{"id":1958,"date":"2015-09-24T06:04:44","date_gmt":"2015-09-24T10:04:44","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1958"},"modified":"2015-10-07T16:47:04","modified_gmt":"2015-10-07T20:47:04","slug":"after-icaac-some-more-thoughts-on-eravacycline-in-cuti-and-ignite-2","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/09\/24\/1958\/after-icaac-some-more-thoughts-on-eravacycline-in-cuti-and-ignite-2\/","title":{"rendered":"After ICAAC: Some More Thoughts on Eravacycline in cUTI and IGNITE-2"},"content":{"rendered":"

\"Erava2blog<\/a>When a well-designed pivotal Phase 3 trial fails to show NI, it demands an explanation.\u00a0 While awaiting the company\u2019s analysis of the data, many possible explanations are bandied about.\u00a0 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.<\/p>\n

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:<\/p>\n

    \n
  1. Tetrracyclines have never been an established drug class for UTI, cUTI or uUTI according to Mandell\u2019s Textbook (and some others too):\n
      \n
    1. UTI chapter does not list tetracycline as a drug for cUTI, only for uUTI<\/li>\n
    2. Tetracycline chapter does not mention use in urinary tract infection at all<\/li>\n
    3. In a PubMed search, no well-controlled trials of a tetracycline antibiotic in cUTI could be identified<\/li>\n<\/ol>\n<\/li>\n
    4. Expert advice was sought in the design of IGNITE-2 for dose-finding and clinical science:\n
        \n
      1. There was PK\/PD modeling of the new dose regimen<\/li>\n
      2. Tetracycline\/tigecycline experts were involved<\/li>\n<\/ol>\n<\/li>\n
      3. Activity of eravacycline in urine may have been borderline or compromised:\n
          \n
        1. Urinary concentrations and antibacterial titers in urine of normal volunteers treated with various doses were studied<\/li>\n
        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<\/li>\n
        3. An acidic urinary pH should have more negatively affected the FQ control drug<\/li>\n
        4. Tetracycline binding to divalent cations may be an issue<\/li>\n<\/ol>\n<\/li>\n
        5. Study design-related issues may have had a negative impact:

          The #1 reason for a failed NI trial is and remains poor dose selection!
          \nICAAC PK\/PD session<\/span><\/span><\/p>\n<\/div><\/p>\n

            \n
          1. The #1 reason for a failed NI trial is and remains poor dose selection!\n
              \n
            1. False sense of security due to early run-in results favoring low-dose eravacycline<\/li>\n
            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<\/li>\n
            3. The highly efficacious comparator (levofloxacin 750 mg qd IV -> PO) would have required an equivalent full dosing of eravacycline<\/li>\n<\/ol>\n<\/li>\n
            4. An inappropriate notion that cUTI is a less serious condition manageable with lower doses than cIAI<\/li>\n
            5. Concerns about side effects may have induced Tetraphase to reduce both the IV and PO dose<\/li>\n
            6. Misplaced marketing considerations: BID dosing may have been chosen to allow for earlier patient discharge at the end of IV therapy<\/li>\n<\/ol>\n<\/li>\n<\/ol>\n

              Even for UTI, we still don\u2019t understand everything in the Drug \u2013 Bug \u2013 Host interaction<\/span><\/p>\n<\/div>There may have been a confluence of several of these factors that produced the poor outcome results.\u00a0 From the perspective of this outsider, some rather major issue was either ignored or not appreciated in its relevance. And let\u2019s admit it: we still don\u2019t understand everything in the Drug \u2013 Bug \u2013 Host Bermuda triangle. Then there are still some other \u201cPoints to Consider\u201d which are not in the remit of this blog.<\/p>\n

              Unfortunately, the overall scenario is not too rosy now for Tetraphase.\u00a0 The million dollar question is: will FDA approve cIAI based on the available data package?\u00a0 Too few patients were included in the Phase 2 trial to qualify as a co-pivotal study, a role it was never intended for.<\/p>\n

              With the failed large cUTI study now part of the dossier, such a \u2018cIAI only\u2019 approval appears even less likely.\u00a0 In this case, less is more:\u00a0 Regulators would have found it easier to accept a \u2018non-standard cIAI package\u2019 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.<\/p>\n

