{"id":2396,"date":"2016-03-23T06:22:41","date_gmt":"2016-03-23T10:22:41","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2396"},"modified":"2016-07-14T23:36:58","modified_gmt":"2016-07-15T03:36:58","slug":"the-cresemba-candidemia-gamble-rien-ne-va-plus","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/03\/23\/2396\/the-cresemba-candidemia-gamble-rien-ne-va-plus\/","title":{"rendered":"The Cresemba Candidemia Gamble \u2013 Rien Ne Va Plus"},"content":{"rendered":"<p><a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?ssl=1\" rel=\"attachment wp-att-2399\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-2399 aligncenter\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?resize=530%2C140&#038;ssl=1\" alt=\"Crescemba Gamble copy\" width=\"530\" height=\"140\" srcset=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?w=640&amp;ssl=1 640w, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?resize=300%2C79&amp;ssl=1 300w\" sizes=\"auto, (max-width: 530px) 100vw, 530px\" \/><\/a><\/p>\n<p>Isavuconazole is a potent triazole; like Voriconazole, it has garnered an indication for invasive aspergillosis. However, it failed where other azole antifungals succeeded: in a pivotal trial, not yet published, the drug was inferior to Caspofungin in the treatment of invasive candidiasis\/candidemia in non-neutropenic patients\u00a0<a href=\"#_ftn1\" name=\"_ftnref1\">[1]<\/a>.<\/p>\n<div class=\"simplePullQuote right\"><p><span style=\"color: #008000\">We want to learn from late-stage failures; analysis of failed trials is an important aspect of clinical drug development and should be shared. Unfortunately, companies are reluctant to do so. They would rather be tight-lipped about such \u2018competitive information\u2019. Which is nonsense and a disservice to investigators and patients<\/span><\/p>\n<\/div>\n<p>To provide some background: in a series of candidemia studies, Fluconazole IV\/PO was shown to be non-inferior to Amphotericin B (AmB) <a href=\"#_ftn2\" name=\"_ftnref2\">[2]<\/a>,<a href=\"#_ftn3\" name=\"_ftnref3\">[3]<\/a>,<a href=\"#_ftn4\" name=\"_ftnref4\">[4]<\/a>. \u00a0In addition, Pfizer Study 150-108 proved that Voriconazole IV\/PO was as efficacious as AmB followed by Fluconazole PO. So it stands to reason that Isavuconazole would also do well in candidemia too, right?<\/p>\n<p>Well, yes and no! There is good reason to believe that Isavuconazole would do as well as these older azoles, with some major caveats:<\/p>\n<ul>\n<li>Fluconazole just barely achieved non-inferiority to AmB in several studies, it was clearly inferior in some subset analyses. In every study, even with the high dose 800 mg loading\/400 mg maintenance regimen, Fluconazole was numerically inferior (see Figure below).<\/li>\n<li>Resistance to azoles has crept up over time in various Candida sp., which would impact Isavuconazole more than AmB.<\/li>\n<\/ul>\n<p>Given this data situation we deduce that Isavuconazole would do better in invasive candidiasis\/candidemia if the comparator were an azole instead of AmB. Either Fluconazole or Voriconazole could serve as comparator drugs, but Voriconazole would be preferred for commercial reasons.<\/p>\n<figure id=\"attachment_2398\" aria-describedby=\"caption-attachment-2398\" style=\"width: 624px\" class=\"wp-caption alignright\"><a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/HR_Antifungal-Class-Comparisons-copy.jpg?ssl=1\" rel=\"attachment wp-att-2398\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"wp-image-2398 size-full\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/HR_Antifungal-Class-Comparisons-copy.jpg?resize=530%2C494&#038;ssl=1\" alt=\"HR_Antifungal Class Comparisons copy\" width=\"530\" height=\"494\" srcset=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/HR_Antifungal-Class-Comparisons-copy.jpg?w=624&amp;ssl=1 624w, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/HR_Antifungal-Class-Comparisons-copy.jpg?resize=300%2C280&amp;ssl=1 300w\" sizes=\"auto, (max-width: 530px) 100vw, 530px\" \/><\/a><figcaption id=\"caption-attachment-2398\" class=\"wp-caption-text\">Candidemia + Invasive Candidiasis Studies<\/figcaption><\/figure>\n<p>Hence, Basilea\u2019s strategy to obtain labeling for Isavuconazole in candidemia would logically look like this:<\/p>\n<ul>\n<li>Option #1: comparison with AmB like the other azoles<br \/>\ndoable, but risky as explained above.<\/li>\n<li>Option #2: comparison with Fluconazole or Voriconazole;<br \/>\nbest chance for Isavuconazole to score a home run, but need to select non-neutropenic patients and try to imitate populations from prior azole trials.<\/li>\n<\/ul>\n<p>Is there \/ was there ever a rationale for a 3<sup>rd<\/sup> option in which Isavuconazole would go head-to-head against\u00a0a candin?<\/p>\n<p>Three large well-controlled trials were conducted in the past comparing a candin with either AmB or Fluconazole <a href=\"#_ftn5\" name=\"_ftnref5\">[5]<\/a>,<a href=\"#_ftn6\" name=\"_ftnref6\">[6]<\/a>,<a href=\"#_ftn7\" name=\"_ftnref7\">[7]<\/a>. In each case, therapy with the candin resulted in numerically superior efficacy, sometimes to the point of statistical superiority.