{"id":2480,"date":"2016-05-12T08:28:57","date_gmt":"2016-05-12T12:28:57","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2480"},"modified":"2016-09-20T12:22:39","modified_gmt":"2016-09-20T16:22:39","slug":"azd-0914-a-new-broad-spectrum-narrow-development-path-drug","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/05\/12\/2480\/azd-0914-a-new-broad-spectrum-narrow-development-path-drug\/","title":{"rendered":"AZD-0914: A New Broad-Spectrum Narrow-Development Path Drug"},"content":{"rendered":"
\"gonorrhea<\/a>
AstraZeneca AZD-0914 now Entasis ETX-0914<\/figcaption><\/figure>\n

At first glance, the list of features that distinguish AZD-0914 from other FQ seems impressive: broad Gram-positive and Gram-negative activity, MRSA and MSSA activity, potency against fluoroquinolone (FQ)-resistant isolates, low frequency for S. aureus resistance, and impressive activity against C. difficile. In addition, researchers\u00a0mention a peculiar MoA for this gyrase\/topoisomerase inhibitor stating (we quote): \u201cwhile its mechanism is similar to that seen with \ufb02uoroquinolones, it is mechanistically distinct\u201d.[1]<\/a><\/p>\n

What is this supposed to mean? Similar mechanism but mechanistically distinct?\u00a0 Such contrived semantics makes us stop and reflect for a moment. Does this seemingly utter contradiction make any sense? The word \u2018similar\u2019 already implies that the properties of the molecules being compared have much in common but are not identical.<\/p>\n

As far as the dissimilar features are concerned (stabilization of gyrase with DNA pieces; prevention of religation), it remains to be seen whether these are epiphenomena of no clinical importance or truly differentiating features as claimed in a couple of posters.[2]<\/a>[3]<\/a> \u00a0So, awaiting justification why these \u2018distinct\u2019 MoA features matter, one would conservatively assume that AZD-0914 works mostly like any other quinolone on the known DNA targets, DNA gyrase and topoisomerase IV. Just with a little more, what\u2019s the word, panache, maybe?<\/p>\n

With no published clinical data for AZD-0914 (or ETX-0914 or Zoliflodacin)\u00a0at this time, we will have to wait for\u00a0answers whether unique features trump the similarities, or the reverse. A\u00a0Phase 2 trial in GC was recently completed and we should learn about\u00a0the\u00a0results soon.<\/p>\n

Why is it that AZD-0914 is only being developed for GC? With a truly novel MoA, there would be a great opportunity to develop this drug in many additional indications now being pursued by other broad-spectrum antibiotics, like delafloxacin, eravacycline, or plazomicin. We have to conclude that the chosen narrow development path of AZD-094 (in GC only) shares the paradoxical features with its MoA: similar but different.<\/p>\n

There is no\u00a0direct relationship between “Mutation Frequency” in lab testing and clinical resistance development<\/span><\/p>\n<\/div>A word about the ubiquitous mention of \u201clow frequency of mutation\u201d is in order: it is a laboratory test done for all antibiotics that has absolutely no relationship to clinical resistance development, a point again emphasized at a recent presentation [4]<\/a>. Single step mutants for AZD-01-914 were selected at <1.4 x 10-14 <\/sup>which we interpret to mean \u201crarely\u201d or \u201cbarely\u201d. Sounds good. But then we also read\u00a0that single step mutants were selected at the much higher frequency of 1 x 10-8 <\/sup>using slightly modified test conditions\u00a0[5]<\/a>. Figures!<\/p>\n

MICs of wild-type N. gonorrhoeae were 0.004 mg\/L and 0.125 mg\/L for ciprofloxacin and AZD-0914, respectively. When the first ciprofloxacin-resistant N. gonorrhoeae treatment failures were reported after approx.10 years of clinical use, the GC isolates had MICs of 1-2 mg\/L. In the case of\u00a0AZD-0914, MICs are much closer to breakpoint levels; does this have an impact on its useful lifespan? With doses for GC of 2 grams and 3 grams PO there should be enough systemic exposure to prevent resistance for a while but we still need to see the full PK profile\u00a0[6]<\/a>. By comparison, standard GC doses for ciprofloxacin were between 250 mg and 500 mg PO.<\/p>\n

In AZ\u2019s larger strategy, anti-infectives no longer have a place<\/span><\/p>\n<\/div>The push to develop the drug in-house was obviously low at AZ which decided to hand the drug over to its spin-off Entasis. This move can be interpreted in different ways: only a die-hard optimist would say that AZ felt so strongly about the drug that it created an independent development group. More realistically speaking, it was a lukewarm endorsement for AZD-0914. In any case, it was a tactical opportunistic move: in AZ\u2019s larger strategy, anti-infectives no longer have a place. If MEDI-4893 (anti-Staph monoclonal antibody) does not do exceptionally well in in the still ongoing Phase 2 trial, a study of the prevention of S. aureus VABP in ICU patients, we will see another reshuffling of priorities at AZ.<\/p>\n

