{"id":420,"date":"2014-06-26T01:56:07","date_gmt":"2014-06-26T01:56:07","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=420"},"modified":"2015-07-22T13:10:17","modified_gmt":"2015-07-22T17:10:17","slug":"fighting-p-aeruginosa-part-ii","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/06\/26\/420\/fighting-p-aeruginosa-part-ii\/","title":{"rendered":"Fighting P. aeruginosa (Part II)"},"content":{"rendered":"<p><a href=\"https:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PipTazo.jpe\"><img loading=\"lazy\" decoding=\"async\" class=\"alignright  wp-image-425\" src=\"https:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PipTazo.jpe\" alt=\"PipTazo\" width=\"180\" height=\"180\" srcset=\"https:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PipTazo.jpe 225w, https:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PipTazo-150x150.jpe 150w\" sizes=\"auto, (max-width: 180px) 100vw, 180px\" \/><\/a>At a still earlier stage of development, we found\u00a0some exciting\u00a0anti-pseudomonal compounds.<\/p>\n<p>First, there is BAL-30072, a sulfactam-derivative.\u00a0 It has an interesting dual MoA as it works not only as a traditional B-lactam but also as an Fe-chelator blocking bacteria from accessing this essential nutrient [i].\u00a0 It has very good anti-pseudomonas activity and often much lower MIC90 against other problem Gram-negatives, like acinetobacter, stenotrophomonas and Burkholderia as well.\u00a0<!--more--><\/p>\n<p>It is should be mentioned that MIC testing was performed in the presence of the iron binder bipyridyl; it will be interesting to learn how MIC determinations under these conditions correlate with animal model data and ultimately with clinical efficacy.\u00a0 Basilea just announced the start of a Phase 1 trial of BAL-30072 in combination with meropenem which seems to provide additive\/synergistic activity [ii].<\/p>\n<p>Shionogi\u2019s cephem antibiotic S-649266 is expected to enter Phase 2 testing in the US later this year; it also affects the bacterial Fe uptake channel in addition to its classic B-lactam action (interference with cell wall biosynthesis).\u00a0 It has activity against metallo-lactamase (e.g., NDM-1)-producing strains of Gram-negatives and against MDR-P. aeruginosa [iii].<\/p>\n<p>With relatively few antipseudomonal drugs in the pipeline, it makes sense to investigate non-traditional approaches, like phage therapy, antitoxins, blockers of virulence mechanisms and quorum sensing, inhibitors of attachment or biofilm production. However, while animal models often suggest prophylactic and therapeutic benefits with these approaches, efficacy data are sparse or non-existing in the clinical setting.<\/p>\n<p>Antibodies to the recently described Type 3 Secretion System (T3SS) are being developed by various companies.\u00a0 Preclinical studies showed that blocking this key virulence factor holds promise prophylactically and possibly therapeutically.\u00a0 Here just 2 more advanced projects:<\/p>\n<ul>\n<li>Kalobios is developing its T3SS monoclonal antibody (KB-001 A) which <a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/TTSS.jpg?ssl=1\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"alignright  wp-image-865\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/TTSS.jpg?resize=197%2C244&#038;ssl=1\" alt=\"TTSS\" width=\"197\" height=\"244\" \/><\/a>targets the PcrV protein, a key component of the toxin delivery apparatus of P. aeruginosa in collaboration with Sanofi.\u00a0 In Phase 1\/2 studies KB-001 was safe, however, the number of CF patients was too small to make any efficacy claims.\u00a0 Results of a new and more definitive trial in cystic fibrosis patients should become available soon [iv].\u00a0 In a small study of ventilated patients colonized with P. aeruginosa, KB-001 showed a favorable trends towards clinical improvement [v].<\/li>\n<li>Shionogi [vi] has filed a patent for h1F3, a humanized monoclonal T3SS antibody directed against PcrV. \u00a0h1F3 neutralizes the cytotoxic effect exerted by P. aeruginosa in cell culture systems due to high-affinity binding.\u00a0 It is still in preclinical testing.<\/li>\n<\/ul>\n<p>IC43 is a hybrid P.\u00a0aeruginosa outer membrane protein OprF\/I vaccine currently in Phase 2\/3 confirmatory efficacy testing at Novartis.