Setanaxib

Setanaxib (development code GKT-831) is an experimental orally bioavailable dual inhibitor of NADPH oxidase isoforms NOX4 and NOX1. Setanaxib is a member of the pyrazolopyridine dione chemical series. The compound is the only specific NOX inhibitor that has entered into clinical trials.

Setanaxib
Clinical data
Other namesGKT-831
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H19ClN4O2
Molar mass394.86 g·mol−1
3D model (JSmol)

Setanaxib, despite having demonstrated biological activity in a number of in vitro and in vivo animal pharmacological models[1][2][3][4][5][6][7] including diabetic nephropathy, retinopathy, atherosclerosis, liver fibrosis, osteoporosis, pulmonary hypertension and idiopathic pulmonary fibrosis, has failed two subsequent phase 2 clinical trials proof-of-concept studies in human.

Setanaxib is currently developed by Genkyotex, a French biotech company based in Archamps.

Development strategy

The strategy of development of setanaxib was initially focused on the treatment of fibrosis and particularly idiopathic pulmonary fibrosis (IPF), a life-threatening disease. Setanaxib obtained orphan drug designation from regulatory agencies in the US and EU in early 2010.[8] Despite excellent in vitro and in vivo pharmacology results obtained in preclinical animal pharmacological models of fibrosis and IPF, and promising phase 1 data showing low toxicity of setanaxib, the company Genkyotex decided to initiate a phase 2 Proof-of-concept in the complex indication of diabetic nephropathy in 2014. As a result, setanaxib did not reach the primary clinical endpoint and the compound failed to make any significant reduction in albuminuria.[9] Thereafter, the company decided to refocus development to initial clinical applications in fibrosis. But in May 2019, setanaxib failed again to reach primary and secondary endpoints in a second phase 2 in patients with primary biliary cholangitis, demonstrating much lower potency than Intercept’s compound Ocaliva, the only drug marketed for PBC so far. These cumulated disappointing clinical data confirm a major issue with setanaxib that clearly lack potency in human.[10]

History

Setanaxib was discovered in the early 2000s by scientists at Genkyotex and was patented in 2007.[11] Setanaxib was initially developed for idiopathic pulmonary fibrosis and obtained orphan drug designation both by FDA and EMEA by end of 2010.[12] Setanaxib was developed by rational drug design following a campaign of high-throughput screening on several NOX isoforms. The initial lead compound GKT136901, a pyrazolopyridine dione derivative was further structurally modified in order to enhance binding affinity and improve pharmacokinetic properties, resulting in the discovery of setanaxib. In 2014, following a reorganization the company did get reed of the research team that discovered setanaxib. Since then no additional compound was discovered by the company despite major investments and attempts with GKT-771, a compound that failed to initiate clinical trials.[13].

Clinical trials

Development of setanaxib candidate showed promise in Phase I clinical trial in healthy volunteers with no adverse effects. However, setanaxib failed its Phase 2 trial in diabetic nephropathy (DN) and did not reach the primary clinical endpoint, making no significant reduction in albuminuria and ending further development for DN.[14] In a second phase 2 trial in primary biliary cholangitis published in May 2019, setanaxib failed again to meet both primary and secondary efficacy endpoints. The compound showed no effect in the 400 mg daily group and a very weak effect in the high dose group of twice 400 mg daily. The 111-patient study tested two doses of setanaxib, 400 mg once daily and 400 mg twice daily, versus placebo. It did not meet its primary endpoint, the percentage change in serum gamma-glutamyl transferase (GGT) at 24 weeks. Genkyotex claimed to show a reduction in ALP with setanaxib, with a nominal p-value of 0.002. However, this analysis took into account the entire treatment period, and in fact, the results were distinctly weaker using only data from the 24-week timepoint. The compound showed 22% reduction in liver stiffness seen with the twice-daily dose of setanaxib, versus a 4% increase with placebo. Liver stiffness, which was measured using noninvasive transient elastography, is an indicator of fibrosis. This was a prespecfied endpoint, but it featured low down in a list of 27 secondary outcomes. In any case, statistical significance was not reached and such findings can only be considered exploratory. A bigger red flag is the fact that the data touted by Genkyotex came from a subgroup of 45 patients who had baseline liver stiffness levels of 9.6kPa or greater, indicating stage 3 fibrosis or higher. Across the entire trial cohort, the liver stiffness data were much less impressive. Overall, setanaxib showed sub-optimal data for two proof-of-concept phase 2 clinical trials that question the future of this compound.[15].

Toxicity and potential risks

Setanaxib did not show any signs of toxicity in phase 1 clinical trials in healthy volunteers. However, the compound is bearing an aniline moiety known to be associated with risks of unpredictable idiosyncratic toxicity.[16]. Indeed, in the paper from Kalgutkar[17], the author analysed toxicity trends associated with the aniline structural alert in the top 200 prescribed drugs and recently approved (2009-2013) small molecule drugs. The authors found that the toxic anilines were the one for which the daily dose-drugs were the ones with higher daily doses (exceeding 100 mg). Current clinical data with setanaxib demonstrates that weak activity in human is found with a very high dose of 2 x 400 mg daily, which classify setanaxib has an aniline-based compound with a high risk of idiosyncratic toxicity particularly in a large population of patients such as metabolic disease or fibrosis.

