GC Therapy –  Shooting for the Stars

Besides ceftriaxone (CTRIAX), cefixime and spectinomycin we have no other highly effective single-dose treatment regimens for urogenital GC. Failures of all 3 drugs have been described but remain rare, can be overcome with higher doses of CTRIAX (1 g instead of 250 mg IM) or with azithromycin combination therapy. Worse is the cure rate for GC at extra-urogenital sites where the gonococcus has always been more difficult to eradicate.

Despite seemingly adequate PK/PD attainment rates, failures can occur and have been documented [1]. We do not understand mechanistically why certain drugs work and others don’t. For example, it is remarkable how CTRIAX maintained activity after more than 20 years of global first-line use, while other drugs failed despite good PK and sufficiently low MIC values.

FDA has set standards for drug developers interested in the indication. The most recent Guidance specifies that efficacy be determined in the microITT population (randomized, treated, positive entry culture), with a NI margin of 10-12% compared to controls.

FDA also mentions that “drugs for the treatment of uncomplicated gonorrhea generally should be administered as a single dose”. Unfortunately, we do not have drugs in development that can meet the single-dose mantra. Both delafloxacin and solithromycin were tried as single dose drugs for uncomplicated GC and failed.

It may be time to rethink our approach to GC treatment. There is no reason to abandon good drugs just because they failed with single administration but would work satisfactorily using a different dosing approach. Why not study a 2-dose regimen?  We understand that compliance will be an issue, but the times, they are a-changing.

Once the current CDC regimen no longer works in ≥90%, what will be our options? GSK-2140944 (gepotidacin) and ETX-0914 (zoliflodacin) have not yet shown efficacy on par with CTRIAX. And they may never. As both are topoisomerase II-inhibitors, we may lose both if one does not work

The Phase 3 GC studies conducted by Melinta and Cempra are not yet published; assuming no operational glitches or mix-ups, no manufacturing issues, and full GCP compliance, these drugs are not inactive against GC but require repeat dosing or reformulation.

Solithromycin for GC
Suffice it to say, even a high dose (900 mg PO x1) of solithromycin was not sufficient to guarantee non-inferiority to CTRIAX + azithromycin.

Current CDC recommendations for treatment of GC is ceftriaxone 250 mg IM plus a single oral dose of azithromycin 1 g PO. This is a powerful combination, and we are not sure why Cempra upped the ante and used a 500 mg dose of CTRIAX, i.e., higher than standard in the ill-fated SOLITAIRE-U (uncomplicated GC study). Hubris? Ignorance? Thy name is Cempra.

We would argue that solithromycin may still work well in GC as a 2- or 3-dose regimen. It has excellent intracellular penetration, and the organism MICs are all in the susceptible range. Coverage for NGU pathogens was more than adequate.

The company’s only explanation for the lower efficacy rate (91.3% for solithromycin vs 100% for the control treatment) is the much longer half-life of the comparator drugs (T½:  CTRIAX = 24 h; azithromycin = 140 h). We agree. With solithromycin’s much shorter T½ (6 hours), an eradication rate of 91.3% actually looks pretty good.

Not to forget, combination therapy was compared with solithromycin monotherapy; the combo of ceftriaxone and azithromycin is additive/synergistic against GC. Fat chance to score a win when the study set-up is so lop-sided to begin with.

Without playing Monday-morning quarterback, one would easily predict that single dose solithromycin did not stand much of a chance. A 2- or 3-dose regimen, even at standard doses, would have an excellent chance of showing equipotency.

Clearly, Cempra management was not interested in GC as an indication for solithromycin, not interested in dose-finding. They banked on single-time GC treatment. That feature just was not built into the molecule, sorry!

Delafloxacin for GC
A similar story to the one above: A one-time high-dose of delafloxacin (900 mg PO) did not show equivalent potency to the standard regimen. Again, no dose-finding was done; the company tested a single dose regimen only and lost.

In the Phase 3 PROCEEDING open-label study comparing delafloxacin (Baxdela) to CTRIAX, the review board stopped the trial early because of insufficient efficacy. At least Melinta chose the correct CTRIAX dose recommended in the US (250 mg IM).

Delafloxacin is a fluoroquinolone, a drug with excellent tissue penetration, enhanced activity in the lower pH intracellular environment, and a half-life of approx. 7 hours. Its MIC90 for N. gonorrheae is 0.125 μg/ml [2]. T>MIC should be in the >24 h range based on published PK and MIC data [3]. Of interest, MIC data for recently isolated N. gonorrheae showed equal if not better susceptibility than cefixime (Suprax), a drug with a shorter (3-4 hour) half-life, fairly high protein-binding (70%), and rather poor intracellular penetration.

Final Thoughts
With that dual-flop in recent GC studies, we believe it is time to reassess the situation, with an eye on preparedness for a time without ceftriaxone. The next GC studies should be handled more flexibly, less dogmatically:

  • We have an issue with PK/PD assessments in GC, an indication for which attainment rates have no relevant track record or reference point for validation.
  • We have an issue with Regulators that do not see value in a 91.3% success rate and instead slavishly apply an NI margin based on study data from the 1980s, using an arch-conservative approach.
  • We have an issue with CDC and WHO STD experts telling us how much of a problem we have once GC coverage falls below 95%, without offering much perspective [4],[5].

But we cannot let the companies off the hook either.  When clinicians in drug development no longer have a say on how to conduct GC studies because marketing insists on single dose therapeutics and won’t settle for anything less. Driving single doses up into the toxic range, hardly tested before, just to have a single-dose drug for GC is not the way to go. Instead, why not develop a depot IM formulation?

Not to forget: Spectinomycin is still not available in the US. This should be a call to action for CDC; it seems senseless to have it listed in all GC guidelines but not on formulary. Maybe we can interest Mr. Shkrely into having a look at this ‘opportunity’.

Abbreviations:
T>MIC   Time above MIC
NGU      non-gonococcal urethritis

References:
[1] M Unemo. Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis, 2015; 15: 364
[2] O Soge. In Vitro Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance. AAC 2016, 60:3106
[3] R Hoover. Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age. Clinical Therapeutics 38: 39, 2016
[4] G Bolan. Emerging Drug-Resistant Gonorrhea: What’s New and What Now. http://www.medscape.com/viewarticle/876378
[5] http://www.sciencemag.org/news/2016/08/world-may-soon-run-out-drugs-treat-gonorrhea

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