\u00a0 Earlier Phase 2 results from a 400 patient trial in ventilated patients showed good immune responses after the 2<sup>nd<\/sup> dose (on Day 7) and significantly lower mortality in the treatment group (22% vs 40%) [vii].\u00a0 Novartis now aims to replicate these results obtained by Intercell in a larger well-controlled registration trial enrolling 800 patients.\u00a0 Primary endpoint is Day 28 mortality.<\/p>\n<hr \/>\n<p><span style=\"color: #ff0000;\"><span style=\"text-decoration: underline;\">NOTE added 7\/15\/2015: \u00a0<\/span><br \/>\nKalobios discontinued the KB001 program on Jan. 6, 20\/15 due to lack of efficacy in a well-controlled CF study which did not show a benefit on any predefined endpoint of efficacy.\u00a0[1] \u00a0For details, p<\/span><span style=\"color: #ff0000;\">lease check our blog at\u00a0<a href=\"https:\/\/allphasepharma.com\/dir\/2015\/07\/21\/1757\/the-demise-of-kb001-part-i-an-anti-pseudomonas-antibody-hits-the-dust-instead-of-paydirt\/\">The Demise of KB001<\/a><\/span><\/p>\n<p><strong>References<\/strong><\/p>\n<p>[i] Page. Antimicrob. Agents Chemother. 54: 2291; 2010<br \/>\n[ii] http:\/\/www.cnbc.com\/id\/101752624#<br \/>\n[iii] http:\/\/www.shionogi.co.jp\/en\/ir\/pdf\/e_p140319.pdf<br \/>\n[iv] http:\/\/kalobios.com\/pr_01102013<br \/>\n[v] http:\/\/www.kalobios.com\/pdf\/Updated%20Anti-PcrV%20_KB001A__Fact%20Sheet_111213.pdf<br \/>\n[vi] http:\/\/www.google.com\/patents\/US20120093808<br \/>\n[vii] http:\/\/www.news-medical.net\/news\/20101025\/Intercells-IC43-Phase-II-trial-against-Pseudomonas-aeruginosa-infections-meets-primary-endpoint.aspx<\/p>\n<p><span style=\"color: #ff0000;\">[1]\u00a0http:\/\/ir.kalobios.com\/releasedetail.cfm?ReleaseID=889910<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>At a still earlier stage of development, we found\u00a0some exciting\u00a0anti-pseudomonal compounds. First, there is BAL-30072, a sulfactam-derivative.\u00a0 It has an interesting dual MoA as it works not only as a traditional B-lactam but also as an Fe-chelator blocking bacteria from accessing this essential nutrient [i].\u00a0 It has very good anti-pseudomonas <a class=\"more-link\" href=\"https:\/\/allphasepharma.com\/dir\/2014\/06\/26\/420\/fighting-p-aeruginosa-part-ii\/\">Continue reading <span class=\"screen-reader-text\">  Fighting P. aeruginosa (Part II)<\/span><span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":868,"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":[3],"tags":[198,403,422,203,201,208,207,209,204,346,202,174,197,210,196,199,200,421,205,206],"class_list":["post-420","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_news","tag-acinetobacter","tag-antibiotic-blog","tag-burkholderia","tag-fe-chelator","tag-h1f3","tag-intercell","tag-kalobios","tag-kb001","tag-mdr-pathogens","tag-meropenem","tag-mic-testing","tag-novartis","tag-p-aeruginosa","tag-pcrv","tag-pseudomonas","tag-s-649266","tag-shionogi","tag-stenotrophomonas","tag-t3ss","tag-type-3-secretion-system"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA123-e1410379729275.jpg?fit=260%2C73&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-6M","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":378,"url":"https:\/\/allphasepharma.com\/dir\/2014\/06\/23\/378\/fighting-p-aeruginosa-part-i\/","url_meta":{"origin":420,"position":0},"title":"Fighting P. aeruginosa (Part I)","author":"Harald","date":"June 23, 2014","format":false,"excerpt":"It has never been easy to cure Pseudomonas aeruginosa infections.\u00a0 Few antibiotics nowadays have reliable activity against this problem pathogen that seems to have more built-in resistance features than most other Gram-negatives.\u00a0 In the past, cephalosporins, aztreonam, penems, ciprofloxacin, and aminoglycosides were useful drugs with reliably cidal activity, especially when\u2026","rel":"","context":"In &quot;The News&quot;","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"PA-01 on Agar","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar-300x274.