{"id":3144,"date":"2017-02-09T00:28:48","date_gmt":"2017-02-09T05:28:48","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=3144"},"modified":"2025-09-20T19:12:55","modified_gmt":"2025-09-21T01:12:55","slug":"smiles-press-conference-plazomicin-delivers","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2017\/02\/09\/3144\/smiles-press-conference-plazomicin-delivers\/","title":{"rendered":"All Smiles at the Press Conference: Plazo+Levo Delivers"},"content":{"rendered":"<p><span style=\"font-size: 15px; font-weight: 300;\"><a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?ssl=1\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-3151 aligncenter\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?resize=530%2C173&#038;ssl=1\" alt=\"\" width=\"530\" height=\"173\" srcset=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?w=552&amp;ssl=1 552w, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?resize=300%2C98&amp;ssl=1 300w\" sizes=\"auto, (max-width: 530px) 100vw, 530px\" \/><\/a>This December, Achaogen released much data on 2 plazomicin trials<\/span><a style=\"font-size: 15px; font-weight: 300;\" href=\"#_ftn1\" name=\"_ftnref1\">[1]<\/a><span style=\"font-size: 15px; font-weight: 300;\">: 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 \u201cstudies\u201d which are too small (20 patients per arm), too messy and too poorly designed to draw any conclusions. We gladly refer this CARE trial to the care of a qualified FDA reviewer with superior analytical skills and more patience.<\/span><\/p>\n<p>Okay, back to EPIC. This is a straightforward cUTI trial for which we have an FDA Guidance that specifies just about every detail (except for the urine color, of course!). Primary efficacy is determined in a rather complicated algorithm based on all of the below:<\/p>\n<ul>\n<li>composite Clinical and Bacteriological Response (CR and BR)<\/li>\n<li>mITT population<\/li>\n<li>both Day 5 and TOC visit evaluations<\/li>\n<li>NI delta = 15%<\/li>\n<\/ul>\n<p>Plazomicin performed as well as meropenem \/ levofloxacin; the overall response rate in the plazomicin arm was 88% at Day 5. Activity against ESBLs was better with plazomicin than with meropenem. In the TOC analyses, plazomicin \/ levofloxacin was statistically superior and Achaogen folks became all excited about this.<a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/EPIC-Design.jpg?ssl=1\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"wp-image-3156 alignleft\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/EPIC-Design.jpg?resize=390%2C209&#038;ssl=1\" alt=\"\" width=\"390\" height=\"209\" \/><\/a><\/p>\n<p>The safety of plazomicin, an IV aminoglycoside, was quite good according to the presenters at the web conference call. Was it really? Half the patients had a relatively short 5 day exposure to plazomicin the other half finished the entire treatment course (7-10 days) on plazomicin IV therapy. Such short exposure times to an aminoglycoside are usually safe, although S-creatinine slowly starts creeping up after a few days, as it did in EPIC. Of concern is certainly the patient whose Clcr dropped from 62 (i.e.,normal) to a Clcr of 22 after the 1<sup>st<\/sup> dose of plazomicin. Let\u2019s face it: plazomicin is an aminoglycoside, and it behaves like one, too.<\/p>\n<p>However, the EPIC presentation made us think about a few things we wanted to run by our readers today.<\/p>\n<p>With both arms using levofloxacin as the PO step-down drug, we would think that the primary efficacy analysis should be based on the study drug effect (CR and BR) at the end of IV therapy (EOIV), and nothing else. Evaluations from a later time point reflect the combined effect of plazomicin IV AND levofloxacin PO; outcome determinations after EOIV clearly cannot be attributed to plazomicin alone and should therefore not be part of the 1<sup>o<\/sup> efficacy statistics.<\/p>\n<p>Unless labeling in the Package Insert specifies that plazomicin \u201chas to be combined with levofloxacin\u201d for the treatment of cUTI. In which case we should rather refer to it as \u2018Plazofloxacin\u2019\u00a0or &#8216;Levomicin&#8217;.<\/p>\n<p>Of course, in the same cUTI patient population, one could have just used levofloxacin IV\/PO and obtained the same results. EPIC, however, shows us convincingly that plazomicin is an effective replacement for IV levofloxacin (or meropenem), just a bit more toxic and in need of TDM.<\/p>\n<div class=\"simplePullQuote right\"><p><span style=\"color: #993366\">Maybe our logic has become a bit warped by listening to too many FDA sessions with hair-splitting arguments about study design but we certainly recall hearing it stated by the Agency on numerous occasions that even a single day of a non-study drug can ruin the efficacy evaluation. Figures!<\/span><\/p>\n<\/div>\n<p>Our second issue is the large number of microbiologically non-evaluable patients in EPIC. Of 609 patients enrolled, only 388, i.e., not even 2\/3, were valid for the key mMITT analysis. The presenters informed us that 1\/3 of patients enrolled did not even have a (valid) urinary pathogen at entry.