dapansutrile (OLT1177)

P2, N=300, Not yet recruiting, University Hospital, Basel, Switzerland | Initiation date: Nov 2023 --> Apr 2024

Gout flare involves multiple inflammatory mediators that may be used as potential therapeutic targets.

P2, N=2, Terminated, Olatec Therapeutics LLC | N=10 --> 2 | Recruiting --> Terminated; The study was terminated due to study design issues that did not allow for determination of efficacy and safety in subjects with Schnitzler Syndrome who are currently well controlled on anakinra therapy.

This was confirmed using an NLRP3 inhibitor, OLT1177, which revealed a similar beneficial effect in combating TNBC progression. Sch B treatment also inhibits IL-1β-induced EMT expression of TNBC cells, which may contribute to the anti-tumor response.

P2, N=300, Not yet recruiting, University Hospital, Basel, Switzerland | N=120 --> 300

P2/3, N=300, Recruiting, Olatec Therapeutics LLC | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Sep 2023 --> Oct 2024

This study provides novel molecular insights on how PDAC cells exploit NLRP3 activation to suppress CD8 T-cell activation. From a translational perspective, we demonstrate that the combination of gemcitabine with the orally active NLRP3 inhibitor OLT1177 increases the efficacy of monotherapy.

P1/2, N=26, Recruiting, April Salama, M.D. | Trial primary completion date: Apr 2023 --> Apr 2024

In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3.

Inhibition of NLRP3 with the small molecule OLT1177 reduced expression of Pdcd1l1 (p < 0.001), Casp1 (p < 0.01) and Il1b (p < 0.01) in primary tumors...These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers.

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.

Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth...These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.