Eravacycline

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Contents

Eravacycline
Eravacycline structure.svg
Names
Preferred IUPAC name
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl)acetamido]-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
Other names
Xerava
Identifiers
3D model (JSmol)
ChemSpider
KEGG
PubChem CID
UNII
  • 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
  • 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
C27H31FN4O8
Molar mass 558.555
Pharmacology
J01AA13 ( WHO )
Legal status
  • EU:Rx-only [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Eravacycline (TP-434, Xerava) is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) [2] and complicated urinary tract infections (cUTI) [3] were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA [4] and is currently available in USA.

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. [5] It is currently being formulated as for intravenous and oral administration.[ citation needed ] [6]

Spectrum of activity [5] [7] [8] [9]

Gram-positive organisms

Gram-negative organisms

Similar to other tetracycline derivatives, eravacycline is poorly active against Pseudomonas aeruginosa with a 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. [10]

Clinical trials

Current and past clinical trial information:

Phase 3 trials

Complicated Intra-abdominal infections (IGNITE 1) [2]

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) [11] is planned for late 2016 with initial results likely available in the fourth quarter of 2017. [12]

Complicated Intra-abdominal Infections (IGNITE 4)

IGNITE 4 assessed twice-daily intravenous eravacycline (1.0 mg/kg every 12 hours) compared to those receiving meropenem (1 g every 8 hours). The study enrolled 500 adult patients with the primary endpoint being clinical response at the test-of-cure visit which is 25–31 days after initial dosing. Primary efficiency analysis was conducted using a 12.5% non-inferiority margin in the microbiological intent-to-treat (micro-ITT) population. [13] [14]

In July 2017, Tetraphase pharmaceuticals released top line data via press showing clinical cure rates in the micro-ITT population to be 90.8% and 91.2% for eravacycline (n=195) and meropenem (n=205), respectively (95% CI: -6.3%, 5.3%). Primary analysis was conducted using a 12.5% non-inferiority margin of the modified intent-to-treat (MITT) and clinically evaluable (CE) patient populations. Clinical cure rates in the MITT population were 92.4% and 91.6% for eravacycline (n=250) and meropenem (n=249), respectively (95% CI: -4.1%, 5.8%). Clinical cure rates in the CE population were 96.9% and 96.1% for eravacycline (n=225) and meropenem (n=231), respectively (95% CI: -2.9%, 4.5%). Eravacycline met the primary efficacy endpoints according to the FDA and EMA guidelines. The secondary analyses were consistent with, and supportive of, the primary outcome according to Tetraphase. [13] There were no treatment-related serious adverse events (SAEs) in the trial. Treatment-emergent adverse event (TEAEs) rates were similar in both treatment groups with the most commonly reported drug-related adverse events (AEs) for eravacycline were infusion site reactions, nausea and vomiting, each occurring at a rate of less than 5%. The most common Gram-negative pathogens in the study included Escherichia coli , Klebsiella pneumoniae , Pseudomonas and Bacteroides . Full data from IGNITE4 will become available as the company prepares to submit its New Drug Application (NDA) in the first quarter of 2018 for Eravacycline treatment of Complicated Intra-abdominal Infections. [13] [14]

Complicated Urinary Tract infections (IGNITE 2) [3]

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, eravacycline 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. [15] Due to the performance of the IV formulation, an additional phase 3 trial is planned to support a supplemental NDA for the cUTI indication. [12]

Complicated Urinary Tract Infections (IGNITE 3) [16] [17]

IGNITE3 is currently ongoing starting January 2017 with expected completion December 2018. This study is evaluating IV eravacycline (1.5 mg/kg every 24 hours) compared to ertapenem (1 g every 24 hours) for the treatment of cUTI. IGNITE3 is currently enrolling approximately 1,000 patients who will be randomized 1:1 to receive intravenous eravacycline or ertapenem for a minimum of 5 days, and will then be eligible for transition to oral levofloxacin. [17] The primary endpoints are Proportion of Participants in the microbiological Intent-to-treat (micro-ITT) Population demonstrating Clinical Cure and Microbiologic Success at the End of Intravenous (EOI) Visit [Time Frame: EOI visit (within 1 day of the completion of intravenous study drug treatment)] & Proportion of Participants in the micro-ITT Population Demonstrating Clinical Cure and Microbiologic Success at the Test-Of-Cure (TOC) Visit [Time Frame: TOC visit (14–17 days after randomization)]. With secondary endpoints (outcomes) testing Proportion of Participants in the microbiological Modified Intent-To-Treat (micro-MITT) Population and the Microbiologically Evaluable (ME) Population Demonstrating Microbiologic Success at the TOC Visit [Time Frame: TOC visit (14–17 days after randomization)] [16]

