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 | |
| 1207283-85-9 | |
| 3D model (Jmol) | Interactive image |
| ChemSpider | 28495485 |
| PubChem | 54726192 |
| |
| |
| Properties | |
| 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
- 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 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.
- 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.
- ↑ "FDA Grants QIDP Designation to Eravacycline, Tetraphase's Lead Antibiotic Product Candidate | Business Wire". www.businesswire.com. Retrieved 2016-11-20.
- 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.
- ↑ 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. - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "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) - 1 2 "Tetraphase Pharmaceuticals Provides Update on Eravacycline Regulatory and Development Status (NASDAQ:TTPH)". ir.tphase.com. Retrieved 2016-11-20.
- ↑ "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) - ↑ "Tetraphase reports 3Q loss". Retrieved 2016-11-20.
- ↑ 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