The IGNITE3 top-line data released on February 14th did not provide the news that most expected, announcing instead a second failure of eravacycline in a Phase III trial for complicated urinary tract infections (cUTIs). Despite the previous failure, the medical community was expecting positive results from this trial, which would have provided data to support a label for cUTIs. However, these results were met with disappointment, and may have permanently closed the door on eravacycline’s access to a significant proportion of the hospital-treated bacterial infection market.
Importantly, this is not the first failure of eravacycline in a Phase III cUTI trial. In September 2015, eravacycline failed to meet the primary endpoint in an IV-to-oral Phase III cUTI trial (IGNITE2) with the comparator of levofloxacin (IV/oral) (Tetraphase, press release, September 8, 2015). As shown in the Table 1, patients enrolled in the IGNITE 2 trial received IV eravacycline or IV levofloxacin for at least 3 days before transition to oral eravacycline or oral levofloxacin to complete the 7-day treatment period. Although the IV-to-oral eravacycline treatment did not reach the 10% non-inferiority margin, a post-hoc analysis revealed that in a subset of patients who only received IV treatment, the IV eravacycline showed a better responder rate than IV levofloxacin (see Table 1). Based on the positive data in this IV-only subpopulation and the fact that oral eravacycline has a low bioavailability, Tetraphase decided to focus on developing IV eravacycline and designed the IGNITE3 trial.
The Phase III IGNITE3 trial aimed to evaluate IV eravacycline’s efficacy and safety in cUTI patients against the comparator IV ertapenem (Table 2.). A total of 1205 cUTI patients were randomized 1:1 to receive eravacycline (1.5mg/kg, q 24h) or ertapenem (1 g, q 24h) for at least five days before the transition to an oral antibiotic under the direction of the managing physician. As shown in Table 1, IV eravacycline failed to meet the FDA primary endpoint (responder rate at end of care[EOC]) using a 10% non-inferiority margin (-10% CI: -14.1%, -6.0%).
Table 1 IGNITE 2 trial design and results (IV/oral eravacycline vs. IV/oral levofloxacin)
(Data source: Tetraphase, corporate presentation, November 2015)
Table 2 IGNITE 3 trial design and results (IV eravacycline vs. IV ertapenem)(Data source: Tetraphase, corporate presentation, November 2015)
(Data source: Tetraphase, press release, February 13, 2018)
Tetraphase has yet to release the full data from this trial and based on available information the reason for the clinical failure is not clear yet. However, it is possible that the concentrations of eravacycline in the urine were not high enough to ensure success. Tetracyclines are not frequently used for the treatment of cUTIs, and tigecycline (a structurally similar tetracycline) is not approved for cUTIs, despite some evidence of its off-label use in this indication. The low usage of tigecycline in treating cUTIs is due to a combination of factors including a low renal excretion fraction and high volume distribution. It is therefore conceivable that a low renal excretion in conjunction with a single administration a day may have led to sub-optimal concentrations of eravacycline in the urine, and ultimately the poor outcomes reported. Though, it is important to note that concentration of eravacycline excreted via the urine seems to be higher than that of tigecycline1,2. Another reason for the failure may be related to the bacterial populations present in the patients. IGNITE3 was designed to exclude patients at risk of Pseudomonas, a pathogen to which both eravacycline and eratapenem have poor activity. However, no specific steps were taken to exclude patients potentially colonized with tigecycline resistant organism, and when susceptibility to tigecycline decreases, eravacycline’s activity decreases as well3. Although relatively uncommon, resistance to tigecycline is increasing, and should always be considered. There are numerous other reasons that could explain this failure, but until the more details about the trial data become available, these reasons are all highly speculative. Whatever the reason behind the failure was, Paratek should pay close attention, since the company is planning a trial in uncomplicated urinary tract infections to evaluate the efficacy of omadacycline, another tetracycline.