Commercial information

Eravacycline is under development by Tetraphase Pharmaceuticals Inc. It is marketed under trade name Xerava in United States.[ citation needed ]

References

  1. ↑ "Xerava EPAR". European Medicines Agency. 8 October 2018. Retrieved 29 June 2024.
  2. 1 2 Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, et al. (16 November 2016). "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. 152 (3): 224–232. doi:10.1001/jamasurg.2016.4237. ISSN   2168-6262. PMID   27851857. S2CID   42977246.
  3. 1 2 "Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI (NASDAQ:TTPH)". ir.tphase.com. Archived from the original on 21 November 2016. Retrieved 20 November 2016.
  4. ↑ "FDA Grants QIDP Designation to Eravacycline, Tetraphase's Lead Antibiotic Product Candidate | Business Wire". businesswire.com. 15 July 2013. Retrieved 20 November 2016.
  5. 1 2 Zhanel GG, Cheung D, Adam H, Zelenitsky S, Golden A, Schweizer F, et al. (1 April 2016). "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. S2CID   36285428.
  6. ↑ "Eravacycline Dosage Guide + Max Dose, Adjustments". Drugs.com. Retrieved 15 May 2025.
  7. ↑ Sutcliffe JA, O'Brien W, Fyfe C, Grossman TH (1 November 2013). "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.
  8. ↑ Solomkin JS, Ramesh MK, Cesnauskas G, Novikovs N, Stefanova P, Sutcliffe JA, et al. (1 January 2014). "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.
  9. ↑ Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, Quale J (1 March 2015). "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.
  10. ↑ Fyfe C, LeBlanc G, Close B, Nordmann P, Dumas J, Grossman TH (22 August 2016). "Eravacycline is active against bacterial isolates expressing the polymyxin resistance gene mcr-1" (PDF). Antimicrobial Agents and Chemotherapy. 60 (11): 6989–6990. doi:10.1128/AAC.01646-16. ISSN   0066-4804. PMC   5075126 . PMID   27550359.
  11. ↑ "Phase 3 IGNITE4 trial to examine safety, efficacy of IV eravacycline in cIAIs". Healio. 19 October 2016. Retrieved 16 January 2023.
  12. 1 2 "Tetraphase Pharmaceuticals Provides Update on Eravacycline Regulatory and Development Status (NASDAQ:TTPH)". ir.tphase.com. Archived from the original on 21 November 2016. Retrieved 20 November 2016.
  13. 1 2 3 "Tetraphase Announces Positive Top-Line Results from Phase 3 IGNITE4 Clinical Trial in Complicated Intra-Abdominal Infections (NASDAQ:TTPH)". ir.tphase.com. Archived from the original on 1 August 2017. Retrieved 27 July 2017.
  14. 1 2 "Efficacy and Safety Study of Eravacycline Compared With Meropenem in Complicated Intra-abdominal Infections - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 27 July 2017.
  15. ↑ "IGNITE2: Eravacycline inferior to levofloxacin, but IV formulation shows promise". Healio. 8 July 2016. Retrieved 16 January 2023.
  16. 1 2 "Efficacy and Safety Study of Eravacycline Compared With Ertapenem in Participants With Complicated Urinary Tract Infections - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 27 July 2017.
  17. 1 2 "Tetraphase Pharmaceuticals Doses First Patient in IGNITE3 Phase 3 Clinical Trial of Once-daily IV Eravacycline in cUTI (NASDAQ:TTPH)". ir.tphase.com. Archived from the original on 7 August 2017. Retrieved 27 July 2017.
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