Tegaserod is a serotonin (5-HT4) agonist marketed for irritable bowel syndrome with constipation in 2002 and for chronic idiopathic constipation in 2004. It was withdrawn in 2007 because of concerns about cardiovascular adverse effects. In 2018, it was resubmitted to the FDA for use in women having irritable bowel syndrome with constipation and low cardiovascular risk. An advisory committee meeting for the resubmission was held on October 17, 2018, with the members voting 11 to 1 in favor of approval. Because we have concerns about its pharmacology and clinical trials that have not been discussed publicly, we present them below.
The FDA clinical pharmacology review of the 2000 submission contains a Figure 1 portraying tegaserod metabolism as shown in the Figure.1
A similar figure appears in the one published article, authored by the developer's staff, on human metabolism of tegaserod.2 Most discussions of tegaserod's activity have been limited to activity of intact tegaserod and inactivity of its major metabolite M29.0. Completely absent from these discussions, as from the Figure, is the fate in humans of half of the molecule, the pentylaminoguanidine (PAG) also generated when tegaserod undergoes acid hydrolysis in the stomach. The 2018 FDA Briefing Document simply states the following: “Information on systemic absorption of PAG in humans is not available.”3
One mole of PAG is generated for every mole of M29.0 and of M7.0. Blood levels of both metabolites are substantial: Cmax for M29.0 is 16-fold and M7.0 8-fold higher than tegaserod's. Hence PAG's blood levels could be 24-fold higher than tegaserod's. Although information on absorption of PAG in humans is unavailable, PAG products are excreted in the urine of mice.1 Regardless, PAG could exert effects in the gut instead of or in addition to those in the blood.
PAG could have direct impacts upon both efficacy and safety of tegaserod. PAG is a derivative of aminoguanidine, which is derived from guanidine. Guanidine has a labeled adverse effect of diarrhea, as well as increased peristalsis, that may preclude use.4 Hence tegaserod's modest benefits could be related to PAG rather than intact tegaserod.
PAG safety concerns are the following:
- Guanidine has a labeled warning regarding fatal bone marrow suppression.4 Low neutrophil count is an adverse event listed in the tegaserod label.5
- An aminoguanidine trial was discontinued for safety reasons, and the drug was abandoned, although the published details are sparse.6
- Tegaserod produces small intestine mucosal hyperplasia and adenocarcinoma in mice. Despite blaming this finding on PAG, the developer estimated a safety margin for human exposure based on tegaserod dosages alone.3
- All in vitro receptor, drug interaction, and genotoxicity studies omitted PAG entirely.
Information is also lacking on the metabolites enclosed in square brackets in the Figure. Like PAG, they may have appreciable blood levels. That they may be pharmacologically active is supported by this fact: One of them is 5-methoxyindole-3-carboxylic acid. A positional isomer of it, 5-methoxyindole-2-carboxylic acid, is a potent hypoglycemic agent.7
In short, tegaserod's pharmacology is half unknown. To understand tegaserod's effects, better information is needed on all of its metabolites.
Finally, tegaserod's interactions with receptors other than 5-HT4 may lead to chest pain and cardiac effects. Tegaserod shows moderate infinity for 5-HT1D and higher than for 5-HT1B.8 Regarding 5-HT1D, a single dose of the selective agonist PNU-142633 produced chest pain in 2 of 34 migraine patients in a double-blind, placebo-controlled study.9 Regarding 5-HT1B, activation of which produces coronary vasoconstriction, tegaserod is a significantly more potent agonist at the 124Cys-variant than at the wild-type 5-HT1B receptor.10 Furthermore, platelets have 5-HT receptors. Although there are variations in the studies of tegaserod effects upon platelets, one study strongly suggests that tegaserod increases platelet aggregation.11
CLINICAL TRIAL CONCERNS
There was evidence of cardiovascular problems with tegaserod starting with its first FDA submission in 2000. The most suspicious findings were regarding ECGs: ST depression was slightly more frequent with tegaserod.3 ECG abnormalities were substantially more frequent in patients older than 65 (21% vs. 12% in the placebo arms). In addition, despite the relatively young (mean age 45) and predominantly female (84%) trial populations with short (12 weeks) exposures, there were 2 cardiac ischemic events reported on tegaserod, 1 angina and 1 myocardial infarction. These events were dismissed in the FDA medical review marked as “Not thought to be due to drug.”12
These findings were suspicious enough to mandate that subject follow-up be complete and cardiovascular events be captured and evaluated thoroughly. Neither of the latter was performed.