<\/p>\n<p>Now let\u2019s put all the pieces together: If an azole can barely match the efficacy of AmB, and AmB is less efficacious than a candin, most folks would predict that Isavuconazole will not do well against a candin. In addition, Isavuconazole has the disadvantage of being \u2018only\u2019 fungistatic while the candins can claim rapid fungicidal activity.<\/p>\n<p>Basilea has not enlightened us to why they chose Caspofungin as the comparator in a pivotal trial. If there were good reasons to think that Isavuconazole had greater intrinsic potency than other azoles, we would like to learn about them. Looking at the situation as an impartial outsider, this trial was ill-conceived and became a debacle, quite avoidable, you might say. It was a poor study design, not lack of antifungal activity which derailed this candidemia study.<\/p>\n<p>Going for Option #3 seems like a choice based on delusions of grandeur. But some folks like to bet against the bank, let\u2019s presume. At the Basel casino, the roulette players,\u201crien ne va plus,\u201d would certainly give Isavuconazole a 1:20 chance of meeting NI goals against a candin, knowing that a\u00a0study with an alpha of 0.05 has a 5% probability of failing to refute the null hypothesis.<\/p>\n<p><strong>References:<\/strong><\/p>\n<p><a href=\"#_ftnref1\" name=\"_ftn1\">[1]<\/a> <a href=\"http:\/\/newsroom.astellas.us\/2015-07-30-Astellas-Provides-Update-on-Phase-3-Study-Evaluating-Isavuconazole-in-Patients-with-Candidemia-and-Other-Invasive-Candida-Infections\">http:\/\/newsroom.astellas.us\/2015-07-30-Astellas-Provides-Update-on-Phase-3-Study-Evaluating-Isavuconazole-in-Patients-with-Candidemia-and-Other-Invasive-Candida-Infections<br \/>\n<\/a><a href=\"#_ftnref2\" name=\"_ftn2\">[2]<\/a> J Rex. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. NEJM 331: 1325, 1994<br \/>\n<a href=\"#_ftnref3\" name=\"_ftn3\">[3]<\/a> J Rex. A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole plus Placebo versus Fluconazole plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects. Clin Infect Dis 2003; 36:1221<br \/>\n<a href=\"#_ftnref4\" name=\"_ftn4\">[4]<\/a> P Phillips. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Canadian Candidemia Study Group. \u00a0Eur J Clin Microbiol Infect Dis. 1997, 16: 337<br \/>\n<a href=\"#_ftnref5\" name=\"_ftn5\">[5]<\/a> P Pappas. Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis. Clin Infect Dis 2007; 45:883<br \/>\n<a href=\"#_ftnref6\" name=\"_ftn6\">[6]<\/a> J Mora-Duarte. Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis. NEJM 347: 2020; 2002<br \/>\n<a href=\"#_ftnref7\" name=\"_ftn7\">[7]<\/a> A Reboli. Anidulafungin versus Fluconazole for Invasive Candidiasis. NEJM 356: 2472, 2007<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Isavuconazole is a potent triazole; like Voriconazole, it has garnered an indication for invasive aspergillosis. However, it failed where other azole antifungals succeeded: in a pivotal trial, not yet published, the drug was inferior to Caspofungin in the treatment of invasive candidiasis\/candidemia in non-neutropenic patients\u00a0[1]. To provide some background: in <a class=\"more-link\" href=\"https:\/\/allphasepharma.com\/dir\/2016\/03\/23\/2396\/the-cresemba-candidemia-gamble-rien-ne-va-plus\/\">Continue reading <span class=\"screen-reader-text\">  The Cresemba Candidemia Gamble \u2013 Rien Ne Va Plus<\/span><span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2399,"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":[1271,1580,1575,403,888,804,595,1581,1499,1497,942,939,1484,1576,1579,5,1495,1347,1585,1583,1578,610,588,1496,1577,153,655,970,1582,938,928],"class_list":["post-2396","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-allphase-pharma-consulting","tag-ampho-b","tag-anidulafungin","tag-antibiotic-blog","tag-aspergillosis","tag-astellas","tag-basilea","tag-cancidas","tag-candidemia","tag-caspofungin","tag-cresemba","tag-diflucan","tag-echinocandin","tag-eraxis","tag-failed-pivotal-trial","tag-fda","tag-fluconazole","tag-fungicidal","tag-fungistatic","tag-harald-reinhart","tag-invasive-candidiasis","tag-isavuconazole","tag-merck","tag-micafungin","tag-mycamine","tag-non-inferiority","tag-pfizer","tag-sba","tag-triazole","tag-vfend","tag-voriconazole"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/03\/Crescemba-Gamble-copy.jpg?fit=640%2C169&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-CE","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2625,"url":"https:\/\/allphasepharma.com\/dir\/2016\/07\/13\/2625\/aspergillus_guideline-zip\/","url_meta":{"origin":2396,"position":0},"title":"Aspergillus_Guideline.ZIP","author":"Harald","date":"July 13, 2016","format":false,"excerpt":"Now, I know we should not make light of any IDSA Guidelines, far from it. This latest, the Aspergillus Guideline [1], like others before, is a thoughtful document which reviews the newest information and reflects expert authoritative thinking on the subject. It also is a hefty 60 pages long, as\u2026","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Rules-Regx-Guidelines - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Rules-Regx-Guidelines-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Rules-Regx-Guidelines-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Rules-Regx-Guidelines-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1371,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/14\/1371\/cresemba-isavuconazole-not-just-another-azole\/","url_meta":{"origin":2396,"position":1},"title":"Cresemba \/ Isavuconazole: \u00a0Not Just Another Azole","author":"Harald","date":"April 14, 2015","format":false,"excerpt":"It is amazing how modifications to the azole structure have produced ever more potent, ever more useful antifungals.