Wed . 19 Apr 2019

Eravacycline

eravacycline clinical trials, eravacycline
Eravacycline TP-434 is a synthetic halogenated tetracycline class antibiotic in development 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 and complicated urinary tract infections cUTI were recently completed with mixed results Eravacylcine has been granted fast track approval by the FDA

Contents

  • 1 Medical Uses
    • 11 Spectrum of activity
      • 111 Gram-positive organisms
      • 112 Gram-negative organisms
  • 2 Clinical Trials
    • 21 Phase 3 trials
      • 211 Complicated Intra-abdominal infections IGNITE 1
      • 212 Complicated Intra-abdominal Infections IGNITE 4
      • 213 Complicated Urinary Tract infections IGNITE 2
        • 2131 Complicated Urinary Tract Infections IGNITE 3
  • 3 Commercial information
  • 4 References
  • 5 External links
  • 6 Notes

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 It is currently being formulated as for intravenous and oral administration

Spectrum of activity ">edit]

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 is poorly active against Pseudomonas aeruginosa with and MIC90 = 16 mcg/mL range 006-64 mcg/mL Eravacycline maintains in-vitro activity against Enterobacteriaceae carrying the mcr-1 gene responsible for polymyxin b/colistin resistance

Clinical Trials

Current and past clinical trial information: https://clinicaltrialsgov/ct2/resultscond=&term=eravacycline&cntry1=&state1=&recrs=

Phase 3 trials

Complicated Intra-abdominal infections IGNITE 1">edit]

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 is planned for late 2016 with initial results likely available in the fourth quarter of 2017

Complicated Intra-abdominal Infections IGNITE 4">edit]

IGNITE 4 assessed twice-daily intravenous eravacycline10 mg/kg every 12 hours compared to those receiving meropenem 1g 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 125% non-inferiority margin in the microbiological intent-to-treat micro-ITT population

On July 25, 2017 Tetraphase pharmaceuticals released top line data via press showing clinical cure rates in the micro-ITT population to be 908% and 912% for eravacycline n=195 and meropenem n=205, respectively 95% CI: -63%,53% Primary analysis was conducted using a 125% non-inferiority margin of the modified intent-to-treat MITT and clinically evaluable CE patient populations Clinical cure rates in the MITT population were 924% and 916% for eravacycline n=250 and meropenem n=249, respectively 95% CI: -41%,58% Clinical cure rates in the CE population were 969% and 961% for eravacycline n=225 and meropenem n=231, respectively 95% CI: -29%,45% 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 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 pneumonia, 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

Complicated Urinary Tract infections IGNITE 2">edit]

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 604 vs 669%; however it was noted that patients who completed therapy with the IV formulation had higher response rates, suggesting formulation issues with the oral option Due to the performance of the IV formulation, an additional phase 3 trial is planned to support a supplemental NDA for the cUTI indication

Complicated Urinary Tract Infections IGNITE 3">edit] IGNITE3 is currently ongoing starting January 2017 with expected completion December 2018 This study is evaluating IV eravacycline 15 mg/kg every 24 hours compared to ertapenem 1g 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 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 & Proportion of Participants in the micro-ITT Population Demonstrating Clinical Cure and Microbiologic Success at the Test-Of-Cure TOC Visit With secondary endpointsoutcomes 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

Commercial information

Eravacycline is under development by Tetraphase Pharmaceuticals Inc Tetraphase reported a 3Q loss of $211 million Following the results of the IGNITE 2 study, in which eravacycline demonstrated inferiority to levofloxacin, tetraphase stocks fell by 78%

References

  1. ^ a b 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:101001/jamasurg20164237 ISSN 2168-6262 PMID 27851857 
  2. ^ a b "Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI NASDAQ:TTPH" irtphasecom Retrieved 2016-11-20 
  3. ^ "FDA Grants QIDP Designation to Eravacycline, Tetraphase's Lead Antibiotic Product Candidate | Business Wire" wwwbusinesswirecom Retrieved 2016-11-20 
  4. ^ a b 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:101007/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:101128/AAC01288-13 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:101128/AAC01614-13 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:101128/AAC04809-14 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 60: 6989–6990 doi:101128/AAC01646-16 ISSN 0066-4804 PMC 5075126  PMID 27550359 
  9. ^ "http://wwwhealiocom/infectious-disease/antimicrobials/news/online/%7B3b5e5b8a-a5eb-4739-a402-3c88c22621d4%7D/phase-3-ignite4-trial-to-examine-safety-efficacy-of-iv-eravacycline-in-ciais" wwwhealiocom Retrieved 2016-11-20  External link in |title= help
  10. ^ a b "Tetraphase Pharmaceuticals Provides Update on Eravacycline Regulatory and Development Status NASDAQ:TTPH" irtphasecom Retrieved 2016-11-20 
  11. ^ a b c "Tetraphase Announces Positive Top-Line Results from Phase 3 IGNITE4 Clinical Trial in Complicated Intra-Abdominal Infections NASDAQ:TTPH" irtphasecom Retrieved 2017-07-27 
  12. ^ a b "Efficacy and Safety Study of Eravacycline Compared With Meropenem in Complicated Intra-abdominal Infections - Full Text View - ClinicalTrialsgov" wwwclinicaltrialsgov Retrieved 2017-07-27 
  13. ^ "http://wwwhealiocom/infectious-disease/antimicrobials/news/online/%7B8b0a64f5-6a4c-4b88-b5ac-9c1fe100778c%7D/ignite2-eravacycline-inferior-to-levofloxacin-but-iv-formulation-shows-promise" wwwhealiocom Retrieved 2016-11-20  External link in |title= help
  14. ^ a b "Efficacy and Safety Study of Eravacycline Compared With Ertapenem in Participants With Complicated Urinary Tract Infections - Full Text View - ClinicalTrialsgov" wwwclinicaltrialsgov Retrieved 2017-07-27 
  15. ^ a b "Tetraphase Pharmaceuticals Doses First Patient in IGNITE3 Phase 3 Clinical Trial of Once-daily IV Eravacycline in cUTI NASDAQ:TTPH" irtphasecom Retrieved 2017-07-27 
  16. ^ "Tetraphase reports 3Q loss" Retrieved 2016-11-20 
  17. ^ 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

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Eravacycline Information about

Eravacycline


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