Background

Inzomelid is an oral, brain-penetrant inhibitor of inflammasomes containing NLRP3, or nod-like receptor family, pyrin domain-containing protein 3. Inflammasomes are multiprotein, cytosolic complexes that function as sensors in the innate immune system. Their activation by pathologic proteins and other stressors triggers production and secretion of proinflammatory cytokines IL1-β and IL-18, and can induce cell death. NLRP3-containing inflammasome activation occurs in many conditions where chronic inflammation plays a role, including Alzheimer’s and Parkinson’s diseases (reviewed in Heneka et al., 2018). Multiple NLRP3 inhibitors are in clinical trials for a range of inflammatory diseases (Li et al., 2023).

NLRP3 is a receptor for Aβ, and mediates the innate immune response to amyloid in microglia, cells involved Alzheimer’s pathogenesis (Halle et al., 2008). Deleting NLRP3 in the APP/PS1 mouse model diminishes Aβ deposition, synapse loss, and memory deficits (Heneka et al., 2013). Loss of NLRP3 also prevents tau tangle formation in human tau-expressing mice in response to injected Aβ (Ising et al., 2019).

No preclinical studies using inzomelid are published. However, a related NLRP3 inhibitor, MCC950, blocked inflammasome activation, promoted microglial clearance of Aβ, reduced Aβ accumulation, and improved cognitive function in APP/PS1 mice (Coll et al., 2015; Dempsey et al., 2017). MCC950 also prevented inflammasome activation by fibrillar α-synuclein, and led to less neuron loss and better dopaminergic signaling in Parkinson’s disease models (Gordon et al., 2018). The scientists behind these studies founded Inflazome, which holds patents on MCC950 and related compounds.

Findings

In March 2020, Inflazome announced completion of a Phase 1 trial of inzomelid in healthy adults and in patients with Cryopyrin-associated periodic syndrome. CAPS is an autoimmune disease caused by gain-of-function mutations in the NLRP3 gene, and affects both peripheral organs and the central nervous system. The trial enrolled 80 participants. Healthy adults received single or multiple ascending doses or placebo. CAPS patients received drug per an open-label protocol. Primary endpoints were safety, tolerability, and blood pharmacokinetics; Secondary outcomes were a pharmacodynamic marker of NLRP3 inhibition in blood, and reduction in CAPS symptoms in patients.

In a March 26, 2020, press release, Inflazome announced a linear relationship between dose and blood levels of drug and a correlation with NLRP3 activity. No data were provided. The release stated that the drug was safe and tolerable, and claimed that one CAPS patient showed rapid improvement after taking inzomelid, on unspecified clinical parameters. According to the company website, Inflazome was prioritizing development of inzomelid for CAPS, PD, AD, and amyotrophic lateral sclerosis.

In April 2020, the company registered a Phase 1 dose-escalation study in people with Parkinson’s disease. The study was to enroll six patients, starting in October 2020. The same month, Roche acquired Inflazome (C&EN News) and withdrew the Phase 1 Parkinson’s trial in December, before it began, citing business reasons.

Roche is currently developing the related NLRP3 inhibitor selnoflast.

Before the company’s acquisition, Inflazome was also developing an NLRP3-targeted PET tracer, with funding from the Michael J. Fox Foundation (press release). No further information has been made public on that effort.

For details on inzomelid trials, see clinicaltrials.gov