PLEASE SHARE YOUR OPINION AND VOTE BELOW
On May 8th, 2015 moxifloxacin/Avelox was approved for treatment of inhalational plague.[1] We learn that the approval followed the ‘animal rule’ process, and that treatment with moxifloxacin was 100% effective in the African Green Monkey (AGM) model of lung infection. By contrast, 0% of animals receiving placebo survived the bacterial challenge.
“Today’s approval provides an additional therapy for the treatment of plague” Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research
The study was done with bioterrorism in mind and the parallels to inhalational anthrax (for which ciprofloxacin and doxycycline are approved) are clear. Yersinia pestis, the plague pathogen, is still around in the southwest of the US, and while most cases are of the bubonic (skin infection) variety, the inhalational route of infection has a high mortality in humans. The fact that Y. pestis can be weaponized is the rationale for the study and explains why the study was supported by NIAID.
So far, so good. It sounds like sound science and good progress on the path to make America safer.
Here is the rub: Why do we have to kill non-human primates again and again to show the obvious? It has been established beyond reasonable doubt that inhalational exposure to Y. pestis kills African Green Monkeys (AGM) very consistently. Like in: 100% if you expose them to multiples of the LD50. At this point, wouldn’t it suffice to either have no placebo group or a much smaller number of controls? The moxifloxacin trial used an equal number as controls as for the active treatment arm (10 animals each). Wouldn’t it be great to design the study differently, esp. the placebo arm, significantly reducing the number of deaths of primates since it is already known that this illness results in 100% mortality in these primates?
As it turns out, an almost identical active vs control experiment was done with levofloxacin / Levaquin in 2011. In that study AGM were given a lethal dose of the pest bacillus by aerosol and – once fever developed – received either placebo or study drug.[2] The results were impressive: despite bacteremia and signs of pneumonia, all levofloxacin-treated animals survived. Even then there were no survivors in the control group (N=8).
…Animals were conditioned to a restraint collar, poles, restraint chairs, and limb restraints. Radiotelemeters (Model T30F, Konigsberg, Inc.) were implanted subcutaneously in the left abdominal wall for continuous monitoring of body temperature, intrathoracic pressure, respiratory rate, heart rate, and electrocardiographic traces. Venous access catheters (Broviac, Cohorts 1 and or Hickman dual-port, Cohort 3) were inserted in the right femoral vein, tunneled through the right flank and back, emerging through the skin of the upper mid-back and protected by a jacket…[from Ref. 2]
The same team at the Loveless Clinic established the value of the AGM model for the evaluation of promising drugs in pneumonic plague.[3] They had the benefit of even earlier experiments, also done with AGM, which show just how superbly the model performs and how well fluoroquinolones control even an established infection. Already in 2006 ciprofloxacin was tested and proved efficacious.[4] In earlier studies with doxycycline, ketolides and beta-lactams there was variable activity and survival rates (see [2] for details), while the AGMs assigned to placebo again invariably died.
Historical controls as a substitute for a placebo group should be encouraged by scientists. They serve just as well knowing that all AGM die from inhalational plague if untreated.
Drug companies and researchers really should not be surprised if animal rights activists are objecting to such unnecessary killing of primates. It is upsetting to see the same experiment repeated over and over again, for no other reason than to demonstrate the already known and published outcomes.
Should we thank the Loveless Clinic for this study in yet another quinolone, with the same results as in the prior quinolone studies of inhalational plague, the results of which we could have anticipated and which brings only a small labeling change to the sponsor?
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References:
[1] http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm446283.htm
[2] Layton R (2011) Levofloxacin Cures Experimental Pneumonic Plague in African Green Monkeys. PLoS Negl Trop Dis 5(2): e959
[3] Layton R: J Med Primatol. 2011; 40: 6
[4] Pitt M. Ciprofloxacin treatment for established pneumonic plague in the African Green Monkey. Abstract B-576, 50th ICAAC meeting 2006
