Plazomicin – A Quick Take On A Complex Drug With A Complex Development Path

Whenever a new drug is in late stage development, its prospects become the focus of intense scrutiny. Plazomicin (ACHN-490), like any Phase 3 drug should be evaluated along the following dimensions:

• Differentiation: within its class & compared to competitors: Does it have a unique clearly definable profile?
• Addressing an unmet need: How big of a gap does it fill, how important is its contribution, how prevalent and exclusively covered is the pathogen?

Plazomicin is an aminoglycoside (AG) of the –micin variety which tells you it’s a

Micromonospora and not a Streptomyces derivative (a bit of semantics but good to know for Trivial Pursuit and the ID Board exam). As you probably know already, AGs have been around since the 60ies and many have been commercialized since then. In the US, approved AGs for IV use are gentamicin (yes, -micin), tobramycin, and amikacin but abroad you also have spectinomycin, sisomicin, dibekacin, and arbekacin.

In the past, the search for new AG centered on (1) compounds to overcome resistance to aminoglycoside-modifying enzymes (AME), the predominant resistance mechanism, and (2) less toxic compounds. How does plazomicin address these points?

Recent MIC data for plazomicin show activity against AG-resistant E. coli and P. aeruginosa, but it also shows fairly high plazomicin MICs for strains that are still genta/tobra/amikacin-susceptible.[1] The jury is still out on how important it is to have plazomicin on the formulary, as it seems to provide extra coverage for some pathogens but also ‘taketh away’ from the established spectrum.

Here is the clinical data situation as of mid-2015:

• SAFETY: A search for evidence of reduced nephrotoxicity comes up empty.  Maybe the sponsor (Achaogen) has data, but we will have to wait for publication of Phase 2 cUTI study results to get a better picture. So this remains an unsubstantiated hope for now.  Unfortunately, AEs were not so rare in Phase 1 with dizziness (30%) and somnolence leading the list. Also hypotension was seen in 5 cases [2].
• With once daily administration, the risk for AG related AEs should be reduced compared to older AGs, no doubt. Hence, in order to compare apples with apples one would like to see data comparing plazomicin qd with gentamicin / tobra / amikacin dosed qd as well.
• EFFICACY: Again clinical data have not yet been published.  A slide presentation on 76 patients dosed with 15 mg/kg in the Phase 2 cUTI trial does not address our question about differentiation [3]. Ideally one would like to see an analysis of data from patients treated with plazomicin and infected with bacteria carrying resistance genes like AAC(3), AAC(6), ANT(2”) and APH(2”) and who responded clinically and microbiologically to the drug. However, comparative MIC testing is not going to be replaced by AME analysis any time soon. In a recent publication there was only a 46.5% concordance between AME genotype and phenotypical resistance.[4]
  Based on company microbiology data, we see potential use of plazomicin for the currently rare cases when Citrobacter, Enterobacter, Serratia, E.coli of the AAC(6’) variety or Acinetobacter sp. resistant to all other AGs is encountered.[5]

In conclusion, at this time we are relying on microbiologic data when discussing plazomicin activity and potential benefits. It is clear already that use of this drug will be limited to genta/tobra/amikacin-R enterobacteriaceae.

While there is differentiation vis-à-vis other AGs in the test tube, how this would translate into a marketable benefit is open to conjecture, remembering netilmicin, another AG with a better spectrum than either genta or tobra. Netilmicin was clearly differentiated: it was not inhibited by several classes of AME (APC, ANT) and caused demonstrably less ototoxicity.[6] That profile was not enough to make it a commercial success.

Plazomicin is now being studied in a superiority trial against colistin in patients with CRE pneumonia/bacteremia.[7] This surely looks like a Herculean or Sisyphean task, if not ‘mission impossible’. It looks like too many smart cooks were in the development kitchen, the way it was designed.

It is no wonder Achaogen’s Phase 3 program ran into problems. After an SPA was agreed with FDA in 2013, FPFV for a Phase 3 study did not materialize until Sept. 2014.  Now we learn that the protocol had to be amended in 1Q15 in order to ‘improve enrollment’. Why was it so difficult to find patients for a drug which was supposed to address an acute medical NEED? Maybe it was a lower-case ‘need’ after all encountered less often in clinical practice than academics and company folks tell us.

Achaogen’s declared goal for NDA submission is now set for 2H2018, which translates into an approval in 2019/2020 or 6½ years after the SPA cleared plazomicin for Phase 3.  Embarrassingly, this seems to be setting a new record for slow drug development.

The 5-yr market exclusivity from its QIDP status is being used up for development efforts as we speak.

 

References:
[1] A. Walkty. AAC. doi:10.1128/AAC.02744-13
[2] http://www.avarx.com/AvaRx/SubDomains/bucket1874840974059574861/Listings/ bucket2606968988994524404/Public.Listing.display.html
[3] http://www.achaogen.com/media-all/2015/5/6/baseline-pathogens-and-patient-outcomes-in-a-phase-2-study-comparing-plazomicin-achn-490-to-levofloxacin-in-complicated-urinary-tract-infection-cuti-including-acute-pyelonephritis-ap
[4] Fernández-Martínez M   Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2015.03.008
[5] Aggen J. AAC 2010; 54: 4636
[6] P Noone.  Sisomicin, Netilmicin and Dibekacin   Drugs 1984, 27: 548
[7] https://clinicaltrials.gov/ct2/show/NCT01970371?term=plazomicin&rank=1