{"id":4089,"date":"2025-03-28T11:55:03","date_gmt":"2025-03-28T17:55:03","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=4089"},"modified":"2025-09-20T19:07:01","modified_gmt":"2025-09-21T01:07:01","slug":"gepotidacin-absssi-fail-adaptively","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2025\/03\/28\/4089\/gepotidacin-absssi-fail-adaptively\/","title":{"rendered":"Gepotidacin ABSSSI – How to Fail Adaptively,"},"content":{"rendered":"

Study Design in ABSSSI \u2013 A Statistician\u2019s Delight<\/strong><\/h1>\n

\"\"<\/a><\/p>\n

The design of the O\u2019Riordan ABSSI study [1] deserves comment.\u00a0 This was a double-blind study of 2 lower dose arms (Part 1) with an add-on open-label (Part 2) high-dose arm. The pimary endpoint was a non-standard composite efficacy and safety endpoint that was never used before.\u00a0 There were 3 protocol amendments.\u00a0 There were a series of 5 (five!) interim analyses using adaptive randomization based on efficacy and withdrawal which resulted in step-wise preference for the highest dose considered beneficial.\u00a0 A clinical utility index (CUI) >85% posterior probability was set as a decision criterion, reflecting a minimal \u2018modeled cure rate\u2019 that needed to be attained.\u00a0 Using this \u2018sponsor-defined analysis\u2019, gepatidocin failed in ABSSSI.<\/p>\n

All these design elements resulted in vastly different dosing group sizes and an imbalance in the 3 major skin infection categories (wound infection, major abscess, cellulitis) among the dosing cohorts.\u00a0 The highest percentage of cellulitis cases (and presumably easiest to treat) were in the 1g q8h \/ 2g TID group.\u00a0 Not surprisingly, pathogen recovery was lowest in this highest-dose group.<\/p>\n

There was an option to switch from IV to PO after 2-3 days of IV therapy, ie. after reaching the 1\u00b0 efficacy endpoint (ECR) as in most ABSSSI studies that have a bioequivalent PO formulation.<\/p>\n

Drug resistance was seen in only 2 MRSA isolates with gepotidacin MIC values very much above the susceptibility range due to Par C and E mutations.\u00a0 We consider this an ominous sign recalling the history of quinolones which initially seemed to have reliable MRSA coverage only to be found out about otherwise soon later.<\/p>\n

In our opinion, this Phase 2 dose-finding study was designed by statisticians and not by clinicians.\u00a0 The GSK team used an academic approach, a novel adaptive design, for dose-finding.\u00a0 It also introduced rather arbitrary decision rules based on a combination of efficacy and safety criteria.\u00a0 ABSSSI studies are not easy to execute, and this trial tried to pack too much into a small size of 122 patients.<\/p>\n

We are not in agreement that gepotidacin has insufficient efficacy in ABSSSI based on this trial.\u00a0 Only 1 patient was discontinued for lack of efficacy, and 4 for AEs.\u00a0 None of the other 10 withdrawals (O\u2019Riordan Table 2) should have been part of the primary efficacy analysis.\u00a0 Therefore it seems that this new indication, in other hands, may well have survived.<\/p>\n

Gepotidacin did better using EOT instead of ECR timepoints. EMA and most other regulatory agencies never subscribed to FDA\u2019s ECR approach for efficacy assessment, and we don\u2019t like it either.\u00a0 Many clinicians argued this point at FDA meetings; for them (and for patients!) it is the EOT response that is important.<\/p>\n

Does it matter that gepotidacin was dropped from further development in ABSSSI by GSK? \u00a0Did it truly get a fair trial?\u00a0\u00a0 Would a more traditional approach have resulted in a different more favorable outcome?\u00a0\u00a0 Hard to say at this stage, but we have a strong bias that a good drug was sacrificed on the altar of statistics.<\/span><\/p>\n

REFERENCES<\/strong><\/p>\n

[1] O’Riordan W, 2017. Efficacy, safety, and tolerability of gepotidacin (GSK2140944) in the treatment of patients with suspected or confirmed Gram-positive acute bacterial skin and skin structure infections. Antimicrob\u00a0Agents Chemother 61:e02095-16. https:\/\/doi.org\/10.1128\/AAC.02095-16<\/p>\n

ABBREVIATIONS<\/strong><\/p>\n

CUI\u00a0 \u00a0 Clinical Utility Index
ECR\u00a0 \u00a0Early Clinical Response
TOC\u00a0 \u00a0Test-of-Cure<\/p>\n\n\n

STUDY SIZE<\/strong>
<\/td>		DOSING
REGIMENS<\/strong><\/td>		<\/strong>1\u00b0  ENDPOINT Composite Cure Rate<\/strong><\/td>KEY
RESULTS<\/strong><\/td><\/tr>
122 patients total;

58\/39\/25 per group<\/td>		750 mg IV q12h x 2d, option to switch to 1500 mg PO BID after 2d

1000 mg IV q12h x 2d, option to switch to 2000 mg PO BID after 2d

1000 mg IV q8h IV x 2d, option to switch to 2000 mg PO TID after 2d<\/td>		Clinical Response at the ECR timepoint<\/span><\/u>

Combined with<\/em>

Withdrawal rate<\/td>		750 mg IV q12h and 1000 mg IV q8h groups met pre-specified success criteria for clinical utility in terms of efficacy

1000 mg IV q12h group did not meet criteria due to observed low efficacy rates<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

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

Study Design in ABSSSI \u2013 A Statistician\u2019s Delight The design of the O\u2019Riordan ABSSI study [1] deserves comment.\u00a0 This was a double-blind study of 2 lower dose arms (Part 1) with an add-on open-label (Part 2) high-dose arm. The pimary endpoint was a non-standard composite efficacy and safety endpoint that Continue reading Gepotidacin ABSSSI – How to Fail Adaptively,<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":4095,"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","enabled":false},"version":2}},"categories":[19,227,3,18],"tags":[81,2159,1271,403,2158,428,727,2161,1770,2162,1583,2160,1110],"class_list":["post-4089","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-absssi","tag-adaptive-design","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-bluejepa","tag-dose-finding","tag-fda-approval","tag-fda-endpoint-criteria","tag-gepotidacin","tag-gsk2140944","tag-harald-reinhart","tag-mrsa-resistance","tag-uuti"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/03\/HR_Gepotidacin-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-13X","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":4126,"url":"https:\/\/allphasepharma.com\/dir\/2025\/04\/03\/4126\/blujepa-gepotidacin-fda-approval-uuti-efficacious-e-coli-nitrofurantoin\/","url_meta":{"origin":4089,"position":0},"title":"BLUJEPA \/ Gepotidacin APPROVED FOR UNCOMPLICATED UTI – 1","author":"Harald","date":"April 3, 2025","format":false,"excerpt":"GSK\u2019s pipeline in anti-infectives is impressive. 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