Eravacycline

Eravacycline

Names
IUPAC name (4S,4aS,5aR,12aS)-4-(Dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[(1-pyrrolidinylacetyl)amino]-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide
Identifiers
CAS Number	1207283-85-9
3D model (Jmol)	Interactive image
ChemSpider	28495485
PubChem	54726192
InChI InChI=1S/C27H31FN4O8/c1-31(2)20-13-8-11-7-12-14(28)9-15(30-16(33)10-32-5-3-4-6-32)21(34)18(12)22(35)17(11)24(37)27(13,40)25(38)19(23(20)36)26(29)39/h9,11,13,20,34,36-37,40H,3-8,10H2,1-2H3,(H2,29,39)(H,30,33)/t11-,13-,20-,27-/m0/s1 Key: HLFSMUUOKPBTSM-ISIOAQNYSA-N InChI=1/C27H31FN4O8/c1-31(2)20-13-8-11-7-12-14(28)9-15(30-16(33)10-32-5-3-4-6-32)21(34)18(12)22(35)17(11)24(37)27(13,40)25(38)19(23(20)36)26(29)39/h9,11,13,20,34,36-37,40H,3-8,10H2,1-2H3,(H2,29,39)(H,30,33)/t11-,13-,20-,27-/m0/s1 Key: HLFSMUUOKPBTSM-ISIOAQNYBD
SMILES CN(C)[C@H]1[C@@H]2C[C@@H]3CC4=C(C=C(C(=C4C(=O)C3=C([C@@]2(C(=O)C(=C1O)C(=O)N)O)O)O)NC(=O)CN5CCCC5)F
Properties
Chemical formula	C27H31FN4O8
Molar mass	558.555
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Eravacycline (TP-434) is a synthetic fluorocycline antibiotic in development by Tetraphase Pharmaceuticals. It is closely related to the glycylglycine antibiotic tigecycline and the tetracycline class of antibiotics. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) ^[1] and complicated urinary tract infections (cUTI)^[2] were recently completed with mixed results. Eravacylcine has been designated as a Qualified Infectious Disease Product (QIDP), as well as for fast track approval by the FDA.^[3]

Medical Uses

Eravacycline has shown broad spectrum of activity against a variety of Gram-positive and Gram-negative bacteria, including multi-drug resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae.^[4] It is currently being formulated as for intravenous and oral administration.

Spectrum of activity ^[4][5][6][7]

Gram-positive organisms

• Staphylococcus aureus (both methicillin-resistant and sensitive strains)
• Streptococcus pneumonia
• Enterococcus faecalis
• Enterococcus faecium (including vancomycin resistant strains)

Gram-negative organisms

• Non-lactose fermenting Gram-negative bacteria
  • Acinetobacter baumannii
  • Stenotrophomonas maltophilia
• Haemophilus influenzae
• Moraxella catarrhalis
• Nesseria gonorrhoeae
• Enterobacteriaceae
  • Escherichia coli (including ESBL-producing strains)
  • Klebsiella pneumoniae (including carbapenem resistant strains)
  • Klebsiella oxytoca
  • Enterobacter species
  • Citrobacter species
  • Proteus mirabilis
  • Serratia marcescens

Similar to other tetracycline derivatives, eravacylcine has is poorly active against Pseudomonas aeruginosa with and MIC₉₀ = 16 mcg/mL (range 0.06-64 mcg/mL). Eravacycline maintains in-vitro activity against Enterobacteriaceae carrying the mcr-1 gene responsible for polymyxin b/colistin resistance.^[8]

Clinical Trials

Phase 3 trials

Complicated Intra-abdominal infections (IGNITE 1)^[1]

The IGNITE 1 trial compared twice-daily IV eravacycline to once-daily ertapenem for the treatment of cIAI. A total of 541 patients were included and eravacycline demonstrated noninferiority to ertapenem. An additional pivotal phase 3 study (IGNITE 4)^[9] is planned for late 2016 with initial results likely available in the fourth quarter of 2017.^[10]

Complicated Urinary Tract infections (IGNITE 2)^[2]

The IGNITE 2 trial compared 7 days of IV eravacycline to IV levofloxacin with the option to convert patients in either group to oral therapy after 3 days for cUTI. Overall, eravacyline was inferior to levofloxacin in response rate (60.4 vs 66.9%); however it was noted that patients who completed therapy with the IV formulation had higher response rates, suggesting formulation issues with the oral option.^[11] Due to the performance of the IV formulation, an additional phase 3 trial is planned to support a supplemental NDA for the cUTI indication.^[10]

