Telcagepant--almost gone, but not to be forgotten (invited editorial related to Ho et al., 2015).

This issue of Cephalalgia contains what is likely to be one of the last reports of a clinical trial of telcagepant (1). Telcagepant was one of the first small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists to make it to Phase III trials. Several drugs in this class showed promise in treating individual attacks of migraine, leading to high hopes for a new era in migraine pharmacotherapy. In the case of telcagepant, these hopes were dashed when, in 2011, development of this drug for clinical use was halted after a small number of participants developed elevated liver function tests in trials testing the drug for migraine prophylaxis. In those studies, individuals were exposed to the drug on a daily rather than an intermittent basis, suggesting that frequent use of the drug could produce acute hepatocellular toxicity. There is still much to be learned from the many clinical trials that were conducted with this drug. The current study by Ho et al. made sensible use of the data from the previous prophylaxis trials, tailoring treatment to the perimenstrual period and limiting the dose to the lowest possible still expected to have a clinical effect, and only for seven consecutive days. This is, in effect, two studies: a large safety study with a nested efficacy study in a subset of the trial population. The target population was an admixture of women with menstrually related migraine (MRM) and pure menstrual migraine (PMM), as defined by International Classification of Headache Disorders, second edition (ICHD-2) appendix criteria. The primary treatment outcome of mean monthly headache days was not statistically significantly different between the telcagepant and placebo groups, so the authors appropriately caution readers that results for the secondary outcomes should be viewed as exploratory at best. This study provides information on a number of important matters. Of foremost interest is the additional data about the risk of hepatocellular injury with telcagepant. Drug-induced liver injury (DILI) may be viewed as an acceptable risk in relation to the benefits of a drug, particularly for those who treat potentially life-threatening illnesses. In the case of migraine, however, which is a highly disabling but not life-threatening illness, there is very little tolerance for even transient laboratory abnormalities due to medical therapy. Ho et al. note that we cannot yet say whether DILI is a mechanism-related effect or one specific to the chemistry of telcagepant, because the pattern of liver injury has not been entirely consistent. In this study, three patients receiving telcagepant but none receiving placebo had eight-fold elevations in alanine aminotransferase (ALT) levels. We are reminded, however, that the development of another molecule—MK 3207—was stopped even sooner than that of telcagepant when serious but delayed hepatic abnormalities were observed, some of which required immunosuppressive treatment (2). Some preclinical evidence supports the view that liver injury may be a predictable class effect of the CGRP inhibitors. Kroeger et al., for example, reported that aCGRP inhibited inflammatory hepatic injury in a mouse in vitro system, suggesting that telcagepant’s antagonist effects potentiate hepatic inflammation in humans (3). A summary of convergent lines of research in the same paper concludes that CGRP-containing, capsaicin-sensitive primary afferents (in hepatic tissue) ‘‘appear to be required for induction of immunemediated liver injury,’’ suggesting that altering CGRP transmission from these hepatic sensory neurons could modulate drug toxicity. In addition, CGRP is a negative immunomodulator, particularly of the innate immune system (4), further suggesting that inhibiting CGRP signaling could potentiate immune-mediated responses.