              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:<\/p>\n

              Sic Transit Gloria Mundi<\/span><\/strong><\/p>\n

              \"sic<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

              When a well-designed pivotal Phase 3 trial fails to show NI, it demands an explanation.\u00a0 While awaiting the company\u2019s analysis of the data, many possible explanations are bandied about.\u00a0 So it was not surprising that the eravacycline cUTI study (IGNITE-2) was mentioned quite often during ICAAC 2015, in sessions and Continue reading After ICAAC: Some More Thoughts on Eravacycline in cUTI and IGNITE-2<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1959,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[19,3,18],"tags":[403,354,1372,59,355,1334,1324,425,384,516,213,39,1371,1327,435,43,1330,426,1110],"class_list":["post-1958","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-antibiotic-blog","tag-ciai","tag-clinical-trial","tag-clinical-trial-results","tag-cuti","tag-dose-modeling","tag-dose-selection","tag-eravacycline","tag-failed-clinical-trials","tag-levaquin","tag-levofloxacin","tag-pkpd","tag-qidp","tag-tetracyclines-for-uti","tag-tetraphase","tag-tigecycline","tag-tp-434","tag-tygacil","tag-uuti"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-vA","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2142,"url":"https:\/\/allphasepharma.com\/dir\/2015\/11\/23\/2142\/eravacycline-conference-call-unrevealing-and-disappointing\/","url_meta":{"origin":1958,"position":0},"title":"Eravacycline Conference Call: Unrevealing and Disappointing","author":"Harald","date":"November 23, 2015","format":false,"excerpt":"Whatever has become of investigative journalism?\u00a0 All we read after the Stifel conference call (11\/17\/2015) is descriptive rehash of information provided by Tetraphase at the conference.\u00a0 No probing questions that we thought investors would ask who just lost 80% of their money.\u00a0 No signs of analytical or strategic readjustment at\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":689,"url":"https:\/\/allphasepharma.com\/dir\/2014\/08\/04\/689\/some-thoughts-about-eravacycline-based-on-the-phase-2-ciai-study\/","url_meta":{"origin":1958,"position":1},"title":"Some Thoughts about Eravacycline Based on the Phase 2 cIAI Study","author":"Harald","date":"August 4, 2014","format":false,"excerpt":"Solomkin et al. conclude that the efficacy and safety of eravacycline compares favorably to the control drug, ertapenem.[1]\u00a0 This top-level assessment is made with the usual caveats (insufficient statistical power, small sample size), but a few points deserve comment. Eravacycline is a fluorocycline; as a tetracycline derivative it follows into\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/08\/eravacycline-copy.jpg?fit=481%2C212&ssl=1&resize=350%2C200","width":350,"height":200},"classes":[]},{"id":2697,"url":"https:\/\/allphasepharma.com\/dir\/2016\/09\/19\/2697\/timely-new-information-on-next-generation-tetracyclines-part-2-eravacycline-and-protein-binding\/","url_meta":{"origin":1958,"position":2},"title":"Timely New Information on Next-Generation Tetracyclines \u2013 Part 2: Eravacycline and Protein Binding","author":"Harald","date":"September 19, 2016","format":false,"excerpt":"A recent paper by Thabit describes a curious finding [1]. The authors measured total and free (i.e.,\u00a0nonprotein-bound) eravacycline levels at ascending doses in a mouse model. They found strikingly small increases in free drug levels when titrating up\u00a0total doses. The effect was rather dramatic: an increase in\u00a0protein binding from 12%\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Horserace Tigecycline Erava","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/09\/Horserace-Tigecycline-Erava.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1937,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/13\/1937\/mme-erava-and-the-mysterious-case-of-auto-combustion\/","url_meta":{"origin":1958,"position":3},"title":"Mme Erava and The Mysterious Case of Auto-Combustion","author":"Harald","date":"September 13, 2015","format":false,"excerpt":"SH:\u00a0My dear Watson, did you read the news of the astonishing debacle that befell Mme Erava and made the headlines, creating anxiety of hitherto unknown proportions in Tetraland? Dr.W.: A disaster of epic proportions, for sure, and a mystery, an explanation which will require some very expert investigation. There is\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/sherlock-holmes-slider.jpg?fit=1200%2C495&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/sherlock-holmes-slider.jpg?fit=1200%2C495&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/sherlock-holmes-slider.jpg?fit=1200%2C495&ssl=1&resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/sherlock-holmes-slider.jpg?fit=1200%2C495&ssl=1&resize=700%2C400 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/sherlock-holmes-slider.jpg?fit=1200%2C495&ssl=1&resize=1050%2C600 3x"},"classes":[]},{"id":3144,"url":"https:\/\/allphasepharma.com\/dir\/2017\/02\/09\/3144\/smiles-press-conference-plazomicin-delivers\/","url_meta":{"origin":1958,"position":4},"title":"All Smiles at the Press Conference: Plazo+Levo Delivers","author":"Harald","date":"February 9, 2017","format":false,"excerpt":"This December, Achaogen released much data on 2 plazomicin trials[1]: the pivotal EPIC study comparing plazomicin \/ levofloxacin with meropenem\u00a0\/ levofloxacin in cUTI is the one we want to look at today because it is interpretable, while the other trial called CARE is not. CARE is one of those observational\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2480,"url":"https:\/\/allphasepharma.com\/dir\/2016\/05\/12\/2480\/azd-0914-a-new-broad-spectrum-narrow-development-path-drug\/","url_meta":{"origin":1958,"position":5},"title":"AZD-0914: A New Broad-Spectrum Narrow-Development Path Drug","author":"Harald","date":"May 12, 2016","format":false,"excerpt":"At first glance, the list of features that distinguish AZD-0914 from other FQ seems impressive: broad Gram-positive and Gram-negative activity, MRSA and MSSA activity, potency against fluoroquinolone (FQ)-resistant isolates, low frequency for S. aureus resistance, and impressive activity against C. difficile. 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