\u00a0 Ketoconazole had limited usability because of its many side effects related to off-target sterol synthesis inhibition, solubility (or lack thereof) and erratic absorption.\u00a0 Solublity was also an issue for itraconazole and posaconazole.\u00a0\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":"Beta-cyclodextrin","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/04\/Beta-cyclodextrin.png?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":5392,"url":"https:\/\/allphasepharma.com\/dir\/2025\/09\/22\/5392\/olorofim-in-a-tight-spot\/","url_meta":{"origin":2396,"position":2},"title":"OLOROFIM in a TIGHT SPOT","author":"Harald","date":"September 22, 2025","format":false,"excerpt":"Regulatory and development status of Olorofim, a novel antifungal.","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/Picture3-1.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/Picture3-1.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/Picture3-1.jpg?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/Picture3-1.jpg?resize=700%2C400&ssl=1 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/Picture3-1.jpg?resize=1050%2C600&ssl=1 3x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/Picture3-1.jpg?resize=1400%2C800&ssl=1 4x"},"classes":[]},{"id":2233,"url":"https:\/\/allphasepharma.com\/dir\/2016\/01\/02\/2233\/new-treatment-guidelines-for-candidiasis-a-major-document-to-study\/","url_meta":{"origin":2396,"position":3},"title":"New Treatment Guidelines for Candidiasis \u2013 A Major Document to Study","author":"Harald","date":"January 2, 2016","format":false,"excerpt":"In a much-quoted analysis, Lee found that most IDSA Guidelines were supported only by Level III quality data, the lowest category of evidence-based support[1]. The article concludes that more well-designed trials were needed, and clinical judgement should ultimately guide patient management. This all sounds fine and good, and the new\u2026","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"InExpertsWeTrust","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/InExpertsWeTrust.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/InExpertsWeTrust.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/InExpertsWeTrust.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/InExpertsWeTrust.jpg?resize=700%2C400 2x"},"classes":[]},{"id":2892,"url":"https:\/\/allphasepharma.com\/dir\/2016\/11\/14\/2892\/inconclusive-data-in-ia-experts-fill-the-void-to-avoid-horror-vacui\/","url_meta":{"origin":2396,"position":4},"title":"Inconclusive Data in IA: Experts Fill the Void To Avoid Horror Vacui","author":"Harald","date":"November 14, 2016","format":false,"excerpt":"Often we come across a study which raises more questions than it answers.\u00a0 Sometimes we read a study publication again and again, and still we cannot figure out what the take-away learning is, as results are simply inconclusive or discordant. Occasionally we encounter studies with results that are so counterintuitive\u2026","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"ia-blog-header","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/IA-blog-header.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/IA-blog-header.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/IA-blog-header.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":5576,"url":"https:\/\/allphasepharma.com\/dir\/2025\/10\/17\/5576\/the-antifungal-landscape-2\/","url_meta":{"origin":2396,"position":5},"title":"The Antifungal Landscape &#8211; 2","author":"Harald","date":"October 17, 2025","format":false,"excerpt":"As many in the field have said before, what we really need are antifungals with a truly novel MoA, not minor changes to well-established classes.[1]\u00a0 There is a shortage of new antifungals for invasive disease.\u00a0Small improvements in PK will hardly move the field forward or excite investors to engage.\u00a0Our current\u2026","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/10\/HR_SLIDER-The-Antifungal-Landscape-2.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/10\/HR_SLIDER-The-Antifungal-Landscape-2.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/10\/HR_SLIDER-The-Antifungal-Landscape-2.jpg?resize=525%2C300&ssl=1 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/2396","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=2396"}],"version-history":[{"count":7,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/2396\/revisions"}],"predecessor-version":[{"id":2639,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/2396\/revisions\/2639"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/2399"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=2396"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=2396"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=2396"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}