<\/p>\n<p>Unfortunately, Achaogen is not alone, other companies did not fare much better in their cUTI studies: The Medicines Company reported a similarly low yield in its carbavance study (mMITT = 68%).<a href=\"#_ftn2\" name=\"_ftnref2\">[2]<\/a> The ceftolozane \/ tazobactam trial looks golden despite a rather low mMITT rate of 73.9%.<a href=\"#_ftn3\" name=\"_ftnref3\">[3]<\/a><\/p>\n<p>When it is so easy to test for significant bacteriuria by doing a dipstick test for nitrite and leukocyte esterase, why then are there so many non-evaluable patients in these trials?\u00a0 We assume that exclusion of urinary isolates not susceptible to study drugs is the reason. In the case of the EPIC trial, we were dealing with 3 antibiotics to which a pathogen had to be susceptible in order to qualify for validity.<\/p>\n<p>So here is our next regulatory question: If plazomicin is approved for cUTI based on the results of a single trial \u2013 the EPIC trial \u2013 which preselected patients for plazomicin, meropenem and levofloxacin susceptibility, will the drug only get approved for cUTI caused by triple-susceptible uropathogens?<\/p>\n<p>Can somebody please tell us again why we should use plazomicin in such patients, when less toxic alternative antibiotics (including IV and PO levofloxacin) would do the trick?<\/p>\n<p><span style=\"color: #339966;\">Ah, regulatory thinking can be so confusing and may have led us astray again. The yin\/yang of Sophism and Sufism, the logical and the mystical, are so close together. Let\u2019s get over it quickly and congratulate Achaogen for a job well done.<\/span><\/p>\n<p>Let us perhaps welcome plazofloxacin to the club of cUTI antibiotics that did better than comparator. Maybe the penems are just not as potent any longer as they used to be.<div class=\"simplePullQuote right\"><p><span style=\"color: #993366\">In case you missed it, cefiderocol recently showed superiority over imipenem.\u00a0 However, this was a fair comparison of IV drug vs IV drug, without a PO step-down to another antibiotic that could have influenced the results<\/span><\/span><span style=\"color: #993366\">.<\/span><\/span><\/p>\n<\/div><\/p>\n<p>Looking disappointedly into the cUTI rear-view mirror: it seems certain now that eravacycline was inferior in the IGNITE2 trial because of a poorly absorbed PO formulation. Tetraphase is working on a replacement for it.<\/p>\n<p><strong>Abbreviations:<br \/>\n<\/strong>EOIV \u00a0 \u00a0 \u00a0End-of-IV therapy<br \/>\nTOC \u00a0 \u00a0 \u00a0 Test-of-Cure<br \/>\nTDM \u00a0 \u00a0 \u00a0 therapeutic drug monitoring<br \/>\nNI \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 non-inferiority<br \/>\nmMITT \u00a0 microbiological modified intent-to-treat<\/p>\n<p><strong>References:<br \/>\n<\/strong><a href=\"#_ftnref1\" name=\"_ftn1\">[1]<\/a> http:\/\/files.shareholder.com\/downloads\/AMDA-2JY46Z\/3839473457x0x921792\/72FDA490-7742-4E15-AD7B-6F99C9A0CF03\/EPIC_CARE_Topline_Announcement_vFinal.pdf<br \/>\n<a href=\"#_ftnref2\" name=\"_ftn2\">[2]<\/a> Carbavance TANGO-1 phase III trial results. Conference call June 27, 2016<br \/>\n<a href=\"#_ftnref3\" name=\"_ftn3\">[3]<\/a> F Wagenlehner. Ceftolozane-tazobactam compared with levo\ufb02oxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI) Lancet 2015; 385: 1949<\/p>\n","protected":false},"excerpt":{"rendered":"<p>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 <a class=\"more-link\" href=\"https:\/\/allphasepharma.com\/dir\/2017\/02\/09\/3144\/smiles-press-conference-plazomicin-delivers\/\">Continue reading <span class=\"screen-reader-text\">  All Smiles at the Press Conference: Plazo+Levo Delivers<\/span><span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":3151,"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":true,"_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":[172,1271,403,1962,463,1955,344,879,1959,355,1957,425,1956,1583,1742,627,516,213,346,747,1960,1958,1964,170,742,199,200,1963,979,435,480,980,728],"class_list":["post-3144","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-achaogen","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-aspect-cuti","tag-carbavance","tag-cefiderocol","tag-ceftolozanetazobactam","tag-complicated-uti","tag-core-trial","tag-cuti","tag-epic-trial","tag-eravacycline","tag-fda-cuti-guidance","tag-harald-reinhart","tag-ignite2","tag-imipenem","tag-levaquin","tag-levofloxacin","tag-meropenem","tag-merrem","tag-mmitt","tag-patient-validity","tag-plazofloxacin","tag-plazomicin","tag-primaxin","tag-s-649266","tag-shionogi","tag-tango-1","tag-tdm","tag-tetraphase","tag-the-medicines-company","tag-therapeutic-drug-monitoring","tag-zerbaxa"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/02\/Plazomicin-sldier.jpg?fit=552%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-OI","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1640,"url":"https:\/\/allphasepharma.com\/dir\/2015\/07\/04\/1640\/plazomicin-a-quick-take-on-a-complex-drug-with-a-complex-development-path\/","url_meta":{"origin":3144,"position":0},"title":"Plazomicin \u2013 A Quick Take On A Complex Drug\u00a0With A Complex Development Path","author":"Harald","date":"July 4, 2015","format":false,"excerpt":"Whenever a new drug is in late stage development, its prospects become the focus\u00a0of intense scrutiny. Plazomicin (ACHN-490), like any Phase 3 drug should be evaluated along the following dimensions: Differentiation: within its class & compared to competitors: Does it have a unique clearly definable profile? Addressing an unmet need:\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Plazomicin copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1958,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/24\/1958\/after-icaac-some-more-thoughts-on-eravacycline-in-cuti-and-ignite-2\/","url_meta":{"origin":3144,"position":1},"title":"After ICAAC: Some More Thoughts on Eravacycline in cUTI and IGNITE-2","author":"Harald","date":"September 24, 2015","format":false,"excerpt":"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\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Erava2blog copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=700%2C400 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=1050%2C600 3x"},"classes":[]},{"id":653,"url":"https:\/\/allphasepharma.com\/dir\/2014\/07\/21\/653\/what-is-the-niche-for-ceftolozane-tazobactam\/","url_meta":{"origin":3144,"position":2},"title":"What is the \u201cNiche\u201d for Ceftolozane \/ Tazobactam?","author":"Harald","date":"July 21, 2014","format":false,"excerpt":"There are currently a total of 6 beta-lactam + beta-lactamase inhibitor combinations in clinical trials. It will be a steep learning curve for the pharma reps (and physicians) to understand the resistance classifications, the confusing ESBL definitions, the CRE nomenclature, and how this all matters in clinical practice, on the\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Tazobactam","src":"http:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/8\/84\/Tazobactam.svg\/220px-Tazobactam.svg.png","width":350,"height":200},"classes":[]},{"id":4303,"url":"https:\/\/allphasepharma.com\/dir\/2025\/05\/05\/4303\/sulopenem-uuti-does-it-suffice\/","url_meta":{"origin":3144,"position":3},"title":"Sulopenem uUTI &#8211; Does It Suffice?","author":"Harald","date":"May 5, 2025","format":false,"excerpt":"Sulopenem \/ ORLYNVAH approved for uUTI When Iterum, a Pfizer spin-off of sorts, took over sulopenem development in 2015, there was still hope for approvals of this drug in multiple indications such as uUTI, cUTI, cIAI and even CABP.\u00a0 Ten years later and after an FDA rejection CRL in 2021,\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","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\/2025\/05\/Sulopenem-in-uUTI-SLIDER.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/05\/Sulopenem-in-uUTI-SLIDER.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/05\/Sulopenem-in-uUTI-SLIDER.jpg?resize=525%2C300&ssl=1 1.5x"},"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":3144,"position":4},"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 &quot;QIDP Antibiotics&quot;","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":1869,"url":"https:\/\/allphasepharma.com\/dir\/2015\/08\/19\/1869\/most-anti-infective-guidelines-get-no-respect-let-alone-use\/","url_meta":{"origin":3144,"position":5},"title":"Most Anti-Infective Guidelines Don&#8217;t Get No Respect (Let Alone Use!)","author":"Harald","date":"August 19, 2015","format":false,"excerpt":"It is no secret that most existing antibiotic guidelines are not getting much use these days.\u00a0 The only indications pursued with any regularity are the feasible ones: ABSSSI, cUTI, and cIAI, much less CABP.\u00a0 Yes, the occasional HABP\/VABP trial is being undertaken by the intrepid but no company has taken\u2026","rel":"","context":"In &quot;Did you know...?&quot;","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"indications - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/indications-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/indications-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/indications-slider.jpg?resize=525%2C300 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/3144","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/comments?post=3144"}],"version-history":[{"count":19,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/3144\/revisions"}],"predecessor-version":[{"id":3168,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/3144\/revisions\/3168"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/3151"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=3144"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=3144"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=3144"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}