Jump to content

DFV890

Add links
From Wikipedia, the free encyclopedia

DFV890
Identifiers
  • 2-[amino-[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-oxo-λ6-sulfanylidene]-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide
PubChem CID
IUPHAR/BPS
DrugBank
Chemical and physical data
FormulaC20H25N3O3S2
Molar mass419.56 g·mol−1
3D model (JSmol)
  • CC(C)(C1=CN=C(S1)S(=CC(=O)NC2=C3CCCC3=CC4=C2CCC4)(=O)N)O
  • InChI=1S/C20H25N3O3S2/c1-20(2,25)16-10-22-19(27-16)28(21,26)11-17(24)23-18-14-7-3-5-12(14)9-13-6-4-8-15(13)18/h9-11,25H,3-8H2,1-2H3,(H2,21,26)(H,23,24)
  • Key:YWPGNFRBLUSVFW-UHFFFAOYSA-N

DFV890 is an investigational new drug that Novartis is developing to treat conditions where the NLRP3 inflammasome is too active. These conditions include COVID-19-associated acute respiratory distress syndrome (CARDS), osteoarthritis, and blood disorders like myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).[1][2][3][4]

DFV890 specifically targets the NLRP3 protein, a key component of the NLRP3 inflammasome complex, which is an important part of the innate immune system. This helps lower the production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18, which are involved in many inflammatory and autoimmune diseases.

Mechanism of action

[edit]

DFV890 is a small-molecule oral inhibitor of the NLRP3 inflammasome, a multiprotein complex that activates caspase-1, which in turn triggers the production and release of pro-inflammatory cytokines IL-1β and IL-18. By blocking NLRP3, DFV890 helps reduce inflammation linked to conditions such as metabolic disorders, autoimmune diseases, and the cytokine storm seen in severe infections like COVID-19.

Pharmacokinetics

[edit]

Pharmacokinetic studies show that DFV890 is generally well-tolerated, with dose-dependent exposure. However, early crystalline suspensions of the drug produced less-than-expected increases in exposure with higher doses. This issue was resolved by switching to a spray-dried dispersion (SDD) formulation. Mild decreases in neutrophil and leukocyte counts were observed, but these were not clinically significant and are consistent with DFV890’s effect on IL-1β signaling.[1][2][3][4]

Development history

[edit]

DFV890 underwent its first-in-human study to evaluate safety, tolerability, and pharmacokinetics in healthy volunteers. The Phase I trial, registered under EudraCT 2018-004402-26, included single ascending doses (SAD, 3–600 mg) and multiple ascending doses (MAD, 10–200 mg once daily or 25–50 mg twice daily) in 122 participants, randomized 3:1 to DFV890 or placebo. No serious adverse events or deaths were reported. The study introduced real-time manufacturing (Translational Pharmaceutics) for flexible dosing, transitioning from crystalline to SDD formulations to improve exposure at higher doses.[5]

Clinical trials

[edit]

COVID-19

[edit]

A Phase IIa randomized, multinational trial (NCT04382053) tested DFV890 (50 mg twice daily) plus standard-of-care (SoC) versus SoC alone in 143 hospitalized patients with COVID-19-associated pneumonia and impaired respiratory function from May 27 to December 24, 2020. The primary endpoint, APACHE II score at Day 14 or discharge, did not show statistical superiority over SoC. However, DFV890 was associated with faster SARS-CoV-2 clearance (by Day 7), improved clinical status, fewer fatal events, and numerically better in-hospital outcomes. The drug was well-tolerated, supporting its potential as a protective therapy for CARDS.[6][7][8]

Osteoarthritis

[edit]

A Phase II double-blinded trial (NCT04886258, EudraCT 2020-006104-17) assessed DFV890’s efficacy, safety, and tolerability in participants with symptomatic knee osteoarthritis. Doses of 10 mg and 25 mg twice daily were evaluated, with primary endpoints including change in Knee Injury and Osteoarthritis Outcome Score (KOOS). The study, conducted across multiple sites, aimed to determine DFV890’s ability to reduce knee pain.[3][9][10][11]

DFV890’s potential as a first-in-class NLRP3 inhibitor is under exploration for additional inflammatory and autoimmune conditions, given NLRP3’s role in diseases like multiple sclerosis, inflammatory bowel disease, and metabolic disorders.[12][13]

References

[edit]
  1. ^ a b Gatlik E, Mehes B, Voltz E, Sommer U, Tritto E, Lestini G, et al. (May 2024). "First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor". Clinical and Translational Science. 17 (5): e13789. doi:10.1111/cts.13789. ISSN 1752-8062. PMC 11101992. PMID 38761014.
  2. ^ a b Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJ, Rendon A, et al. (June 2023). "DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function". Infection. 51 (3): 641–654. doi:10.1007/s15010-022-01904-w. ISSN 1439-0973. PMC 9473473. PMID 36104613.
  3. ^ a b c "Dose Optimization and Expansion Study of DFV890 in Adult Patients With Myeloid Diseases". Novartis. Retrieved 2025-05-27.
  4. ^ a b Novartis Pharmaceuticals (2025-05-15). A Phase 1b, Open Label, Multi-center, Dose Optimization and Dose Expansion Study to Assess the Safety and Efficacy of DFV890 in Adult Patients With Myeloid Diseases (Report). clinicaltrials.gov.
  5. ^ Gatlik E, Mehes B, Voltz E, Sommer U, Tritto E, Lestini G, et al. (May 2024). "First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor". Clinical and Translational Science. 17 (5): e13789. doi:10.1111/cts.13789. ISSN 1752-8062. PMC 11101992. PMID 38761014.
  6. ^ Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJ, Rendon A, et al. (June 2023). "DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function". Infection. 51 (3): 641–654. doi:10.1007/s15010-022-01904-w. ISSN 1439-0973. PMC 9473473. PMID 36104613.
  7. ^ Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJ, Rendon A, et al. (June 2023). "DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function". Infection. 51 (3): 641–654. doi:10.1007/s15010-022-01904-w. ISSN 1439-0973. PMC 9473473. PMID 36104613.
  8. ^ Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJ, Rendon A, et al. (June 2023). "DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function". Infection. 51 (3): 641–654. doi:10.1007/s15010-022-01904-w. ISSN 1439-0973. PMC 9473473. PMID 36104613.
  9. ^ Sherlock M (2023-03-13). "DFV890 (NLRP3 inhibitor)". Molecular Sherlock. Retrieved 2025-05-27.
  10. ^ "DFV890 in Symptomatic Knee Osteoarthritis - Clinical Trials Registry - ICH GCP". ichgcp.net. Retrieved 2025-05-27.
  11. ^ "DFV890 in Symptomatic Knee Osteoarthritis - Clinical Trials Registry - ICH GCP". ichgcp.net. Retrieved 2025-05-27.
  12. ^ Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJ, Rendon A, et al. (2023-06-01). "DFV890: a new oral NLRP3 inhibitor—tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function". Infection. 51 (3): 641–654. doi:10.1007/s15010-022-01904-w. ISSN 1439-0973. PMC 9473473. PMID 36104613.
  13. ^ Gatlik E, Mehes B, Voltz E, Sommer U, Tritto E, Lestini G, et al. (May 2024). "First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor". Clinical and Translational Science. 17 (5): e13789. doi:10.1111/cts.13789. ISSN 1752-8062. PMC 11101992. PMID 38761014.
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=DFV890&oldid=1292635456"