There is another topoisomerase II drug in development, gepotidacin or\u00a0GSK-2140944. Its MIC50 for N. gonorrhoeae is\u00a0approx. 0.5 mg\/L (range: 0.25-1 mg\/L) [7]<\/a>. This drug is being developed not only for GC, but also for skin infections and CABP. Here the moniker “similar but different”\u00a0makes more sense, perhaps.<\/p>\n

Of note,\u00a0gepotidacin is now the only antibacterial left in GSK’s development portfolio [8]<\/a>.<\/p>\n

Publications:
\n<\/strong>[1]<\/a> M Hubard.\u00a0 AAC\u00a0 59: 467; 2015
\n[2]<\/a> Kern G\u00a0 2011. Poster F1-1840. 51st ICAAC, 17 to 20 September 2011, Chicago, IL.
\n[3]<\/a> Palmer T.\u00a0 Poster C-1422. 54th ICAAC, 5 to 9 September 2014, Washington, DC|
\n[4]<\/a> Dan I. Andersson. Preclinical studies \u2013 predicting emergence of resistance. Oral Presentation #S217, ECCMID Amsterdam April 2016
\n[5]<\/a> S. Foerster. Front. Microbiol. 6: 1377, 2015
\n[6]<\/a> No results from Phase 1 studies listed on clinicaltrials.gov (accessed 5\/9\/16)
\n[7]<\/a>\u00a0R Jones. AAC pii: AAC.00527-16.\u00a02016 May 9
\n[8]<\/a>\u00a0http:\/\/www.gsk.com\/media\/1017505\/product-pipeline-march-2016.pdf<\/p>\n","protected":false},"excerpt":{"rendered":"

At first glance, the list of features that distinguish AZD-0914 from other FQ seems impressive: broad Gram-positive and Gram-negative activity, MRSA and MSSA activity, potency against fluoroquinolone (FQ)-resistant isolates, low frequency for S. aureus resistance, and impressive activity against C. difficile. In addition, researchers\u00a0mention a peculiar MoA for this gyrase\/topoisomerase Continue reading AZD-0914: A New Broad-Spectrum Narrow-Development Path Drug<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2482,"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":[19,3,18],"tags":[81,172,1633,403,585,609,783,236,1306,425,1222,1631,1630,1065,1635,246,1636,1063,1583,1632,1180,599,251,83,1053,813,170,1371,435,1629,356,1634,1637],"class_list":["post-2480","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-absssi","tag-achaogen","tag-anti-staphylococcal-monoclonal-antibody","tag-antibiotic-blog","tag-astrazeneca","tag-azd-0914","tag-cabp","tag-delafloxacin","tag-entasis","tag-eravacycline","tag-etx-0914","tag-fom","tag-frequency-of-mutation","tag-gc","tag-gepoticidin","tag-gsk","tag-gsk-2140944","tag-gyrase-inhibitor","tag-harald-reinhart","tag-medi-4893","tag-medimmune","tag-melinta","tag-moa","tag-mrsa","tag-mssa","tag-n-gonorrhoeae","tag-plazomicin","tag-qidp","tag-tetraphase","tag-topoisomerase-ii-inhibitor","tag-vabp","tag-vabp-prophylaxis","tag-zoliflodacin"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/05\/gonorrhea-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-E0","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1907,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/03\/1907\/mrsa-fluoroquinolones-an-interesting-bunch-playing-a-high-stakes-game\/","url_meta":{"origin":2480,"position":0},"title":"MRSA Fluoroquinolones \u2013 An Interesting Bunch Playing a High-Stakes Game","author":"Harald","date":"September 3, 2015","format":false,"excerpt":"Fluoroquinolones (FQ) of the ofloxacin\/ciprofloxacin generation were mainly active against Gram-negative bacteria, distinguishing themselves as cidal IV\/PO drugs with high\u00a0potency\u00a0against most lactose- and non-lactose fermenters.\u00a0 They were excellent against problem pathogens like P. aeruginosa, had excellent efficacy\u00a0against Salmonellae, the Gonococcus and other Neisseriae, and you could count on them for\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"antiMRSA 1 copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1561,"url":"https:\/\/allphasepharma.com\/dir\/2015\/06\/17\/1561\/treating-gc-in-the-face-of-dwindling-antibiotic-options-2\/","url_meta":{"origin":2480,"position":1},"title":"Treating GC in the Face of Dwindling Antibiotic Options \u2013 (2)","author":"Harald","date":"June 17, 2015","format":false,"excerpt":"For GC antibiotics, the development path looks like a trip down the road less traveled, leading into some uncharted territory. 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When narrowing down the search looking for clinical trials only, there are none. Taxis Pharmaceuticals obtained QIDP status for its candidate drug TXA-709 in late 2016 and it is still in preclinical testing. 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