{"id":1640,"date":"2015-07-04T14:04:16","date_gmt":"2015-07-04T18:04:16","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1640"},"modified":"2016-12-14T02:47:08","modified_gmt":"2016-12-14T07:47:08","slug":"plazomicin-a-quick-take-on-a-complex-drug-with-a-complex-development-path","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/07\/04\/1640\/plazomicin-a-quick-take-on-a-complex-drug-with-a-complex-development-path\/","title":{"rendered":"Plazomicin \u2013 A Quick Take On A Complex Drug\u00a0With A Complex Development Path"},"content":{"rendered":"<p><a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?ssl=1\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"alignright size-full wp-image-1645\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?resize=530%2C149&#038;ssl=1\" alt=\"Plazomicin copy\" width=\"530\" height=\"149\" srcset=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?w=640&amp;ssl=1 640w, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?resize=300%2C84&amp;ssl=1 300w\" sizes=\"auto, (max-width: 530px) 100vw, 530px\" \/><\/a><\/p>\n<p>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:<\/p>\n<ul>\n<li>Differentiation: within its class &amp; compared to competitors: Does it have a unique clearly definable profile?<\/li>\n<li>Addressing an unmet need: How big of a gap does it fill, how important is its\u00a0contribution, how prevalent and exclusively covered is the pathogen?<\/li>\n<\/ul>\n<p>Plazomicin is an aminoglycoside (AG) of the \u2013micin variety which tells you it\u2019s a <div class=\"simplePullQuote right\"><p><span style=\"color: #003366\">Aminoglycoside<\/span> r<span style=\"color: #000080\">esearch centers on compounds that are\u00a0(1) resistant to aminoglycoside-modifying enzymes, and\u00a0(2) less nephro- and\/or ototoxic<\/span><\/p>\n<\/div>Micromonospora and not a Streptomyces derivative (a bit of semantics but good to know for Trivial Pursuit and the ID Board exam). As you probably know already, AGs have been around since the 60ies and many have been commercialized since then. In the US, approved AGs for IV use are gentamicin (yes, -micin), tobramycin, and amikacin but abroad you also have spectinomycin, sisomicin, dibekacin, and arbekacin.<\/p>\n<p>In the past, the search for new AG centered on (1) compounds to overcome resistance to aminoglycoside-modifying enzymes (AME), the predominant resistance mechanism, and (2) less toxic compounds. How does plazomicin address these points?<\/p>\n<p>Recent MIC data for plazomicin show activity against AG-resistant E. coli and P. aeruginosa, but it\u00a0also shows fairly high plazomicin MICs for strains that are still genta\/tobra\/amikacin-susceptible.<a href=\"#_ftn1\" name=\"_ftnref1\">[1]<\/a>\u00a0The jury is still out on how important it is to have plazomicin on the formulary, as it seems to provide extra coverage for some pathogens but also \u2018taketh away\u2019 from the established spectrum.<\/p>\n<p>Here is the clinical data situation as of mid-2015:<\/p>\n<ul>\n<li>SAFETY: A search for evidence of reduced nephrotoxicity comes up empty.\u00a0 Maybe the sponsor (Achaogen) has data, but we will have to wait for publication of Phase 2 cUTI study results to get a better picture. So this remains an unsubstantiated hope for now.\u00a0 Unfortunately, AEs were not so rare in Phase 1 with dizziness (30%) and somnolence leading the list.\u00a0Also\u00a0hypotension was seen in 5 cases <a href=\"#_ftn2\" name=\"_ftnref2\">[2]<\/a>.<\/li>\n<li>With once daily administration, the risk for AG related AEs should be reduced compared to older AGs, no doubt. Hence, in order to compare apples with apples one would like to see data comparing plazomicin qd with gentamicin \/ tobra \/ amikacin dosed qd as well.<\/li>\n<li>EFFICACY: Again clinical data have not yet been published. \u00a0A slide presentation on 76 patients dosed with 15 mg\/kg in the Phase 2 cUTI trial does not address our question about differentiation <a href=\"#_ftn3\" name=\"_ftnref3\">[3]<\/a>. Ideally one would like to see an analysis of data from patients treated with plazomicin and infected with bacteria carrying resistance genes like AAC(3), AAC(6), ANT(2\u201d) and APH(2\u201d) and who responded clinically and microbiologically to the drug. However, comparative MIC testing is not going to be replaced by AME analysis any time soon. In a recent publication there was only a 46.5% concordance between AME genotype and phenotypical resistance.<a href=\"#_ftn4\" name=\"_ftnref4\">[4]<\/a><br \/>\nBased on company microbiology data, we see potential use of plazomicin for the currently rare cases when Citrobacter, Enterobacter, Serratia, E.coli of the AAC(6\u2019) variety or Acinetobacter sp. resistant to all other AGs is encountered.