AZD-0914: A New Broad-Spectrum Narrow-Development Path Drug

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 mention a peculiar MoA for this gyrase/topoisomerase inhibitor stating (we quote): “while its mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct”.[1]

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

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][3]  So, awaiting justification why these ‘distinct’ 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’s the word, panache, maybe?

With no published clinical data for AZD-0914 (or ETX-0914 or Zoliflodacin) at this time, we will have to wait for answers whether unique features trump the similarities, or the reverse. A Phase 2 trial in GC was recently completed and we should learn about the results soon.

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.

A word about the ubiquitous mention of “low frequency of mutation” 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]. Single step mutants for AZD-01-914 were selected at <1.4 x 10^-14 which we interpret to mean “rarely” or “barely”. Sounds good. But then we also read that single step mutants were selected at the much higher frequency of 1 x 10^-8 using slightly modified test conditions [5]. Figures!

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 AZD-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 [6]. By comparison, standard GC doses for ciprofloxacin were between 250 mg and 500 mg PO.

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’s 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.

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

Of note, gepotidacin is now the only antibacterial left in GSK’s development portfolio [8].

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