LONDON – The Parkinson's disease charity Michael J Fox Foundation (MJFF) is funding Inflazome Ltd. to develop a PET tracer to show if the company's orally available compounds are engaging NLRP3 inflammasome targets in the brain.

The tracer also will make it possible to select patients at the appropriate stages of neurodegenerative diseases for inclusion in trials and to help select doses. It could eventually be used as a diagnostic.

Matt Cooper, CEO and co-founder of Inflazome, said the company already has laid the ground for development of the PET tracer, which will take 18 months to two years to complete.

"It's definitely doable, hence the support from MJFF," he told BioWorld. "It would be for use in clinical trials and would also be a commercial product."

MJFF is putting more than $1 million into work on the PET tracer, which in addition to Parkinson's disease would be relevant to other inflammasome driven diseases, including Alzheimer's, epilepsy, multiple sclerosis and rare inherited neurodegenerative diseases, and also for assessing the impact of traumatic brain injury.

Inflammasomes are large multiprotein complexes which assemble in the cell cytoplasm in response to infection, cellular injury or autoimmune perturbations. Although an essential part of the innate immune response, overactivation is the cause of chronic inflammation.

NLRP3 (NOD-like receptor family, pyrin-domain containing protein 3) is one of 14 related proinflammatory protein complexes. Its assembly activates the proteolytic enzyme caspase-1, leading to the production of proinflammatory cytokines IL-1beta and IL-18 via one pathway, and going by a different route, to programmed cell death through pyroptosis.

Alongside the PET tracer, Dublin-based Inflazome is funding the development of blood and cerebrospinal fluid tests for diagnosing disease and monitoring response to NLRP3 inhibition. These tests will be based on picking up inflammasome proteins that have been released following pyroptosis.

Cooper hopes the PET tracer will be ready for Inflazome's first clinical trial in the rare autoinflammatory disease cryopyrin-associated autoinflammatory syndrome (CAPS), to help in assessing the correct dose. "It would be very, very useful, though we will still run the trial without it, we won't wait for it," he said.

Inflazome has demonstrated it can inhibit NLRP3 in the cells of CAPS patients in vitro, and safety aside, the first-in-human study is intended to demonstrate target engagement and assess the pharmacokinetics.

While Inflazome is using CAPS as a pathfinder, it also has carried out preclinical research in Parkinson's disease, validating NLRP3 as a target by showing inhibition can block inflammation in microglia, the immune cells of the brain, in a mouse model of Parkinson's.

The inhibitors also prevent inflammasome proteins from being released as a result of pyroptosis, breaking the cycle of chronic inflammation.

That finding also is important because extracellular inflammasome proteins recently have been implicated in amyloid beta deposition in Alzheimer's disease.

In other rodent models of Parkinson's, Inflazome has shown NLRP3 inhibition has a neuroprotective effect, reducing the loss of dopaminergic neurons and improving motor performance.

Funding for the research to validate NLRP3 in Parkinson's disease also came from MJFF, with the charity Shake It Up Australia.

Although it is hoped the PET tracer will help with selection of patients for clinical trials, it is not known at what point in the etiology of Parkinson's or any other neurodegenerative disease NLRP3 inhibition will be effective.

"We won't know what stage it is relevant to until we do phase II," Cooper said.

After the announcement last week of yet another failure in Alzheimer's, with Biogen Inc. and Eisai Co. Ltd. pulling their amyloid beta neutralizing drug aducanumab, there is a dire requirement for new targets in the disease, Cooper said.

"The field recognizes we need to look to mechanisms beyond tau and abeta," he said.

Rather than focusing on a single toxic protein, addressing over activation of microglia could prevent chronic inflammation and restore the protective role of microglia in cellular housekeeping.

"What we are doing is different," Cooper said. "But it doesn't mean it is going to work."

Last November Inflazome raised $45.3 million in a series B to begin clinical development. Following the round it appointed one of the leaders of the field, Thomas Jung, as chief medical officer. Jung led the clinical development of Novartis AG's Illaris (canakinumab) in the treatment of CAPS and was central to the expansion of the IL-1beta inhibitor into other indications, including cardiovascular disease.

Novartis' trial of Illaris in targeting the inflammatory aspects of cardiovascular disease showed it reduced the risk of heart attack and stroke, independently of blood lipid levels. However, there was no survival benefit because Illaris raised the risk of death from infection. (See BioWorld, Aug. 29, 2017.)

Production of interleukin-1beta is driven by multiple inflammasomes. Inflazome says that as an alternative, inhibition of NLRP3 will be safer, leaving other inflammasomes at the ready to respond to infection. In addition, as orally available treatments, its drugs could be withdrawn in case of a severe infection.