhibition. After raising $17 million in series A funding in 2016, the company embarked on a substantial medicinal chemistry effort to further characterize MCC-950's mechanism of action and to identify molecules with superior drug-like properties to take forward into preclinical and clinical development.

"It's a very unusual target – it's very hard to drug obviously," Cooper told BioWorld. "It's an unusual mechanism of action." (See BioWorld Today, Sep. 12, 2016.)

Cooper, who also holds an academic post at the University of Queensland, in Brisbane, Australia, was a corresponding author on a paper published in the Oct. 31, 2018 issue of Science Translational Medicine, which reported that sub-nanomolar doses of MCC-950 abolished alpha-synuclein-mediated NLRP3 inflammasome activation in microglial cells of mice with a genetically induced form of Parkinson's disease and also prevented the extracellular release of an inflammasome adaptor protein with the unwieldy name apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). The latter forms ASC specks – large hydrophobic aggregates – which are released from cells after pyroptosis and, in Alzheimer's, were recently reported to seed the spread of amyloid beta deposition.

The Parkinson's pathology is also thought to spread to dopaminergic neurons in a prion-like fashion, suggesting a general downstream pathological mechanism for NLRP3 inflammasome activation. Cooper and colleagues also showed that MCC-950 had a neuroprotective effect in several rodent models of Parkinson's – it reduced the loss of dopaminergic neurons and improved motor performance.

Inflazome has at this point filed 29 patent applications on its work, but it is keeping its cards close to its chest in terms of a lead indication. Its medicinal chemistry work has enabled it to keep its options open.

"We're looking at a brain-penetrant series and a periphery-restricted series," Cooper said. It has more than one clinical candidate. The range of potential conditions it can address is wide – the company had 54 possibilities on its initial longlist, he said. "The key thing is which one you do first and why," he said. The company plans to conduct trials that will be relatively inexpensive, of short duration and that will offer unambiguous read-outs. "We're not going to do a Cantos 2 prophylaxis follow-up."

Novartis AG's landmark Cantos trial of Ilaris (canakinumab), the IL-1beta inhibitor already approved for treating CAPS, demonstrated that targeting the inflammatory aspects of cardiovascular disease in patients with significant levels of an inflammatory biomarker (high-sensitivity C reactive protein) reduced the risk of heart attack and stroke independently of lowering patients' lipid levels. The same trial also showed that those on canakinumab had a markedly lower risk of cancer than those on placebo – the effect was particularly pronounced in lung cancer. (See BioWorld, Aug. 29, 2017.)

Canakinumab treatment did not result in any survival benefit, however, as canakinumab therapy increased the risk of death from infection. This offset whatever improvement in mortality resulted from its cancer prevention effects. The FDA last month issued a complete response letter to an application from Novartis for approval in cardiovascular disease risk reduction, although the Basel, Switzerland-based pharma is prospectively evaluating canakinumab's potential in several phase III cancer trials.

Inflazome has, since its inception, maintained that targeting the NLRP3 inflammasome is a safer and more precise way of reducing chronic, sterile inflammation than eliminating all IL-1beta signaling. Selectively blocking the NLRP3 inflammasome, which is one of 14 intracellular inflammasomes, still permits the transient production of IL-1beta in response to acute infection, while damping down damaging chronic inflammation associated with NLRP3 inflammasome over-activation.

It's still an open question whether intervening will be beneficial when the associated pathological process has been underway for a decade or two. "That's always a concern with these diseases – that you're shutting the stable door after the horse has bolted, to use the classic analogy," O'Neill told BioWorld. "At worst, it won't restore function, but it will stop progression," he said.

But Cooper's work in Parkinson's models suggests that there are grounds for more optimism than that, he added.

Competition in the field of NLRP3 inflammasome inhibition is heating up. Cambridge, U.K.-based Nodthera Ltd. raised $40 million in a series A round earlier this year. A year after its sale to Bristol-Myers Squibb Co., Boston-based IFM Therapeutics LLC, a developer of Sting and NLRP3 inflammasome agonists, launched a new venture, IFM Tre, to focus on NLRP3 inflammasome antagonists. It raised $31 million in a series A round in July. San Diego-based Jecure Therapeutics Inc. took in $20 million last year to develop drugs for treating non-alcoholic steatohepatitis and liver fibrosis. Each of these companies is still preclinical, but New York-based Olatec Therapeutics LLC, is already in a phase II trials of dapansutrile (OLT-1177) in acute gout flares, cardiovascular disease and Schnitzler's Syndrome, a rare and late-onset inflammatory condition.

Inflazome's funding round "was heavily over-subscribed in Europe and the U.S.", Cooper said. Forbion, of Naarden, The Netherlands, led the financing. Longitude Capital of Menlo Park, Calif., also joined as a new investor, while founding investors Novartis Venture Fund and Fountain Healthcare Partners, of Dublin, also participated. Forbion's Marco Boorsma and Longitude's David Hirsch have joined the Inflazome board.

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