{"id":2064,"date":"2015-10-22T10:47:03","date_gmt":"2015-10-22T14:47:03","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2064"},"modified":"2016-03-23T04:39:10","modified_gmt":"2016-03-23T08:39:10","slug":"polyphor-pol7080-and-the-journey-to-the-land-of-pyocyanea-part-3","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/10\/22\/2064\/polyphor-pol7080-and-the-journey-to-the-land-of-pyocyanea-part-3\/","title":{"rendered":"Polyphor POL7080 And The Journey to The Land of Pyocyanea (Part 3)"},"content":{"rendered":"

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

VABP is clearly the main\u00a0indication to be pursued by a drug like POL7080.\u00a0 Here is the question: How to conduct a study demonstrating efficacy for a drug which only has a\u00a0single-organism spectrum? \u00a0Which is actually no spectrum at all. \u00a0Existing guidelines for the development of ID drugs are indication-driven, with the notable exception of MTB and malaria agents. \u00a0One can study an MRSA drug in ABSSSI, but there is no equivalent indication for P. aeruginosa.<\/p>\n

Finding sufficient numbers of the \u201cright\u201d patients for efficacy determinations will be incredibly difficult as long as we don’t have a rapid bedside diagnostics to\u00a0prove the\u00a0presence of \u00a0P. aeruginosa\u00a0in a\u00a0VABP patient.\u00a0 Enrolling VABP patients indiscriminately before culture results become available means enrolling a patient population where 70- 80% will not have the target organism, i.e., P. aeruginosa, in their respiratory secretions. \u00a0As the majority of VABP patients will harbor other pathogens (like S. aureus or another gram-negative), most randomized patients will not contribute to address the central efficacy question. Dropping patients with negative cultures for P.aeruginosa from the study creates havoc with the randomization and is anathema to statisticians (and the FDA) but maybe the only feasible way to deal with the situation.\u00a0 The current VABP Guidelines are very strict and FDA really does not care much about feasibility, to put it mildly.\u00a0 Following the FDA path for VABP is an option, but not a realistic one.<\/p>\n

There is another big problem: Almost all ICU patients are started\u00a0on antibiotics right after intubation and long before the onset of pneumonia.\u00a0 Hence, ventilated ICU patients are not \u201cantibiotic-na\u00efve\u201d.\u00a0 This prophylaxis often includes antipseudomonas drugs. \u00a0While not condoned by current ATS\/IDSA guidelines it is current practice nonetheless and\u00a0happens all over the world.\u00a0 Hence, only pretreated \u2018break-through\u2019 cases will become available for study.<\/p>\n

Some other feasibility issues cannot be adequately addressed here\u00a0but should at least be mentioned briefly.\u00a0 They relate to the \u2018disappearance of VAP\u2019 as a diagnosis in ICU patients, the positive impact of the \u2018VAP bundle\u2019, and the frequent practice to co-administer aminoglycosides for synergy in possible P. aeruginosa cases. Therefore, enrolling VABP patients with P. aeruginosa becomes a sisyphean effort.<\/p>\n

You guessed it: The cleanest way to conduct a proper VABP study for POL7080 would be with the help of a rapid diagnostic test which identifies P. aeruginosa in respiratory secretions, BAL fluid or tracheal aspirates at the time of enrollment.\u00a0 Roche would be the ideal company to combine a diagnostic with POL7080, select appropriate patients based on rapid identification of P. aeruginosa and randomly allocate them to standard treatment vs POL7080 plus a partner antibiotic.\u00a0 This is a workable approach, not easy but feasible and hopefully acceptable to regulators.<\/p>\n

Most VABP patients will not present with pure P. aeruginosa pneumonia but with a mixed gram-negative flora. P.aeruginosa will be part of the mix of pathogens, mostly gram-negatives and S. aureus.\u00a0 This is probably quite helpful as initial treatment with an experimental drug for pure P. aeruginosa pneumonia, a disease with a mortality of 70%, is probably not advisable.\u00a0 But in the presence of mixed flora, we can follow the P. aeruginosa component under POL7080 therapy. Such a \u00a0study would compare a SoC broad-spectrum antipseudomonal drug (like cefepime, pipercillin\/tazobactam, ceftazidime, meropenem or doripenem) with the combination of, say, ceftriaxone plus POL7080.<\/p>\n