<a href=\"#_ftn5\" name=\"_ftnref5\">[5]<\/a><\/li>\n<\/ul>\n<p>In conclusion, at this time we are relying on microbiologic data when discussing plazomicin activity and potential benefits. It is clear already that use of this drug will be limited to genta\/tobra\/amikacin-R enterobacteriaceae.<\/p>\n<p>While there is differentiation vis-\u00e0-vis other AGs in the test tube, how this would translate into a marketable benefit is open to conjecture, remembering netilmicin, another AG with a better spectrum than either genta or tobra. Netilmicin was clearly differentiated: it was not inhibited by several classes of AME (APC, ANT) and caused demonstrably less ototoxicity.<a href=\"#_ftn6\" name=\"_ftnref6\">[6]<\/a>\u00a0That profile was not enough to make it a commercial success.<\/p>\n<p>Plazomicin is now being studied in a superiority trial against colistin in patients with CRE pneumonia\/bacteremia.<a href=\"#_ftn7\" name=\"_ftnref7\">[7]<\/a>\u00a0This surely looks like a Herculean or Sisyphean task, if not \u2018mission impossible\u2019. It looks like too many smart cooks were in the development kitchen, the way it was designed.<\/p>\n<p>It is no wonder Achaogen\u2019s Phase 3 program ran into problems. After an SPA was agreed with FDA in 2013, FPFV for a Phase 3 study did not materialize\u00a0until Sept. 2014.\u00a0 Now we learn that the protocol had to be amended in 1Q15 in order to \u2018improve enrollment\u2019. Why was it so difficult to find patients for a drug which was supposed to address an acute medical NEED? Maybe it was a lower-case \u2018need\u2019 after all encountered\u00a0less often in clinical practice than academics and company folks tell us.<div class=\"simplePullQuote right\"><p><span style=\"color: #800000\">Plazomicin is setting a new record for slow drug development<\/span><\/p>\n<\/div><\/p>\n<p>Achaogen\u2019s declared goal for NDA submission is now set for 2H2018, which translates into an approval in 2019\/2020 or 6\u00bd years after the SPA cleared plazomicin for Phase 3.\u00a0 Embarrassingly, this seems to be\u00a0setting a new record for slow drug development.<\/p>\n<p>The 5-yr market exclusivity from its QIDP status is being used up for development efforts as we speak.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>References:<br \/>\n<\/strong><a href=\"#_ftnref1\" name=\"_ftn1\">[1]<\/a> A. Walkty. AAC. doi:10.1128\/AAC.02744-13<br \/>\n<a href=\"#_ftnref2\" name=\"_ftn2\">[2]<\/a> <a href=\"http:\/\/www.avarx.com\/AvaRx\/SubDomains\/bucket1874840974059574861\/Listings\/bucket2606968988994524404\/Public.Listing.display.html\"><span style=\"color: #000000;\">http:\/\/www.avarx.com\/AvaRx\/SubDomains\/bucket1874840974059574861\/Listings\/ bucket2606968988994524404\/Public.Listing.display.html<\/span><br \/>\n<\/a><a href=\"#_ftnref3\" name=\"_ftn3\">[3]<\/a> http:\/\/www.achaogen.com\/media-all\/2015\/5\/6\/baseline-pathogens-and-patient-outcomes-in-a-phase-2-study-comparing-plazomicin-achn-490-to-levofloxacin-in-complicated-urinary-tract-infection-cuti-including-acute-pyelonephritis-ap<br \/>\n<a href=\"#_ftnref4\" name=\"_ftn4\">[4]<\/a> Fern\u00e1ndez-Mart\u00ednez M\u00a0 \u00a0Int J Antimicrob Agents (2015), http:\/\/dx.doi.org\/10.1016\/j.ijantimicag.2015.03.008<br \/>\n<a href=\"#_ftnref5\" name=\"_ftn5\">[5]<\/a> Aggen J. AAC 2010; 54: 4636<br \/>\n<a href=\"#_ftnref6\" name=\"_ftn6\">[6]<\/a> P Noone.\u00a0 Sisomicin, Netilmicin and Dibekacin \u00a0\u00a0Drugs 1984, 27: 548<br \/>\n<a href=\"#_ftnref7\" name=\"_ftn7\">[7]<\/a> https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01970371?term=plazomicin&amp;rank=1<\/p>\n","protected":false},"excerpt":{"rendered":"<p>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 &amp; compared to competitors: Does it have a unique clearly definable profile? Addressing an unmet need: <a class=\"more-link\" href=\"https:\/\/allphasepharma.com\/dir\/2015\/07\/04\/1640\/plazomicin-a-quick-take-on-a-complex-drug-with-a-complex-development-path\/\">Continue reading <span class=\"screen-reader-text\">  Plazomicin \u2013 A Quick Take On A Complex Drug\u00a0With A Complex Development