After ICAAC: Some More Thoughts on Eravacycline in cUTI and IGNITE-2

When a well-designed pivotal Phase 3 trial fails to show NI, it demands an explanation.  While awaiting the company’s analysis of the data, many possible explanations are bandied about.  So it was not surprising that the eravacycline cUTI study (IGNITE-2) was mentioned quite often during ICAAC 2015, in sessions and in the hallways.

While we cannot claim to have any first-hand information of the data situation, nor vouch for some of the explanations proffered, the following points can be made:

1. Tetrracyclines have never been an established drug class for UTI, cUTI or uUTI according to Mandell’s Textbook (and some others too):
   1. UTI chapter does not list tetracycline as a drug for cUTI, only for uUTI
   2. Tetracycline chapter does not mention use in urinary tract infection at all
   3. In a PubMed search, no well-controlled trials of a tetracycline antibiotic in cUTI could be identified
2. Expert advice was sought in the design of IGNITE-2 for dose-finding and clinical science:
   1. There was PK/PD modeling of the new dose regimen
   2. Tetracycline/tigecycline experts were involved
3. Activity of eravacycline in urine may have been borderline or compromised:
   1. Urinary concentrations and antibacterial titers in urine of normal volunteers treated with various doses were studied
   2. Tetracyclines do not lose activity in the acidic urinary milieu: pH has an MIC reducing effect against most uropathogens. However, data on how pH impacts the activity of eravacycline are not available
   3. An acidic urinary pH should have more negatively affected the FQ control drug
   4. Tetracycline binding to divalent cations may be an issue
4. Study design-related issues may have had a negative impact:

   The #1 reason for a failed NI trial is and remains poor dose selection!
   ICAAC PK/PD session

   1. The #1 reason for a failed NI trial is and remains poor dose selection!
      1. False sense of security due to early run-in results favoring low-dose eravacycline
      2. Dose selection makes no sense: The rationale for the lower dosing regimen in cUTI (1.5 mg/kg IV q24h followed by 200 mg PO q12h) compared to the (successful) dose in cIAI (1 mg/kg IV q12h) needs scrutiny
      3. The highly efficacious comparator (levofloxacin 750 mg qd IV -> PO) would have required an equivalent full dosing of eravacycline
   2. An inappropriate notion that cUTI is a less serious condition manageable with lower doses than cIAI
   3. Concerns about side effects may have induced Tetraphase to reduce both the IV and PO dose
   4. Misplaced marketing considerations: BID dosing may have been chosen to allow for earlier patient discharge at the end of IV therapy

There may have been a confluence of several of these factors that produced the poor outcome results.  From the perspective of this outsider, some rather major issue was either ignored or not appreciated in its relevance. And let’s admit it: we still don’t understand everything in the Drug – Bug – Host Bermuda triangle. Then there are still some other “Points to Consider” which are not in the remit of this blog.

Unfortunately, the overall scenario is not too rosy now for Tetraphase.  The million dollar question is: will FDA approve cIAI based on the available data package?  Too few patients were included in the Phase 2 trial to qualify as a co-pivotal study, a role it was never intended for.

With the failed large cUTI study now part of the dossier, such a ‘cIAI only’ approval appears even less likely.  In this case, less is more:  Regulators would have found it easier to accept a ‘non-standard cIAI package’ consisting of a single Phase 3 trial together with PK/PD and other supporting data if they did not have the failed cUTI trial to deal with which really puts into question the entire eravacycline efficacy projection.

It is just amazing how quickly reality pops the balloon of euphoria and inflated hopes. With the pope in town, we can ring in the new Eravacycline Hymn:

Sic Transit Gloria Mundi