Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1), Parkinson's Disease (Phase 1)
Company: Inflazome Ltd.
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).
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.
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.
The company expects to begin a Phase 2 dose-finding trial in 2020 for CAPS. According to the company website, Inflazome is prioritizing development of inzomelid for CAPS, PD, AD, and amyotrophic lateral sclerosis.
Inflazome is also developing an NLRP3-targeted PET tracer, with funding from the Michael J. Fox Foundation (press release).
For details on inzomelid trials, see clinicaltrials.gov
Last Updated: 17 Apr 2020
- Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018 Oct;19(10):610-621. PubMed.
- Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008 Aug;9(8):857-65. PubMed.
- Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.
- Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, Griep A, Santarelli F, Brosseron F, Opitz S, Stunden J, Merten M, Kayed R, Golenbock DT, Blum D, Latz E, Buée L, Heneka MT. NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-673. Epub 2019 Nov 20 PubMed.
- Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Mar;21(3):248-55. Epub 2015 Feb 16 PubMed.
- Dempsey C, Rubio Araiz A, Bryson KJ, Finucane O, Larkin C, Mills EL, Robertson AA, Cooper MA, O'Neill LA, Lynch MA. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017 Mar;61:306-316. Epub 2016 Dec 18 PubMed.
- Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, Robertson AA, Butler MS, Rowe DB, O'Neill LA, Kanthasamy AG, Schroder K, Cooper MA, Woodruff TM. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018 Oct 31;10(465) PubMed.
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- Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AA, Atkin JD, Cooper MA, Schroder K, Yerbury JJ, Gordon R, Woodruff TM. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020 Feb;68(2):407-421. Epub 2019 Oct 9 PubMed.