{"id":1981,"date":"2015-10-05T05:47:15","date_gmt":"2015-10-05T09:47:15","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1981"},"modified":"2017-04-07T08:57:51","modified_gmt":"2017-04-07T12:57:51","slug":"polyphor-pol-7080-and-the-journey-to-the-land-of-pyocyanea-part-1","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/10\/05\/1981\/polyphor-pol-7080-and-the-journey-to-the-land-of-pyocyanea-part-1\/","title":{"rendered":"Polyphor POL7080 And The Journey to The Land of Pyocyanea\u00a0 (Part 1)"},"content":{"rendered":"

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

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 sees value even in a narrow-spectrum specialty drug, there is hope that others will follow.<\/p>\n

Roche then acquired a Phase I beta-lactamase inhibitor OP-0595 from Meiji \/ Fedora early in 2015. Also known as FPI-1459, it has now been christened as Roche \/ Genentech drug RG-6080. This is a diazabicyclooctane beta-lactamase inhibitor (BLI) which does not have a beta-lactam\u00a0ring structure. We are not told what other beta-lactam drug will be combined with it.<\/p>\n

POL7080 has also been renamed, it now goes by the new moniker RG7929. \u00a0I will continue to call it POL7080 here just for convenience because this renaming game is simply getting out of hand. Many companies keep at least the compound number designation constant but many do not. GSK, Novartis, Roche and others have their own ways of confusing the ancestry (and the reviewers); in published information the drug may even be referred to under a code name. OK, back to POL7080.<\/span><\/p>\n

Let\u2019s briefly review the attributes which make POL7080 such an interesting compound: First, it is a totally novel drug, with a MoA we never heard of before. The target is LptD, also called OstA, which is an essential outer membrane protein.[1]<\/a>\u00a0 The drug is a synthetic cyclopeptide and peptidomimetic and hence an IV drug only[2]<\/a>,[3]<\/a>\u00a0 It has excellent bactericidal activity against P. aeruginosa: MICs are consistently in the <0.5 mg\/L range. While Providencia species are\u00a0susceptible as well, S. maltophilia and B. cepacia are\u00a0not and neither are\u00a0other Gram-negatives.[4]<\/a><\/p>\n

In a mouse septicemia model using two P. aeruginosa strains, POL7080 reduced mortality.[5]<\/a>\u00a0In a murine P. aeruginosa pneumonia model, the drug worked against MDR and non-MDR P. aeruginosa strains, but tissue log CFUs reductions were not all that impressive.[6]<\/a><\/p>\n

An SAD \/ MAD Phase I study for safety and PK was conducted in 52 healthy volunteers. Maximum exposures were 10 mg\/kg\/day for the SD, and 2 mg\/kg q8h (6 mg\/kg\/day) for the MD cohorts. The max. duration of exposure was 6 days. POL7080 was given IV q12h or q8h, with 2-3 hour infusion times. A summary of Phase 1 findings is available in abstract form only but we are told that renal excretion is the main route of elimination and that despite a long half-life no significant accumulation was observed. Like other cationic molecules, e.g., aminoglycosides (AG), proximal tubular reuptake is via the megalin receptor.[7]<\/a>\u00a0 Hence, drug-drug interaction with colistin and AGs are\u00a0to be expected, making such\u00a0combinations problematic.<\/p>\n

The authors state that no significant side effects were seen in Phase 1 studies.
\nNB: Such bland boilerplate proclamations of safety have become a standard fixture of company press releases and early abstracts; let’s\u00a0wait for further human data before accepting this as more than a \u2018forward looking statement\u2019. Somebody please explain why the infusion has to be administered so slowly? How about the history of the protegrin class which is known for hemolysis? Anyway, let\u2019s move on.<\/span><\/p>\n

Details of the serum PK profile have not been published, only interpretations of the data.\u00a0 Based on PK\/PD modeling and PopPK a dose of 7.5 mg\/kg per day for treatment of \u201cVAP patients with normal renal function\u201d should be adequate for pathogens up to an MIC of 1 mg\/L. This daily dose is obviously higher than the doses tested in Phase 1. As we know from painful experience, ICU and VAP patients have significantly\u00a0altered PK, with higher Vd requiring higher dosing. This was considered in the Monte-Carlo simulations; hence, the recommendation is for doses of 200 mg IV q8h (or higher) in this patient population.[8]<\/a>\u00a0 When you do the math this means that 10-12 mg\/kg\/day may actually be required.<\/p>\n

In November 2014, POL7080 became a QIDP drug, a designation from FDA which this drug deserves more than most recent nominees (which include SYM-1219 for bacterial vaginosis!).<\/p>\n

Since its acquisition, Roche has moved the drug into Phase 2 starting with a few rather small PK and safety studies.<\/p>\n