Path<\/span><span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1645,"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":[19,227,3,18],"tags":[172,1111,1118,1112,1119,403,1114,1121,1113,5,766,1120,1126,1124,1115,1007,170,1123,1122,1116,843,715,1117,1125,887],"class_list":["post-1640","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-achaogen","tag-achn-490","tag-ame","tag-amikacin","tag-aminoglycoside-modifying-enzymes","tag-antibiotic-blog","tag-arbekacin","tag-clinical-development","tag-dibekacin","tag-fda","tag-gentamicin","tag-market-exclusivity","tag-micromonospora","tag-nda-submission-phase-3-timelines","tag-nephrotoxicity","tag-netilmicin","tag-plazomicin","tag-plazomicin-adverse-events","tag-protocol-adjustment","tag-qd-dosing","tag-renal-toxicity","tag-spa","tag-special-protocol-assessment","tag-streptomyces","tag-tobramycin"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/Plazomicin-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-qs","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":3144,"url":"https:\/\/allphasepharma.com\/dir\/2017\/02\/09\/3144\/smiles-press-conference-plazomicin-delivers\/","url_meta":{"origin":1640,"position":0},"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 &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\/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":378,"url":"https:\/\/allphasepharma.com\/dir\/2014\/06\/23\/378\/fighting-p-aeruginosa-part-i\/","url_meta":{"origin":1640,"position":1},"title":"Fighting P. aeruginosa (Part I)","author":"Harald","date":"June 23, 2014","format":false,"excerpt":"It has never been easy to cure Pseudomonas aeruginosa infections.\u00a0 Few antibiotics nowadays have reliable activity against this problem pathogen that seems to have more built-in resistance features than most other Gram-negatives.\u00a0 In the past, cephalosporins, aztreonam, penems, ciprofloxacin, and aminoglycosides were useful drugs with reliably cidal activity, especially when\u2026","rel":"","context":"In &quot;The News&quot;","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"PA-01 on Agar","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar-300x274.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1946,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/21\/1946\/allphase-pharma-the-first-100-blog-posts\/","url_meta":{"origin":1640,"position":2},"title":"ALLPHASE PHARMA &#8211;  THE FIRST 100  BLOG POSTS","author":"Harald","date":"September 21, 2015","format":false,"excerpt":"After the first 100 blogs, it is appropriate to reflect on reader preferences.\u00a0 When I arbitrarily select a topic, it is not always clear whether what interests me also interests you. Since its start\u00a01\u00bd years ago, this blog has grown steadily in readership. \u00a0So we did a few things right\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":"blog100 - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/blog100-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/blog100-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/blog100-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2802,"url":"https:\/\/allphasepharma.com\/dir\/2016\/10\/18\/2802\/qidp-drug-update-part-1-an-updated-who-is-who\/","url_meta":{"origin":1640,"position":3},"title":"QIDP Drug Update \u2013 Part 1: An Updated Who Is Who","author":"Harald","date":"October 18, 2016","format":false,"excerpt":"It is time for a new look at the field of QIDP drugs. 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Looking at the more recent crop of ID products that garnered QIDP status, you wonder whether there is\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\/2017\/03\/Great-Heist-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/Great-Heist-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/Great-Heist-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":157,"url":"https:\/\/allphasepharma.com\/dir\/2014\/04\/22\/157\/antibiotics-with-qidp-designation\/","url_meta":{"origin":1640,"position":5},"title":"Antibiotics with QIDP Designation &#8211;   &#8211;    &#8211;  Updated 9-30-14","author":"Harald","date":"April 22, 2014","format":false,"excerpt":"For the latest QIDP listing, please click HERE \u00a0 Since\u00a0FDA issued the QIDP designation in 2012, many companies have requested this important 'label'. \u00a0Which should not come as a surprise: QIDP status confers significant benefits - and there is no downside. While an official FDA list of drugs that have\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\/2014\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1640","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=1640"}],"version-history":[{"count":19,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1640\/revisions"}],"predecessor-version":[{"id":2941,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1640\/revisions\/2941"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/1645"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=1640"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=1640"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=1640"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}