Background

NT-0796 is an oral, brain-penetrant inhibitor of inflammasomes that contain NLRP3, aka nod-like receptor family pyrin domain-containing protein 3. Inflammasomes are multiprotein, cytosolic complexes that function as sensors in the innate immune system. They are found in microglia in the brain, and in monocytes and macrophages outside the brain. Their activation by pathologic proteins and other stressors triggers production and secretion of the proinflammatory cytokines IL1-β and IL-18. Inflammasomes can induce cell death.

NLRP3-containing inflammasome activation is implicated in a growing number of neurodegenerative conditions where chronic inflammation plays a role, including Alzheimer’s and Parkinson’s diseases, as well as in obesity and cardiovascular disease (reviewed in Li et al., 2023).

In Alzheimer’s mouse models, inhibition of the NLRP3 inflammasome has been shown to reduce amyloid and tau pathology (Heneka et al., 2013; Ising et al., 2020).

NT-0796 inhibits NLRP3 inflammasome-mediated cytokine production in human blood with an IC50 of 6.8 nanomolar (Harrison et al., 2023). It enters the brain of mice with a blood-to-brain ratio of 0.79. NT-0796 is a prodrug that undergoes intracellular conversion to its active form in human immune cells. This activation does not occur in mice, which lack the necessary enzyme. A humanized mouse line was produced for pharmacokinetic and pharmacodynamic profiling of the compound (Smolak et al., 2024). In diet-induced obesity in these mice, NT-0796 caused weight loss as potently as did the GLP1 inhibitor semaglutide, and improved markers of cardiovascular risk (Thornton et al., 2024). It did not cause weight loss in non-obese mice.

Findings

From August 2021 to August 2022, NodThera ran a Phase 1 first-in-human study to assess safety and pharmacokinetics of NT-0796 in 76 healthy volunteers. Single ascending doses from 1 to 300 mg were given as a liquid formulation. Multiple MAD cohorts were planned based on results of the single-dose study, and included CSF sampling. Pharmacodynamic outcomes included inflammatory cytokines IL-1β, IL-18, IL-6, and TNFα in serum, and after ex vivo stimulation of blood cells from participants. In May 2022, the company reported the drug was safe after single dosing, and showed dose-proportional pharmacokinetics. Treatment lowered inflammatory cytokine levels in the ex vivo blood cell assay (press release). A September 2022 press release on the multiple-dose part of the study claimed brain penetration to levels higher than needed to achieve an anti-inflammatory effect, and a reduction in blood levels of the inflammatory biomarker C-reactive protein after treatment. No doses were specified, or data shown.

In 2023, the company began a Phase 1b/2a trial to measure the effect of NT-0796 on inflammatory and disease specific biomarkers in patients with Parkinson’s disease (press release). This trial does not appear in registries. According to NodThera, the first part of the study tested a new capsule formation in healthy volunteers, who received 150 mg twice a day for one week. A cohort with Parkinson’s disease received the same dose for four weeks. In a July 2023 press release, the company claimed significant reductions in inflammatory markers in CSF in four healthy volunteers after one week treatment. They also claimed a 13 percent reduction in CSF neurofilament light chain after one week.

Results of the completed trial were presented at the March 2024 AD/PD conference. The drug appeared safe. Adverse events were mainly mild, transient, and unrelated to drug. There were no serious adverse events. The capsule formulation extended the drug’s half-life compared to the liquid. CSF levels of drug in PD patients were two to three times higher than in elderly volunteers with the same plasma levels. After one or four weeks of treatment, patients had reductions in CSF IL-1, and IL-6, and a trend toward reduction in neurofilament light chain and soluble Trem2. Blood markers of peripheral inflammation were also reduced. Participants did not lose weight. The company is conducting long-term toxicology studies to facilitate a new trial.

In October 2023, NodThera began a Phase 1/2 trial to assess inflammation, weight loss, and safety in obese volunteers.

For details on the Phase 1 trial, see ANZCTR.org. For other trials, see clinicaltrials.gov.