Cardiac Risks Hold Up Approval of Two Antipsychotics

At an April 7 meeting, the advisory committee voted unanimously that the efficacy of sertindole in treating schizophrenia was adequately demonstrated in the clinical trials. Lundbeck, the Danish company that developed sertindole, was also seeking approval for the indication that the drug reduces the risk of suicide attempts. This application was based on a randomized, open-label, controlled clinical trial in which sertindole was compared with risperidone. The committee, however, was not sufficiently convinced by the suicide data and voted 12-1 against approving the claim.

While sertindole is not marketed in the United States, it is not a new molecule. In the 1990s, it was approved for marketing by regulators in the United Kingdom and Europe and received approvable letters from the FDA. However, after signals of potentially life-threatening cardiac risks, including prolonged QT interval and arrhythmia, began to emerge in sertindole users, European regulators suspended the drug's marketing in 1999, and the new drug application in the United States was withdrawn.

The drug has mixed affinity for dopamine D₂, 5-HT_2A, 5-HT₆, and alpha₁ receptors, but does not bind to histamine H₁ receptors and does not have anticholinergic activity. Thus, it has demonstrated antipsychotic efficacy and is associated with lower risks of sedation and weight gain and is less likely to affect cognition than are some antipsychotics.

To address regulators' concerns about the drug's effect on the heart, Lundbeck conducted retrospective epidemiological studies and a prospective, randomized, unblinded trial, known as the Sertindole Cohort Prospective (SCoP) trial, in which sertindole was directly compared with risperidone. The results convinced European regulators to lift the ban, and the drug reentered the market in 2005. The drug is also available in Asia and Latin America. The FDA, however, remains worried about the drug's cardiac risks.

The SCoP trial enrolled nearly 10,000 patients. After taking either sertindole (n=4,930) or risperidone (n=4,928) for one year, there were 64 deaths in the sertindole group and 61 deaths in the risperidone group. This difference in all-cause mortality was not statistically significant.

However, the FDA reviewers told the advisory committee that cardiac-related deaths occurred in 31 sertindole-treated patients, compared with 12 risperidone-treated patients, based on the agency's analyses of data and case descriptions submitted by Lundbeck. This difference was statistically significant (p=0.0022), with a hazard ratio of 2.841 in the sertindole group. In addition, sudden cardiac deaths, defined as “a death that occurred within 24 hours of onset of symptoms and with no other obvious noncardiac cause” and judged by independent reviewers, occurred in 13 sertindole-treated patients and three risperidone-treated patients. The sertindole group had a nearly fivefold increased risk (hazard ratio 4.988, p=0.0121).

Sertindole has long been linked to prolonged QT interval, which is a risk factor for arrhythmia and sudden cardiac death. Clinical trial data showed that 10.6 percent of sertindole-treated patients experienced an increase of greater than 60 milliseconds, and 1.9 percent had an increase of more than 500 milliseconds in their QTc intervals.

In addition, Lundbeck acknowledged that the occurrence of QT interval prolongation and cardiac events in sertindole users appeared to be difficult to predict, although FDA analysis suggested that the risk may be related to sertindole plasma concentration.

Primarily influenced by the cardiac risk, the advisory committee members voted “no” on the agency's question of whether sertindole is acceptably safe for the “broad treatment of schizophrenia.” If the company implements strong warnings and risk-management guidelines on the labels for prescribers and patients, however, eight members voted“ yes” on the question of whether sertindole can be approved for use in certain subgroups of patients, while two voted “no” and three abstained. The committee agreed that sertindole should not be used as first-line treatment because of the small but potentially fatal cardiac risk.

The suicide claim for sertindole was given a thumbs-down by the committee because of marginal statistical results from the SCoP trial. The analyses related to the rates of suicide attempts, based on standardized criteria, did not reach statistical significance despite numerically lower rates in the sertindole group.

Cardiac risk also made the committee reluctant to support the expansion of quetiapine indications to MDD and GAD.

At an April 8 meeting, AstraZeneca presented clinical trial data in which quetiapine XR was shown to be more effective than placebo as monotherapy for MDD and GAD and as adjunctive therapy for MDD. Wayne Ray, Ph.D., director of the Division of Pharmacoepidemiology and a professor of preventive medicine at Vanderbilt University School of Medicine, was brought in by the FDA to discuss higher rates of sudden cardiac death associated with antipsychotics observed in a large case-control study he and his colleagues had conducted. The study was published in the January 15 New England Journal of Medicine (Psychiatric News, March 6).

In that study, the rates of sudden cardiac death were similar between patients taking first-generation and second-generation antipsychotics.

Quetiapine is currently approved for treating schizophrenia and bipolar disorder. An approval for MDD and GAD indications would substantially increase the drug's market share since it would then likely be prescribed more often by primary care physicians. The potentially large expansion of the patient population taking quetiapine also was worrisome because of weight gain and negative metabolic effects associated with the drug, some committee members indicated.

Most but not all of the advisory committee members agreed that the efficacy of quetiapine XR in MDD and GAD patients was demonstrated by the company. Six members voted “yes” and three voted “no” to the question of whether the safety of monotherapy quetiapine XR was demonstrated as an adjunct treatment for MDD. The drug was not studied for adjunct treatment for GAD.

However, the committee unanimously rejected the claim that the drug is acceptably safe as a monotherapy for the broad treatment for MDD and GAD. If certain conditions are met, however, such as the addition of strongly worded label warnings, some committee members were in favor of declaring quetiapine XR safe enough to be approved as a monotherapy, but not first-line treatment, for treating either disorder. The vote on this issue was 4-4.

The FDA usually—but not always—follows advisory committee recommendations. ▪