Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II–III Systolic Heart Failure

Wohlford, George; Tassell, Benjamin Van; Billingsley, Hayley; Kadariya, Dinesh; Canada, Justin M.; Carbone, Salvatore; Mihalick, Virginia; Bonaventura, Aldo; Vecchiè, Alessandra; Chiabrando, Juan Guido; Bressi, Edoardo; Thomas, Georgia; Ho, Ai-Chen; Marawan, Amr; Dell, Megan; Trankle, Cory R.; Turlington, Jeremy; Markley, Roshanak; Abbate, Antonio

doi:10.1097/fjc.0000000000000931

Cited by 81 publications

(42 citation statements)

References 38 publications

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“…Such a treatment offers an opportunity to reduce hospitalization and the need for supplemental oxygen, particularly in subjects with high risk co-morbidities. At the present time, OLT1177 (rINN dapansutrile) is the only orally active specific NLRP3 inhibitor (Marchetti et al 2018) that has shown efficacy in two inflammatory diseases, acute gout flares and heart failure (Kluck et al 2020, Wohlford et al 2020).…”

Section: Resultsmentioning

confidence: 99%

Targeting of the NLRP3 Inflammasome for early COVID-19

Marchetti

Mould

Tengesdal

et al. 2021

Preprint

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Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus 2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1α are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1β, triggering both local as well as systemic inflammation. This cascade of inflammatory cytokines in patients with COVID-19 is termed Cytokine Release Syndrome (CRS), and is associated with poor outcomes and death. Many studies reveal that blocking IL-1β activities in COVID-19 patients reduces disease severity and deaths. Here we report highly significant circulating levels of IL-1β, IL-1 Receptor antagonist, IL-6, TNFα, IL-10 and soluble urokinase plasminogen activator receptor in COVID-19 patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) early in the infection. We observed increased NLRP3 gene expression in myeloid cells correlated with IL-1β gene expression and also with elevated circulating IL-1β levels. We conclude that early in SARS-CoV-2 infection, NLRP3 activation takes place and initiates the CRS. Thus, NLRP3 is a target to reduce the organ damage of inflammatory cytokines of the CRS.

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Section: Resultsmentioning

confidence: 99%

Targeting of the NLRP3 Inflammasome for early COVID-19

Marchetti

Mould

Tengesdal

et al. 2021

Preprint

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“…In addition, oral OLT1177 administered to patients with acute gout flares significantly reduced joint pain as well as plasma cytokines IL-1β and IL-6 ( 19 ). In addition, OLT1177 was well tolerated and free of side effects in patients with heart failure; in the cohort receiving 2,000 mg daily, there was an improvement in left ventricular ejection fraction over 14 d ( 48 ). Being active orally and well-tolerated, these findings support the potential for OLT1177 to be tested in humans with early cognitive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Lonnemann

Hosseini

Marchetti

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

177

103

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Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer’s disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.

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“…Upadacitinib treatment in rheumatoid arthritis resulted in hepatic dysfunction in 7.6% of the patients ( 57 ). By comparison, patients treated with oral OLT1177 for gout flares ( 38 ) or heart failure ( 58 ) report no side effects but rather an increase in well-being.…”

Section: Discussionmentioning

confidence: 99%

Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression

et al. 2021

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Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL‐6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor. In vivo, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (p< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (p<0.01) and II6 expression by 53% (p<0.05). Disruption of tumor-derived NLRP3, either pharmacologically or genetically, reduced STAT3 signaling in bone marrow cells. In PMN-MDSCs isolated from tumor-bearing mice treated with OLT1177, we observed significant reductions in immunosuppressive genes such as Pdcd1l1, Arg1, Il10 and Tgfb1. In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1β induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs.

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Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II–III Systolic Heart Failure

Cited by 81 publications

References 38 publications

Targeting of the NLRP3 Inflammasome for early COVID-19

Targeting of the NLRP3 Inflammasome for early COVID-19

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression

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