But it remains\u00a0unclear in which major population Roche will conduct its efficacy testing for POL7080. Polyphor indicated that it would want the drug to be developed in \u201cVABP caused by P. aeruginosa\u201d. If this is the chosen indication for Phase 3, it will need a very unorthodox and innovative development path, both by regulatory and clinical standards.<\/p>\n

We\u00a0will address these options and the VABP \u2018minefield\u2019 in Part 2 of this blog.<\/p>\n

Abbreviations:<\/strong>
\nVd \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0volume of distribution
\nPopPK \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 population PK
\nSD, MD \u00a0 \u00a0 \u00a0 \u00a0 \u00a0single dose, multiple dose
\nVAP, VABP \u00a0 ventilator-associated (bacterial) pneumonia
\nSAD, MAD \u00a0 \u00a0 single \/ multiple ascending dose<\/p>\n

References:
\n<\/b>[1]<\/a> Srinivas N.\u00a0 Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 2010, 327:1010
\n[2]<\/a> Olbrecht D. F1-3995. Mechanism of Action of POL7080, a Novel Anti-Pseudomonal Compound.\u00a0 IDSA Poster Session: Peptides and Peptide Mimetics. 2008
\n[3]<\/a> Mendez-Samperio P.\u00a0\u00a0 Peptidomimetics as a new generation of antimicrobial agents: current progress.\u00a0 Review.\u00a0 Infection and Drug Resistance e 2014:7 229
\n[4]<\/a> Sader H.\u00a0 P1456 Abstract (poster session) In vitro evaluation of antimicrobial spectrum and determination of optimal MIC test conditions for the novel protein epitope mimetics antibiotic POL7080.\u00a0 ECCMID 2012
\n[5]<\/a> Moir T.\u00a0 New classes of antibiotics.\u00a0 Current Opinion in Pharmacology 2012, 12:535
\n[6]<\/a> Lundberg C. P0302 Poster Session.\u00a0 POL7080 is highly efficacious in the murine pneumonia model. \u00a0ECCMID 2015
\n[7]<\/a> Kuhlmann O. Metabolism And Excretion Of The New LptD Peptide Antibiotic RG7929.\u00a0 Poster A-973.\u00a0 ICAAC 2015 \u2013 San Diego
\n[8]<\/a> Muller A.\u00a0 P0303.\u00a0 Poster Session I.\u00a0 New therapeutic alternatives. The impact of creatinine clearance on the dosing of POL7080, a new macrocyclic antibiotic.\u00a0 ECCMID 2014<\/p>\n","protected":false},"excerpt":{"rendered":"

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 Continue reading Polyphor POL7080 And The Journey to The Land of Pyocyanea\u00a0 (Part 1)<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1983,"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":[19,227,3,18],"tags":[176,1363,403,1360,495,1359,1368,1372,177,1354,1356,246,1365,1367,1353,174,1362,1355,1366,197,1361,923,173,1364,1357,1358,1369,184,1238,356,79,734],"class_list":["post-1981","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-aminoglycoside","tag-anti-pseudomonal","tag-antibiotic-blog","tag-bacterial-vaginosis","tag-betalactamase-inhibitor","tag-bli","tag-cationic-drug","tag-clinical-trial","tag-colistin","tag-fedora","tag-fpi-1459","tag-gsk","tag-lptd","tag-megalin-receptor","tag-meiji","tag-novartis","tag-novel-moa","tag-op-0595","tag-osta","tag-p-aeruginosa","tag-peptidomimetic","tag-pol7080","tag-polyphor","tag-protegrin","tag-rg-6080","tag-rg-7929","tag-rg6080","tag-roche","tag-sym-1219","tag-vabp","tag-vap","tag-ventilator-associated-pneumonia"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-vX","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":1981,"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":2064,"url":"https:\/\/allphasepharma.com\/dir\/2015\/10\/22\/2064\/polyphor-pol7080-and-the-journey-to-the-land-of-pyocyanea-part-3\/","url_meta":{"origin":1981,"position":1},"title":"Polyphor POL7080 And The Journey to The Land of Pyocyanea (Part 3)","author":"Harald","date":"October 22, 2015","format":false,"excerpt":"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\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"bridge Pyocyanea-P3","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P3.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P3.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-P3.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2289,"url":"https:\/\/allphasepharma.com\/dir\/2016\/02\/10\/2289\/the-10-x-20-goal-are-we-on-track\/","url_meta":{"origin":1981,"position":2},"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. The IDSA\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"10x20 blog - slider copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/02\/10x20-blog-slider-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/02\/10x20-blog-slider-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/02\/10x20-blog-slider-copy.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/02\/10x20-blog-slider-copy.jpg?resize=700%2C400 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/02\/10x20-blog-slider-copy.jpg?resize=1050%2C600 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