Abstract
In this issue, Gomez-Mancilla et al. (1) report on a ‘proof of concept study’ testing the efficacy of PNU-142633, a selective 5-HT1D receptor agonist, in the acute treatment of migraine. As there was no statistically significant better effect of PNU-142633 compared to placebo the authors concluded that ‘antimigraine efficacy is not mediated solely through the 5-HT1D receptor subtype’. This would be an important, although from a safety point of view disappointing, conclusion in the 10-year-long debate as to whether the antimigraine mechanism of triptans is mediated primarily via vascular 5-HT1B or via neuronal 5-HT1D receptors (2, 3). Unfortunately, before accepting this conclusion, a number of important questions must first be answered.
Firstly, for patenting issues, PNU-142633 was designed using a Gorilla 5-HT1D receptor clone which is not identical to the human receptor 5-HT1D raising doubts as to its affinity for the human receptor; the human binding data of the compound have not been discussed in sufficient detail.
Secondly, there is no discussion as to whether the achieved in vivo drug plasma levels of PNU-142633 in this trial were also sufficient to block neurogenic inflammation in vitro. In other words, were the drug plasma levels reached high enough to adequately stimulate the target receptors in human?
Thirdly, there is no discussion with respect to the posthoc power of this study, nor are confidence intervals presented for the treatment difference. This information is crucial to assess the chance of a false negative result. A calculation, based on the available data, estimates the 95% confidence interval for the treatment difference between placebo and PNU-142633 to be between −44% and +12%; if correct this would indeed suggest a low likelihood of a clinically relevant treatment effect.
Fourthly, it is difficult to assess from the available baseline characteristics how representative the study population was for typical migraine and what the time from onset of the attack to the treatment was. The placebo response was remarkably high. In other words, was the drug given to the right population and within the right time frame?
Finally, 2/34 patients treated with PNU-142633 had chest pain suggesting that chest symptoms may not necessarily be solely mediated via vascular 5-HT1B (coronary vasoconstrictor) receptors. Again, this is potentially an important observation. However, it is unclear whether the study patients had received an informed consent which included a detailed description of chest symptoms and whether the study population had had previous experience with triptans. This could have biased them towards reporting chest symptoms.
In conclusion, the results from this study so far provide only very limited evidence that 5-HT1D receptors are not involved in the antimigraine mechanisms of triptans. A full explanation of the above issues would be helpful.