Regardless of this latest setback, Tetraphase has reiterated their intention to continue development of eravacycline for cIAIs. Indeed both the FDA as well as the EMA are reviewing applications for eravacycline based on the positive outcomes shown in the IGNITE1 and IGNITE4 cIAI trials of IV eravacycline. Further, Tetraphase’s management emphasized in their latest press release that they remain positive on the commercial opportunity for eravacycline in cIAI, and are planning on targeting infections caused by difficult to treat Gram-negative bacteria and mixed infections in specific patient populations. Obtaining regulatory approval for cIAI should not be a problem – the clinical efficacy in cIAI is supported by positive data in two Phase III trials, and after four completed Phase III trials there are no concerns with the safety of the drug. However, successfully commercializing eravacycline will be a complicated task and convincing physicians and payers of the value of eravacycline will present challenges. The current treatment landscape for cIAIs already offers multiple potent and broad spectrum antimicrobials, including tygecycline (Pfizer’s Tygacil, generics) and ertapenem (Merck’s Invanz, generics). Tetraphase will have to create a value message that differentiates it from its competitors, and is able to convince physicians who are more experienced with currently marketed therapies to prescribe eravacycline. Moreover, most of current therapies are available as less costly generics, which hospital pharmacy directors and Pharmacy and Therapeutics committee members regard as a positive attribute, and may constrain uptake of eravacycline. On the bright side, eravacycline has a broad spectrum, which includes activity against pathogens considered critical by the CDC and WHO (e.g., carbapenem resistant Enterobacteriaceae, carbapenem resistant Acinetobacter, and MRSA). Tetraphase could benefit from following the example of companies such as Merck, Shionogi or Achaogen, and evaluate the efficacy of eravacycline in trials that target specific pathogens. It could also evaluate efficacy in additional indications such as hospital-acquired pneumonia and ventilator-associated pneumonia (HAP/VAP), which are in dire need of new treatments. On the conference call to discuss the IGNITE3 results, Tetraphase management team suggested this might be a path they would explore; however our view is that such trials would require a significant economic investment, and an eventual label extension to include other indications or specific pathogens could take several more years.
Additional clinical development considerations aside, the implications of the failure in IGNITE3 for eravacycline are clear and will no doubt negatively impact the potential revenues for this product in the antibacterial space. Lacking a label for cUTI will mean losing an important source of potential revenue for eravacycline, as significantly more patients in the U.S. and Europe receive treatment for cUTIs than for cIAIs. Once admired and highly anticipated by the medical community, who saw an added value for the IV-to-oral delivery, eravacycline has become an IV-only molecule that has continued to collect setbacks. The question that remains: will a cIAI label alone be enough to ensure a bright future for eravacycline and Tetraphase?
Learn more about DRG’s complete pipeline assessment and latest pharmaceutical forecast in hospital-treated bacterial infections here.
- Sutcliff JA et al. Antibacterial Activity of Eravacycline (TP-434), a Novel Fluorocycline, against Hospital and Community Pathogens. Antimicrob Agents Chemother. 2013 Nov;57(11):5548-58.
- Zhanel GG et al. Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent. Drugs. 2016 Apr;76(5):567-88.
- Livermore DM et al. In Vitro Activity of Eravacycline against Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii . Antimicrob Agents Chemother. 2016 Jun; 60(6): 3840–3844.
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Nuno T. Antunes, Ph.D. is principal business insights analyst on the Infectious, Niche, and Rare Diseases team at Decision Resources Group. Previously, he was a Latin America Market Access senior analyst in the Global Market Access Insights Team, where he developed expertise in market access, pricing and reimbursement, health technology assessment, and health policy.
Nuno holds a Ph.D. in animal health from the Universidad de las Palmas de Gran Canaria, Spain, and a D.V.M. degree from the Universidade de Trás-os-Montes e Alto Douro, Portugal. Prior to joining DRG, he conducted research in antimicrobial resistance and antimicrobial development, and worked in the medical devices industry as a scientist.
Jiamin Zhuo is an analyst on Infectious, Niche, & Rare Disease team at DRG, currently covering the hospital antibiotic markets, including Gram-Negative Infection and MRSA infection.