{"id":1265,"date":"2015-02-11T00:16:06","date_gmt":"2015-02-11T05:16:06","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1265"},"modified":"2016-10-25T13:47:40","modified_gmt":"2016-10-25T17:47:40","slug":"commenting-on-comments-the-ceftaroline-trial-program-in-cabp","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/02\/11\/1265\/commenting-on-comments-the-ceftaroline-trial-program-in-cabp\/","title":{"rendered":"Commenting on Comments:\u00a0 The Ceftaroline Trial Program in CABP"},"content":{"rendered":"

The ceftaroline (Teflaro\u00ae) program was executed at a time when FDA was debating a new CABP Guidance with new outcome measures: no longer was the time-honored TOC assessment acceptable, instead improvement on Day 3-5 was to become the new primary endpoint.\u00a0 FDA made other significant changes to the old 1998 Guidance as well, like a tightening of entry criteria (requiring selection of more severely ill patients) and adding a no-prior-antibiotic rule (based on the often misunderstood Pertel publication\u00a0[1]<\/a>).\u00a0 Conducting anti-infective trials during this time was not for the faint of heart, and any of the newly introduced criteria could have \u2018sunk\u2019 the ceftaroline NDA submission.<\/p>\n

However, ceftaroline passed the AIDAC review (Sept. 2010) with flying colors\u00a0[2]<\/a>, a feat for which I give much credit to the outstanding team at Cerexa that managed the drug during Phase 3.\u00a0 Of course, it helps to have an excellent horse in the race:\u00a0 ceftaroline response rates beat the comparator (ceftriaxone\/Rocephin\u00ae) – at least numerically – in almost every analysis set, sometimes with nice p-values <0.05.\u00a0 Even the FDA reviewer liked what he saw.<\/p>\n

\"Teflaro<\/a>
Numerically higher but not clinically better: Table copied from a Teflaro advertisement showing comparative data in the most favorable light. Note: Despite data pooling, the actual number of pathogens is surprisingly small.<\/figcaption><\/figure>\n

In a recent editorial\u00a0[3]<\/a> Welte comments on\u00a0the ceftaroline Phase 3 trial published in the same journal issue and the program at-large.<\/p>\n

His comments deserve, well, further comment:<\/p>\n

First point <\/strong>he makes is about the rather large PK\/PD differences between ceftaroline and ceftriaxone and how these\u00a0may have affected outcomes and given ceftaroline an advantage. He postulates that the large differences in protein binding (20% vs 95%), the longer infusion time, a higher penetration into pulmonary tissue, and a higher intrinsic kill rate may have contributed to the superior and earlier treatment responses seen with ceftaroline.<\/p>\n

My comment:<\/strong> A big MAYBE.\u00a0 Faster killing was postulated to be a differentiating factor for other drugs before.\u00a0 Daptomycin (compared to vancomycin) and moxifloxacin (compared to non-fluoroquinolones) looked really good based on in-vitro data. Unfortunately, what was easily demonstrable in the test tube could not be proven in the clinical trial program, at least not reproducibly. There was 1 daptomycin study in cSSSI which showed faster symptom resolution but this finding was not confirmed in a follow-up trial. Sorry, there goes my belief system!<\/p>\n

Same story with moxifloxacin where a single study (in which Welte participated [5]) showed a faster response.\u00a0 Sadly, publication bias and marketing efforts seem to have pushed the positive results into the limelight while non-confirmatory data did not get the same attention.\u00a0 In fact, a thorough review of published trials concluded that \u201cmoxifloxacin does not differ significantly compared to other fluoroquinolones or other classes of antibiotics in clinically relevant outcomes for the treatment of adult patients with community acquired pneumonia’.[4]<\/a>\u00a0 \u00a0I am unable to find a publication of the moxifloxacin QUICK\u00a0study which also did not confirm a \u2018faster efficacy\u2019 claim. Whatever it was that made ceftaroline look good, it was not simply PK that made the difference.<\/p>\n

Second point<\/strong> the editorialist makes is about the low number of sick patients included in CABP trials. The mortality rate in the Phase 3 ceftaroline trial being only 1% gives the impression that this study does not reflect\u00a0the \u2018real world\u2019 where CAP is associated with rates of 20%.\u00a0Hence, he suggests that many more patients with PORT scores of 5 should be included in CABP studies.<\/p>\n

My comment:<\/strong>\u00a0I would agree in principle. This is not a new argument by any stretch:\u00a0FDA had similar concerns and pushed up the disease severity requirements significantly. The new Guidelines specifically demand that \u201c75 percent of patients in trials have PORT scores of III or higher\u201d.\u00a0CABP trial may never have mortality rates of 20% (a figure often quoted in the literature) but the 1% rate seems very low indeed.<\/p>\n