Regarding subject follow-up, the completion rates for the double-blind trials were only about 81% despite treatment periods of 12 weeks. The withdrawal of consent rates was about 5%, and the lost-to-follow-up rates were about 3%. These rates are derived from tables in an FDA review and the developer's briefing document.12,13 Neither document discusses any limitations that these rates might impose. However, these rates are concerning because in cardiovascular trials, withdrawal of consent has masked adverse events14 and published lost-to-follow-up rates greatly underestimate the extent of poor follow-up.15 Furthermore, these missing data rates greatly exceed the rates of cardiovascular events (about 0.1%) in the tegaserod trials. Because few events would be expected in these short duration trials in predominantly young, female, cardiovascularly healthy subjects, missing even a few events would lead to a substantial underestimation of tegaserod's cardiac risk.
Regarding cardiovascular events, the different results of the 3 adjudications attest to limitations in data collection. The first adjudication, an internal one by the developer, counted 18 patients with cardiovascular events for tegaserod and 2 for placebo. The second, by NY's Mt. Sinai Hospital, counted 13 for tegaserod and 1 for placebo. The third, by Duke Clinical Research Institute, counted 7 for tegaserod and 1 for placebo. The patient narratives and tabulations in the briefing documents for the 2018 FDA advisory committee meeting confirm the inadequacy of the data collection.8,16 With better data collection, multiple adjudications would not have been necessary, or the repeat adjudications would have been more consistent. Regardless, the adjudications all support that there is an increased cardiovascular risk with tegaserod—but of an unknown magnitude.
The tegaserod experience has implications not only for its clinical use but also for how drugs should be evaluated and approved. Regarding clinical use,… the proposal to remarket tegaserod for a low-risk population is not irrational. The situation with tegaserod seems similar to that for triptan use in migraine: The absolute risk is low in individuals who otherwise have a negligible risk. However, for tegaserod, there is much uncertainty about its pharmacology, its clinical trial results, and its cardiac risk magnitude that, if the uncertainty is communicated to potential recipients, we suspect that many would reject the drug.
Regarding drug evaluation, the tegaserod lessons are the following:
- Basic pharmacology is important. The ignorance of the fate and role of PAG in humans, persisting after 18 years, is unacceptable.
- The exposures in tegaserod's development program at the initial submission were consistent with the recommendations of the International Conference on Harmonization.17 They were inadequate for confirming cardiac (or cancer) risks. Signals for cardiac or cancer risks in a typical drug development program at approval are subtle, so that they must be searched for specifically and followed up aggressively.
- The completeness of follow-up and event determination in trials is frequently neglected both during the trial and during its review. The medical community does not insist that these critical processes be performed well and does not even require good metrics documenting their success or failure. They must be improved for trial results, and meta-analyses of them, to be trusted.
- Drug safety issues frequently involve body systems other than the one targeted for benefit. Drug safety reviewers should be more broadly trained than the specialists evaluating targeted efficacy. The FDA should transfer the safety review of drugs from its specialist divisions to a separate division dedicated to drug safety.
2. Vickers AEM, Zollinger M, Dannecker R, et al. In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions. Drug Metab Dispos. 2001;29:1269.
7. Yan LJ. Reexploring 5-methoxyindole-2-carboxylic acid (MICA) as a potential antidiabetic agent. Diabetes Metab Syndr Obes Targets Ther. 2018;11:183–186.
9. Gomez-Mancilla B, Cutler NR, Leibowitz MT, et al. Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia Int J Headache. 2001;21:727–732.
10. Haenisch B, Bonisch H. Pharmacological characterization of tegaserod at the wild type and 124Cys variant of the human 5-HT1B receptor. Pharmacogenet Genomics. 2011;21:432–435.
11. Serebruany VL, El Mouelhi M, Pfannkuche H-J, et al. Investigations on 5-HT(4) receptor expression and effects of tegaserod on human platelet aggregation in vitro. Am J Ther. 2010;17:543–552.
15. Marciniak TA, Cherepanov V, Golukhova E, et al. Drug discontinuation and follow-up rates in oral antithrombotic trials. JAMA Intern Med. 2016;176:257–259.