Of course, any VABP study with\u00a0a new antipseudomonal agent should be done without the co-administration of a second antipseudomonal drug.\u00a0 ATS\/IDSA Guidelines for VABP therapy suggest the addition of tobramycin for synergistic P. aeruginosa coverage but such combination therapy would hopelessly confounds any\u00a0efficacy analysis.\u00a0 Remember, such synergy has never been proven convincingly in non-immunocompromised patients, and the\u00a02005\u00a0ATS\/IDSA recommendations\u00a0are reasonably flexible. \u00a0(Note: Work is ongoing on an updated Guidance).<\/p>\n

Of course, questions will be raised about the contribution of P. aeruginosa to a polymicrobial\u00a0disease process, i.e., when P. aeruginosa\u00a0is part of a mixed flora.\u00a0 Such questions are valid but also academic as in clinical practice the organism – once identified – would not be ignored but covered with an anti-pseudomonal\u00a0antibiotic. No single\u00a0VABP trial will clarify this\u00a0issue which could\u00a0not be answered in over\u00a050 years of pneumonia studies. I would think that eradication of the pathogen by POL7080 would be\u00a0a meaningful endpoint in support of the efficacy of POL7080 in this patient population and indication.<\/p>\n

FDA wants sponsors to document efficacy along the coordinates how a patient ‘feels, functions and survives\u2019.\u00a0 Clearly, equal survival rates at 28-days is important.\u00a0 While the \u2018feely\u2019 part is probably impossible to capture in VABP patients, duration of ICU stay and duration of ventilation support can be captured in the CRFs and substitute for a missing PRO assessment.\u00a0

The FERMAT \/ REINHART conjecture states:<\/strong>
\nThere is a way to develop POL7080 but it does not fit on the margin of this page<\/span><\/p>\n<\/div><\/p>\n

Despite these difficulties, a workable development path can be found which should satisfy Health Authorities demanding solid proof of efficacy.\u00a0 POL7080 is a unique drug which requires an innovative approach and will need the support of clinicians, academics and regulators to make it to the market; Phase 3 should not become \u2018Mission Impossible\u2019.<\/p>\n

References:
\n<\/strong>FDA Guidance for Industry. Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment. 2014<\/p>\n

Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia.\u00a0 Am J Respir Crit Care Med Vol 171. pp 388\u2013416, 2005<\/p>\n

Abbreviations:
\n<\/strong>SoC \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 standard-of-care
\nCRF \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0case report form
\nPRO\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 patient reported outcome
\nBAL\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 broncho-alveolar lavage
\nVAP\/VABP \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0ventilator-associated (bacterial) pneumonia<\/p>\n","protected":false},"excerpt":{"rendered":"