Having said that, there is no reason why future ceftaroline CABP trials could not explore sicker patient populations.\u00a0In my humble opinion, a stepwise exploration of an antibiotic\u2019s efficacy makes more sense: not everything can or needs to be studied during the registration phase; there is plenty of opportunity to further expand the label and explore the usefulness of a drug in Phases 3b and 4.<\/p>\n

Case in point: the MoxiRapid trial cited by Welte\u00a0[5]<\/a> was done fairly late in the life cycle of moxifloxacin.\u00a0Let\u2019s also not forget the daptomycin experience:\u00a0 When Cubist tested the drug in CABP (comparator: ceftriaxone!), it became evident that it was inferior and did not perform en par with the SOC.\u00a0It would have been a nightmare if the majority of patients enrolled had been in the PORT 5 category.\u00a0Give drugs a chance!<\/p>\n

Many drugs have expanded their label into \u2018difficult\u2019 indications in a process which required time, learning and building the safety and efficacy database.\u00a0 Often, an upward adjustment in dosing was needed to address the more challenging infection types.\u00a0 Highly resistant pathogens, or the immune compromised and severely ill populations are usually not tested in the early stages of drug development, and for good reasons.\u00a0 Few remember that IV ciprofloxacin started as a 200 mg and 300 mg IV q12h drug in Europe, even failed in an early EORTC trial\u00a0[6]<\/a>, but then became an excellent performer\u00a0at doses of 400 mg IV q12h and q8h for severe infections.<\/p>\n

It seems there is some research in clinical research after all\u2026<\/p>\n

Abbreviations<\/strong>:<\/p>\n

PORT\u00a0\u00a0\u00a0\u00a0 Pneumonia Patient Outcomes Research Team
\nPSI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0Pneumonia Severity Index
\nEORTC\u00a0 European Organization for Research on Treatment of Cancer
\nAIDAC\u00a0\u00a0 Anti-Infective Drug Advisory Committee
\nSOC \u00a0 \u00a0 \u00a0Standard of Care
\ncSSSI \u00a0 \u00a0complicated skin-skin structure infection
\nTOC \u00a0 \u00a0 \u00a0Test-of-Cure visit<\/p>\n

References:<\/strong><\/p>\n

[1]<\/a> Pertel\u00a0 CID 2008; 46:1142
\n[2]<\/a> http:\/\/www.fda.gov\/downloads\/AdvisoryCommittees\/CommitteesMeetingMaterials\/Drugs\/Anti-InfectiveDrugsAdvisoryCommittee\/UCM230379.pdf
\n[3]<\/a> www.thelancet.com\/infection\u00a0\u00a0 Vol 15\u00a0\u00a0 February 2015, p. 132
\n[4]<\/a> http:\/\/www.ti.ubc.ca\/moxifloxacin-community-acquired-pneumonia
\n[5]<\/a> Welte\u00a0 CID\u00a0 2005; 41:1697
\n[6]<\/a> Meunier\u00a0 Antimicrob Agents Chemother. 1991; 35: 873<\/p>\n","protected":false},"excerpt":{"rendered":"

The ceftaroline (Teflaro\u00ae) program was executed at a time when FDA was debating a new CABP Guidance with new outcome measures: no longer was the time-honored TOC assessment acceptable, instead improvement on Day 3-5 was to become the new primary endpoint.\u00a0 FDA made other significant changes to the old 1998 Continue reading Commenting on Comments:\u00a0 The Ceftaroline Trial Program in CABP<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1270,"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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[227,3,18],"tags":[778,403,215,783,828,816,834,229,92,832,823,5,99,826,224,833,47,830,39,824,825,827,831,829],"class_list":["post-1265","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_news","category-the_viewpoint","tag-aidac","tag-antibiotic-blog","tag-avelox","tag-cabp","tag-ceftaroline","tag-ceftriaxone","tag-cerexa","tag-cubicin","tag-cubist","tag-dose-adjustment","tag-eortc","tag-fda","tag-fda-guidance","tag-fine-score","tag-fluoroquinolone","tag-mortality-endpoint","tag-moxifloxacin","tag-moxirapid","tag-pkpd","tag-port","tag-psi","tag-rocephin","tag-soc","tag-teflaro"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/CAP-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-kp","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1869,"url":"https:\/\/allphasepharma.com\/dir\/2015\/08\/19\/1869\/most-anti-infective-guidelines-get-no-respect-let-alone-use\/","url_meta":{"origin":1265,"position":0},"title":"Most Anti-Infective Guidelines Don’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 "Did you know...?"","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":[]},{"id":3297,"url":"https:\/\/allphasepharma.com\/dir\/2017\/04\/12\/3297\/fda-radical-reform\/","url_meta":{"origin":1265,"position":1},"title":"FDA Needs Radical Reform","author":"Harald","date":"April 12, 2017","format":false,"excerpt":"The nomination of Dr. Scott Gottlieb for\u00a0FDA commissioner, a political appointee, has created the usual bipartisan furor. 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