Challenges and future perspectives of the therapeutic concept of Nox inhibition

With the multiple failures of setanaxib in clinical trials proof-of-concept, the concept of developing Nox inhibitors with the objective of treating potential diseases is now becoming extremely weak. The effects of antioxidants or scavengers in clinical trials has always been very disappointing in human clinical trials in many diseases[18] and as a result, no antioxidative therapy reached the market due to failed clinical trials. Setanaxib is claimed to act through a different mechanism of action than standard antioxidants or scavengers. However, setanaxib owns similar features than standard antioxidants. Indeed, the compound requires a very high dose in human (2 x 400 mg once-a-day) in order to demonstrate very little or no pharmacological effect. Also, the compound has scavenging activity similarly to standard antioxidants. Indeed, GKT136901 a strongly similar chemical analogue of setanaxib was found to be a selective scavenger of peroxinitrite.[19] Setanaxib demonstrated a great ability to treat rodents in a number of animal pharmacological models similarly to standard antioxidants. However, all of those antioxidant compounds failed in treating human diseases, similarly setanaxib did fail to repeat pharmacological effects in human clinical trials. The multiple failures of the lonely Nox Inhibitor setanaxib should hamper the future of the concept of Nox inhibition which is not identified as a hot topic by large pharmaceutical companies and major biotech partners. Genkyotex remains the lonely company developing Nox inhibitor with currently little future perspectives. On the other hand, if the hypothesis of testing NOX has only been addressed with suboptimal compounds such as setanaxib, or compounds with various chemical liabilities, the hypothesis has not yet been tested properly. Thus, future research should focus on creating genuine target-engaging NOX inhibitors, which can be used as probes and drug leads to properly test the NOX inhibition hypothesis.

References
  1. Deliyanti D, Wilkinson-Berka JL (July 2015). "Inhibition of NOX1/4 with GKT137831: a potential novel treatment to attenuate neuroglial cell inflammation in the retina". Journal of Neuroinflammation. 12: 136. doi:10.1186/s12974-015-0363-z. PMC 4518508. PMID 26219952.
  2. Somanna NK, Valente AJ, Krenz M, Fay WP, Delafontaine P, Chandrasekar B (May 2016). "The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4". Journal of Cellular Physiology. 231 (5): 1130–41. doi:10.1002/jcp.25210. PMC 5237386. PMID 26445208.
  3. Asensio-López MC, Soler F, Sánchez-Más J, Pascual-Figal D, Fernández-Belda F, Lax A (March 2016). "Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes". Archives of Biochemistry and Biophysics. 594: 26–36. doi:10.1016/j.abb.2016.02.021. PMID 26906075.
  4. Gray SP, Jha JC, Kennedy K, van Bommel E, Chew P, Szyndralewiez C, Touyz RM, Schmidt HH, Cooper ME, Jandeleit-Dahm KA (May 2017). "Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease". Diabetologia. 60 (5): 927–937. doi:10.1007/s00125-017-4215-5. PMID 28160092.
  5. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, Brenner DA (December 2012). "Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent". Hepatology. 56 (6): 2316–27. doi:10.1002/hep.25938. PMC 3493679. PMID 22806357.
  6. Jiang JX, Chen X, Serizawa N, Szyndralewiez C, Page P, Schröder K, Brandes RP, Devaraj S, Török NJ (July 2012). "Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo". Free Radical Biology & Medicine. 53 (2): 289–96. doi:10.1016/j.freeradbiomed.2012.05.007. PMC 3392471. PMID 22618020.
  7. Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, Hart CM (November 2012). "The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation". American Journal of Respiratory Cell and Molecular Biology. 47 (5): 718–26. doi:10.1165/rcmb.2011-0418OC. PMC 3547100. PMID 22904198.
  8. "FDA granting Genkyotex Orphan Drug Designation of GKT137831 for IPF - Genkyotex S.A." pauahosting.co.nz. Retrieved 2017-05-14.
  9. "Genkyotex' NOX inhibitor candidate Fails to follow through on Phase II". Labiotech.eu. 2015-09-10. Retrieved 2017-05-14.
  10. "French Biotech gets a Second Opportunity to Fight Liver Fibrosis". Labiotech.eu. 2017-05-03. Retrieved 2017-05-14.
  11. US grant 8389518, "Pyrazolo pyridine derivatives as NADPH oxidase inhibitors"
  12. "FDA granting Genkyotex Orphan Drug Designation of GKT137831 for IPF - Genkyotex S.A." pauahosting.co.nz. Retrieved 2017-05-14.
  13. https://www.evaluate.com/vantage/articles/news/trial-results/rose-tinted-glasses-might-not-save-genkyotex
  14. "Genkyotex' NOX inhibitor candidate Fails to follow through on Phase II". Labiotech.eu. 2015-09-10. Retrieved 2017-05-14.
  15. Rose-tinted glasses might not save Genkyotex. Armstrong. May 2019
  16. Kalgutkar AS (2015). "Should the incorporation of structural alerts be restricted in drug design? An analysis of structure-toxicity trends with aniline-based drugs". Current Medicinal Chemistry. 22 (4): 438–64. doi:10.2174/0929867321666141112122118. PMID 25388012.
  17. Kalgutkar AS (2015). "Should the incorporation of structural alerts be restricted in drug design? An analysis of structure-toxicity trends with aniline-based drugs". Current Medicinal Chemistry. 22 (4): 438–64. doi:10.2174/0929867321666141112122118. PMID 25388012.
  18. M Davies A, G Holt A (November 2018). "Why antioxidant therapies have failed in clinical trials". Journal of Theoretical Biology. 457: 1–5. doi:10.1016/j.jtbi.2018.08.014. PMID 30121293.
  19. Schildknecht S, Weber A, Gerding HR, Pape R, Robotta M, Drescher M, Marquardt A, Daiber A, Ferger B, Leist M (2014). "The NOX1/4 inhibitor GKT136901 as selective and direct scavenger of peroxynitrite". Current Medicinal Chemistry. 21 (3): 365–76. doi:10.2174/09298673113209990179. PMID 23848532.
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