DUBLIN – Roche Holding AG is taking a second shot on the NLRP3 inflammasome by acquiring Dublin-based Inflazome Ltd. for €380 million (US$447.8 million) up front plus undisclosed milestones linked to the progress of its two clinical-stage candidates inzomelid and somalix. In terms of cash on the table, the deal is the largest yet for a portfolio of drug candidates that acts on the NLRP3 inflammasome, and it represents a profitable exit for Inflazome’s investors, who put €55 million into the company over two funding rounds, in 2016 and in 2018.

The deal was agreed on August 7 and closed Sept. 18.

Initial discussions had been going on since last year, Inflazome’s vice president of business development Jeremy Skillington told BioWorld, but the company had been in dialogue with a wide range of potential buyers for some time. “We had laid a of groundwork,” he said.

Clinical data, inevitably, was key to the outcome. “We always knew there would be no deal without phase I data,” he said. “It did get competitive in the end. There were multiple offers on the table.”

Crucially, Inflazome managed to generate inzomelid patient data, on top of healthy volunteer data, before the lockdown. A single patient with cryopyrin associated periodic syndromes (Caps), a rare genetic inflammatory condition arising from a gain-of-function mutation in the NLRP3 gene, experienced a rapid reduction in disease flare shortly after receiving the drug and was in remission within a matter of days.

Given the direct relationship between the drug’s mechanism and the Caps pathology – it is caused by a gain-of-function mutation in the gene encoding the NLRP3 protein (NOD-, LRR- and pyrin domain-containing protein 3) – this was a key insight into the inzomelid’s potential and kick-started the acquisition process in earnest. “People were able to evaluate it appropriately then,” Skillington said. It also successfully completed a phase I study in healthy volunteers of somalix. “We’re phase II ready. It’s a question for Roche to decide and determine what to do next,” he said.

Inflazome has pursued a parallel discovery and development strategy from the outset. Inzomelid is brain-penetrant and is in development for Parkinson’s disease as well as Caps. It has received grant funding from the Michael J. Fox Foundation to develop a PET tracer to guide drug development in Parkinson’s. Somalix is peripherally restricted and was being lined up for a study in cardiovascular disease. This would build on the Ilaris (canakinumab) outcomes study, called Cantos, which Basel, Switzerland-based Novartis AG conducted. The big pharma firm found that its interleukin-beta-1 inhibitor reduced the rate of heart attack and stroke and but not mortality in high-risk patients who had previously experienced myocardial infarction.

Inflazome’s scientific founders have always maintained that targeting the NLRP3 inflammasome, instead of IL-1beta, offered a more comprehensive approach to tackling chronic conditions that have an inflammatory component. That’s because activation of the NLRP3 inflammasome – a pro-inflammatory cytosolic complex that assembles in response to the detection of microbial, environmental or endogenous danger signals – leads to maturation of IL-1beta and IL-18 and, by a separate pathway, to pyroptosis, a form of inflammatory programmed cell death. The mechanism is implicated in several dozen diseases.

CEO Matt Cooper and chief scientific officer Luke O’Neill, who hold academic posts at the University of Queensland, in Brisbane, Australia, and Trinity College Dublin, respectively, kick-started the initial industry effort to target the NLRP3 inflammasome by unpicking the mechanism of MCC-950, a discarded Pfizer Inc. drug candidate which the New York-based pharma firm had classified as an IL-1beta inhibitor. They reported in a paper, published online in Nature Medicine on Feb. 16, 2015, that it selectively blocked NLRP3 activation at nanomolar concentrations.

The present deal removes one of the few remaining independent biotechs focused on the mechanism, which has been a significant area of interest for big pharma. Basel-based Roche has already shelled out $100 million – according to its 2018 annual report – to acquire Jecure Therapeutics, which had been developing a portfolio of liver-targeted NLRP3 inflammasome inhibitors. Novartis last year acquired IFM Tre for $310 million plus $1.265 billion in milestones. Nodthera Ltd. Cambridge, U.K.-based Nodthera Ltd. is still independent, having raised $55 million over the summer to continue development of an early stage pipeline. Also this year, Natick, Mass.-based Ventus Therapeutics Inc. raised $60 million in series A funding to develop the next generation of NLRP3 inflammasome inhibitors, informed by structural biology research.

Inflazome’s investors include Forbion, Longitude Capital, Fountain Healthcare Partners and Novartis Venture Fund. For Dublin-based Fountain, a founding investor of Inflazome, the deal is its second biotech exit in successive months. It was also an investor in Stevenage, U.K.-based Kandy Therapeutics Ltd., which Leverkusen, Germany-based Bayer AG acquired last month for $425 million up front.

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