Commercial information

Eravacycline is under development by Tetraphase Pharmaceuticals Inc. Tetraphase reported a 3Q loss of $21.1 million.^[12] Following the results of the IGNITE 2 study, in which eravacycline demonstrated inferiority to levofloxacin, tetraphase stocks fell by 78%.^[13]

References

1. 1 2 Solomkin, Joseph; Evans, David; Slepavicius, Algirdas; Lee, Patrick; Marsh, Andrew; Tsai, Larry; Sutcliffe, Joyce A.; Horn, Patrick (2016-11-16). "Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial". JAMA surgery. doi:10.1001/jamasurg.2016.4237. ISSN 2168-6262. PMID 27851857. 
2. 1 2 "Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI (NASDAQ:TTPH)". ir.tphase.com. Retrieved 2016-11-20. 
3. ↑ "FDA Grants QIDP Designation to Eravacycline, Tetraphase's Lead Antibiotic Product Candidate | Business Wire". www.businesswire.com. Retrieved 2016-11-20. 
4. 1 2 Zhanel, George G.; Cheung, Doris; Adam, Heather; Zelenitsky, Sheryl; Golden, Alyssa; Schweizer, Frank; Gorityala, Bala; Lagacé-Wiens, Philippe R. S.; Walkty, Andrew (2016-04-01). "Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent". Drugs. 76 (5): 567–588. doi:10.1007/s40265-016-0545-8. ISSN 1179-1950. PMID 26863149. 
5. ↑ Sutcliffe, J. A.; O'Brien, W.; Fyfe, C.; Grossman, T. H. (2013-11-01). "Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens". Antimicrobial Agents and Chemotherapy. 57 (11): 5548–5558. doi:10.1128/AAC.01288-13. ISSN 1098-6596. PMC 3811277. PMID 23979750. 
6. ↑ Solomkin, Joseph S.; Ramesh, Mayakonda Krishnamurthy; Cesnauskas, Gintaras; Novikovs, Nikolajs; Stefanova, Penka; Sutcliffe, Joyce A.; Walpole, Susannah M.; Horn, Patrick T. (2014-01-01). "Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections". Antimicrobial Agents and Chemotherapy. 58 (4): 1847–1854. doi:10.1128/AAC.01614-13. ISSN 1098-6596. PMC 4023720. PMID 24342651. 
7. ↑ Abdallah, Marie; Olafisoye, Olawole; Cortes, Christopher; Urban, Carl; Landman, David; Quale, John (2015-03-01). "Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City". Antimicrobial Agents and Chemotherapy. 59 (3): 1802–1805. doi:10.1128/AAC.04809-14. ISSN 1098-6596. PMC 4325809. PMID 25534744. 
8. ↑ Fyfe, Corey; LeBlanc, Gabrielle; Close, Brianna; Nordmann, Patrice; Dumas, Jacques; Grossman, Trudy H. (2016-08-22). "Eravacycline is active against bacterial isolates expressing the polymyxin resistance gene mcr-1". Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.01646-16. ISSN 0066-4804. PMC 5075126. PMID 27550359. 
9. ↑ "http://www.healio.com/infectious-disease/antimicrobials/news/online/%7B3b5e5b8a-a5eb-4739-a402-3c88c22621d4%7D/phase-3-ignite4-trial-to-examine-safety-efficacy-of-iv-eravacycline-in-ciais". www.healio.com. Retrieved 2016-11-20.  External link in |title= (help)
10. 1 2 "Tetraphase Pharmaceuticals Provides Update on Eravacycline Regulatory and Development Status (NASDAQ:TTPH)". ir.tphase.com. Retrieved 2016-11-20. 
11. ↑ "http://www.healio.com/infectious-disease/antimicrobials/news/online/%7B8b0a64f5-6a4c-4b88-b5ac-9c1fe100778c%7D/ignite2-eravacycline-inferior-to-levofloxacin-but-iv-formulation-shows-promise". www.healio.com. Retrieved 2016-11-20.  External link in |title= (help)
12. ↑ "Tetraphase reports 3Q loss". Retrieved 2016-11-20. 
13. ↑ Feroldi, Brian (2016-11-20). "Why Tetraphase Pharmaceuticals Dropped 74% of Its Value in 2015 -- The Motley Fool". The Motley Fool. Retrieved 2016-11-20. 

External links

• "Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI: Eravacycline Did Not Achieve Primary Endpoint in Pivotal Portion of cUTI Trial"
• Tetraphase pipeline

Notes

• Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development