A GO / NO GO decision:  Delafloxacin Stumbles in Gonorrhea Study

The treatment history of N. gonorrhoeae makes for fascinating reading.  This organism has always been able to keep the upper hand in the war of bug versus drug.  Once susceptible to sulfa drugs, to penicillin, tetracyclines and fluoroquinolones, it sequentially become resistant in the matter of a decade to every class of drug.  At one time it looked like the organism would become PCN-susceptible again but that hope did not really materialize.  Hence, we are all a bit nervous about the time when ceftriaxone loses its efficacy.mic-2

As cefixime resistance has slowly crept up and the drug is no longer an alternative to ceftriaxone, we are looking for a new antibiotic that can provide >95% efficacy, i.e., eradication, of genital gonorrhea with a single shot (or a single pill).  This is a high bar for any antibiotic, no doubt, but this is the hurdle applied by regulatory agencies.

Now we hear that delafloxacin, a promising new fluroquinolone, did not make the grade:  According to a recent press release, Melinta (formerly Rib-X) had to stop the Phase 3 gonorrhea study for reasons of “insufficient efficacy”.[1]

While this is disappointing news, it is also very unexpected news.  The activity of delafloxacin against MDR N. gonorrhoeae isolates was studied extensively by Rib-X / Melinta.  Delafloxacin and a panel of antibiotics (spectinomycin, ciprofloxacin, ceftriaxone, tetracycline, penicillin) were tested against 141 isolates from 2 institutions.  Compared to ciprofloxacin, delafloxacin showed a very clear MIC separation, being many dilution steps more potent.  More importantly, the MIC90 values for delafloxacin were very low, in the 0.125-0.5 mg/L range.  With a single oral dose, serum levels should be more than adequate for organisms in this and even higher MIC ranges.MIC

So why is there “insufficient efficacy” in a clinical study which presumably did not enroll the worst pan-resistant GC patients from Bangkok?   Has the susceptibility changed so much that isolates in 2014 are now much more resistant than 6 years ago (2007-2010) when the surveillance microbiology study was done?   All this seems unlikely as FQ resistance is usually conferred by the gyrA or parC topoisomerase, which is mostly chromosomally mediated and multistep in nature.  Is a new quinolone-resistant strain at work here?

This does not bode well for delafloxacin, a drug whose claim to fame is based on superior MIC data for MRSA.  The recently completed Phase 3 trial in ABSSSI seems to have met its non-inferiority goals against vancomycin + aztreonam.  Let’s hope that there won’t be a repeat of the GC experience with MRSA, the main differentiating feature of delafloxacin.  A NO GO for claps is a bitter disappointment, but a GO for MRSA is a must.  Hopefully, efficacy against MRSA will hold up in clinical practice and not turn out short-lived as with ciprofloxacin.[2]

NOTE 1: It seems that the delafloxacin’s QIDP designation is not in jeopardy as it was received for addressing the unmet need in GC and for ABSSSI, the latter being the only indication left for Melinta to pursue.[3]

NOTE 2: Solithromycin (Cempra) is a macrolide analogue currently in Phase 3 testing as a single dose treatment for uncomplicated gonorrhea.  Phase 2 results were impressive: 22/22 (100%) of evaluable patients were cured.[4]

 

References:
[1] http://www.melinta.com/news.php?c=41
[2] H. Blumberg J Infect Dis. 1991 163:1279
[3] http://www.melinta.com/news.php?c=24
[4] http://www.cempra.com/common/pdf/abstracts/Abstract_ECCMID%202013_Soli%20for%20gonorrhea_Oral%20Pres.pdf

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