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1401,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/30\/1401\/a-renaissance-for-old-drugs-fosfomycin-and-colistin\/","url_meta":{"origin":420,"position":1},"title":"A Renaissance for Old Drugs: Fosfomycin and Colistin","author":"Harald","date":"April 30, 2015","format":false,"excerpt":"Fosfomycin Who would have thought that a drug that has been around since 1969 [2] could become eligible for QIDP status in 2015? Well, Zavante Therapeutics recently garnered the coveted QIDP designation for fosfomycin IV. This formulation has been available in Europe for a quite some\u00a0time but not in the\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"","width":0,"height":0},"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":420,"position":2},"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 &quot;QIDP Antibiotics&quot;","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":1757,"url":"https:\/\/allphasepharma.com\/dir\/2015\/07\/21\/1757\/the-demise-of-kb001-part-i-an-anti-pseudomonas-antibody-hits-the-dust-instead-of-paydirt\/","url_meta":{"origin":420,"position":3},"title":"The Demise of KB001 (Part 1): An Anti-Pseudomonas Antibody Hits the Dust (Instead of Paydirt)","author":"Harald","date":"July 21, 2015","format":false,"excerpt":"In January this year, Kalobios informed investors that KB001-A had failed to meet efficacy criteria in a Phase 2 trial of cystic fibrosis (CF) patients.\u00a0 In this well-controlled well-executed placebo-controlled trial of182 patients, the primary endpoint and just about every other efficacy endpoint of interest was missed.\u00a0 Neither did KB001\u2026","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"KaloBios  slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/KaloBios-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/KaloBios-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/KaloBios-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1769,"url":"https:\/\/allphasepharma.com\/dir\/2015\/07\/28\/1769\/the-demise-of-kb001-part-2-an-anti-pseudomonas-antibody-hits-the-dust-instead-of-paydirt\/","url_meta":{"origin":420,"position":4},"title":"The Demise of KB001 (Part 2): An Anti-Pseudomonas Antibody Hits the Dust (instead of Paydirt)","author":"Harald","date":"July 28, 2015","format":false,"excerpt":"FOR\u00a0PART 1, CLICK HERE Should we assume that the results of this Global Epi Study were the reason why Sanofi became disillusioned about the prospects of KB001? \u00a0Or was it an internal strategic decision based on portfolio-review where KB001 just no longer made the cut? The results of the Global\u2026","rel":"","context":"In &quot;The News&quot;","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"KB Part 2 NEW","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/KB-Part-2-NEW.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/KB-Part-2-NEW.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/KB-Part-2-NEW.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":445,"url":"https:\/\/allphasepharma.com\/dir\/2014\/07\/02\/445\/why-the-next-novel-antibiotic-will-cost-40k-or-more\/","url_meta":{"origin":420,"position":5},"title":"Why The Next Novel Antibiotic Will Be A Blockbuster And Cost $40k","author":"Harald","date":"July 2, 2014","format":false,"excerpt":"Looking at all antibiotics in the pipeline, I can\u2019t help but think that \u2013 by 2018 \u2013 there\u00a0will be\u00a0some blockbuster anti-infectives coming to the market. Why do I say this?\u00a0 What is going to generate this revenue stream for companies when the new crop of drugs will be restricted by\u2026","rel":"","context":"In &quot;The Viewpoint&quot;","block_context":{"text":"The Viewpoint","link":"https:\/\/allphasepharma.com\/dir\/category\/the_viewpoint\/"},"img":{"alt_text":"pills","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/07\/pills-300x225.jpg?resize=350%2C200","width":350,"height":200},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/420","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=420"}],"version-history":[{"count":9,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/420\/revisions"}],"predecessor-version":[{"id":1768,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/420\/revisions\/1768"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/868"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=420"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=420"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=420"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}