Background

Selnoflast is an 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). According to company information, selnoflast does not enter the brain.

NLRP3 is a receptor for Aβ, and mediates the innate immune response to amyloid in microglia, cells involved in 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 data is published for selnoflast, also known as RO7486967. It is one of a series of compounds related to the NLRP3 inhibitor MCC950, which was shown to block inflammasome activation, promote microglial clearance of Aβ, reduce Aβ accumulation, and improve 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 developed and held the patent on MCC950 and related compounds.

Findings

From September 2019 to February 2020, Inflazome conducted Phase 1 single- and multiple-ascending-dose study of selnoflast in 64 healthy adults and 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. According to a February 2020 press release, the drug was safe and tolerable, with dose-proportional pharmacokinetics and pharmacodynamic effects.

In October 2020, Roche acquired Inflazome. The company abandoned a planned study of another NLRP3 inhibitor inzomelid/emlenoflast, and began developing selnoflast.

Starting in November 2021, Roche sponsored a Phase 1b study in 19 patients with ulcerative colitis, treated with 450 mg or placebo, once daily for seven days. Serum drug concentrations were claimed to exceed those required for 90 percent NLRP3 inhibition throughout the dosing period. Target engagement was confirmed by the diminished production of IL-1β by blood cells following ex-vivo LPS stimulation. Treatment did not change plasma IL-18, nor did it alter IL-1-related gene expression in colon tissue biopsies. Selnoflast-treated participants had more adverse events than those on placebo. None were serious; headache and indigestion were most common. The investigators concluded the drug was safe and well-tolerated, but unlikely to affect inflammation in patients with ulcerative colitis (Klughammer et al., 2023).

In September 2022, the company began a Phase 1b trial in 72 people with early Parkinson’s disease. The study, at 20 centers in Europe and the U.S., compares 28 days of RO7486967 to placebo against primary outcomes of adverse events and suicidality. Secondary outcomes are pharmacokinetics, and brain neuroinflammation measured by binding of the 18 kDa translocator protein (TSPO) PET ligand [18F]-DPA-714. The trial is expected to finish in January 2025.

Roche is running additional Phase 1b trials for asthma and coronary artery disease. A trial for chronic obstructive pulmonary disease finished in June 2022.

For details of these trials, search for selnoflast, RO7486967, or IZD-334 on clinicaltrials.gov and the International Clinical Trials Registry.