VABP is clearly the main\u00a0indication to be pursued by a drug like POL7080.\u00a0 Here is the question: How to conduct a study demonstrating efficacy for a drug which only has a\u00a0single-organism spectrum? \u00a0Which is actually no spectrum at all. \u00a0Existing guidelines for the development of ID drugs are indication-driven, with Continue reading Polyphor POL7080 And The Journey to The Land of Pyocyanea (Part 3)<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2065,"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":[19,18],"tags":[1271,403,1302,347,741,432,5,1380,1378,1583,590,346,747,295,1377,923,173,184,356,1379],"class_list":["post-2064","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_viewpoint","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-cefepime","tag-ceftazidime","tag-doribax","tag-doripenem","tag-fda","tag-feasibility","tag-fortaz","tag-harald-reinhart","tag-malaria","tag-meropenem","tag-merrem","tag-mtb","tag-pipercillintazobactam","tag-pol7080","tag-polyphor","tag-roche","tag-vabp","tag-vabp-guidance"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P3.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-xi","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2061,"url":"https:\/\/allphasepharma.com\/dir\/2015\/10\/20\/2061\/polyphor-pol7080-and-the-journey-to-the-land-of-pyocyanea-part-2\/","url_meta":{"origin":2064,"position":0},"title":"Polyphor POL7080 And The Journey to The Land of Pyocyanea\u00a0 (Part 2)","author":"Harald","date":"October 20, 2015","format":false,"excerpt":"Roche\u2019s current Phase 2 program is strangely ambiguous. RG-7929 has not made it into www.clinicaltrials.gov yet, only POL7080 is listed. An uncontrolled open label study in \u201cpatients with non-CF acute exacerbation of bronchiectasis due to P. aeruginosa requiring IV treatment\u201d is enrolling. Well, good luck finding those patients! At best,\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"bridge Pyocyanea-P2","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P2.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P2.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P2.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1981,"url":"https:\/\/allphasepharma.com\/dir\/2015\/10\/05\/1981\/polyphor-pol-7080-and-the-journey-to-the-land-of-pyocyanea-part-1\/","url_meta":{"origin":2064,"position":1},"title":"Polyphor POL7080 And The Journey to The Land of Pyocyanea\u00a0 (Part 1)","author":"Harald","date":"October 5, 2015","format":false,"excerpt":"When Roche inlicensed Polyphor\u2019s anti-pseudomonas drug POL7080 in November 2013, it marked a turning point. It seemed that Big Pharma that had all but abandoned the field in the last decade and was getting engaged in anti-infectives again. When a company with as\u00a0much experience in antibiotic drug development as Roche\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"bridge Pyocyanea copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":3851,"url":"https:\/\/allphasepharma.com\/dir\/2025\/01\/03\/3851\/critical-review-whos-list-antibacterials-clinical-development\/","url_meta":{"origin":2064,"position":2},"title":"A Critical Review of WHO\u2019s List of Antibacterials in Clinical Development","author":"Harald","date":"January 3, 2025","format":false,"excerpt":"WHO compiles a list of antibacterials in clinical development on a regular basis, the last in mid-2024 [1].\u00a0 The information is up-to-date and detailed: it provides MoA and antibacterial spectrum, coverage of problem pathogens, the development phase, and whether it can be considered an \u2018innovative\u2019 drug (based on a set\u2026","rel":"","context":"In "Recent Literature"","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\/01\/WHO-Blog.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":5040,"url":"https:\/\/allphasepharma.com\/dir\/2025\/08\/21\/5040\/an-intro-to-emblaveo-aztreonam-avibactam\/","url_meta":{"origin":2064,"position":3},"title":"An Intro to Emblaveo (aztreonam + avibactam)","author":"Harald","date":"August 21, 2025","format":false,"excerpt":"The FDA web site usually provides label and review documents for approved drugs.[1]\u00a0 Emblaveo, the combination of aztreonam and avibactam, was approved in February 2025, almost \u00bd year ago, but clinical review documents are still not posted at the site.[2]\u00a0 Hence, we do not know how Regulators felt about the\u2026","rel":"","context":"In "Recent Literature"","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\/08\/avibactam-Stick-Model.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=700%2C400&ssl=1 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=1050%2C600&ssl=1 3x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=1400%2C800&ssl=1 4x"},"classes":[]},{"id":1362,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/08\/1362\/arties-law-avoid-bad-advice-and-dont-follow-mission-impossible-advice\/","url_meta":{"origin":2064,"position":4},"title":"Artie\u2019s Law: Avoid Bad Advice and Don\u2019t Follow \u2018Mission Impossible\u2019 Advice","author":"Harald","date":"April 8, 2015","format":false,"excerpt":"In this day and age, few truly broad spectrum antibiotics are in development, although this does not hold true for narrow-spectrums.\u00a0 Just think of all the MRSA drugs (quinolones, FabI inhibitors), the pseudomonas drugs (NCEs and monoclonals) or some narrow spectrum drugs that will need to be tested in MDR\u2026","rel":"","context":"In "The Viewpoint"","block_context":{"text":"The Viewpoint","link":"https:\/\/allphasepharma.com\/dir\/category\/the_viewpoint\/"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":2289,"url":"https:\/\/allphasepharma.com\/dir\/2016\/02\/10\/2289\/the-10-x-20-goal-are-we-on-track\/","url_meta":{"origin":2064,"position":5},"title":"The 10 x \u201920 Goal \u2013 Are We On Track?","author":"Harald","date":"February 10, 2016","format":false,"excerpt":"In the last decade (2000-2010), we saw the number of new antibiotic approvals drop successively each year; FDA changed the rules of the approval process without providing public guidance; many antibiotic companies fled the therapeutic area; investments were redirected to oncology projects which had a much better ROI. 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