Several interesting articles appeared recently which shed light on the efficacy of eravacycline and the safety of omadacycline, both in Phase 3 and both in a head-to-head race to the market. Well, the term ‘race’ is bit of a stretch as both drugs have seen very significant delays in development. Omadacycline from Paratek has lost many years due to program changes, corporate reshuffling and changing partnerships to the point that its remaining patent life is now rather short. Eravacycline from Tetraphase has suffered a serious setback last year; the company had to restructure its pivotal trial program and adjust submission timelines.
Please refer to our earlier blogs on both compounds for details and insights
Today in Part 1 we review a paper by Tanaka et al. which deals with the effect of omadacycline on the heart [1]. Preclinical investigations showed that omadacycline is a blocker of muscarinic M2 receptors in the heart, blocking vagal parasympathomimetic imput in a dose-dependent fashion. This affects several cardiac tissues, but especially the sinus (SA) node. Not surprisingly, tachycardia and an increase in blood pressure were seen in cynomolgous monkeys exposed to omadacycline. In fact, the magnitude of the effect was quite pronounced if not alarming: pulse rate increases between 27 to 58 bpm, and systolic blood pressure rises of 5 to 23 mmHg over controls were observed.
Well, nobody likes to administer a drug that whips the heart into overdrive during an infection. Fortunately, this is unlikely to happen in real life. Tanaka et al. refer us to clinical data from Phase 1 and 2 studies suggesting that cardiac M2 effects were rather modest, if not irrelevant. However, the reference provided – an article by Noel [2] – only mentions effects on heart rate, not on blood pressure. It almost seems as if this Phase 2 cSSSI trial was conducted before the full M2 effects of the drug became known. It is also unclear whether rigorous cardiac monitoring was conducted in this study beyond capturing standard vital signs. In any event, the AE profile of omadacycline in this Phase 2 study was tigecycline-like (mainly GI effects with nausea/vomiting); there was no mention of cardiac or vascular AEs.
Good to know but questions remain. There are already a few drugs on the market that have effects on the M2 receptor; we would have expected some comparison data to put matters in perspective. Instead, much of the Tanaka paper is devoted to investigations into QT prolongation which was not found to be an issue with omadacycline.
It’s always good to have some good news to share when you have to come out with problem data.
As is well known, QT prolongation was studied in great detail by Bayer when moxifloxacin (Avelox) was in development. To the company’s credit, world-renowned experts were consulted to study the effects of moxifloxacin on the conduction system; indeed, during an Advisory Board session FDA reviewers were complimentary of the way this issue was prospectively addressed and scientifically dissected by the company.
In contrast, the studies of omadacycline’s effect on the cardiac M2 receptors were all written up by Paratek insiders who – to the best of our knowledge – have no particular expertise in cardiology, cardiac physiology or pharmacology, or in muscarinic receptor research. It remains to be seen whether the data (and the benign assessment provided) will hold up to expert scrutiny.
Will omadacycline become the future control drug for M2 testing like moxifloxacin has become for TQTc studies? Unlikely, we already have several other drugs that could be used for that purpose, like diphenhydramine and chlorpromazine.
References:
[1] K Tanaka. In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline. AAC 2016; 60: 5247
[2] G Noel. A Randomized, Evaluator-Blind, Phase 2 Study Comparing the Safety and Efficacy of Omadacycline to Those of Linezolid for Treatment of Complicated Skin and Skin Structure Infections. AAC 2012; 56: 5650
Abbreviations:
ABSSSI acute bacterial skin / skin-structure infection
TQTc thorough QT study
cSSSI complicated skin/skin structure infection (an earlier version of ABSSSI)
M2 a (mainly cardiac) muscarinic receptor
