CATIE Suggests Zyprexa Useful As Initial Schizophrenia Treatment – NEJM

Results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study suggest Lilly's Zyprexa may be well suited as initial therapy in the treatment of schizophrenia, according to an editorial accompanying the study.

While Zyprexa (olanzapine) was shown to have greater efficacy than four other atypical antipsychotics and one conventional antipsychotic, the greater benefit was countered by an increased risk of weight gain and metabolic side effects, according to study authors Jeffrey Lieberman (Columbia University), et al.

In the companion editorial, however, Robert Freedman (University of Colorado) suggests that Zyprexa could have utility as the first line of treatment before patients are switched to other drugs to avoid olanzapine's side effects.

"Although no one postulates that the biologic effect of clozapine and olanzapine are permanent, the positive effects often persist when, because of metabolic effects, treatment is switched to other second-generation or even first-generation drugs," he said.

"It would...seem reasonable to try olanzapine and clozapine in any patient with schizophrenia who has not had a full clinical remission of the illness," Freedman concluded.

"However, it is also prudent to switch treatment from these drugs to one of the others if a metabolic syndrome is threatening the patient's general health."

The next phase of the CATIE program will examine drug switching. Further analysis will also be done on cost-effectiveness.

The National Institute of Mental Health-funded trial, which was conducted to compare the effectiveness of atypical and conventional antipsychotics, was published in the Sept. 22 issue of the New England Journal of Medicine.

The 18-month study examined four atypicals - Zyprexa, AstraZeneca's Seroquel (quetiapine), Johnson & Johnson's Risperdal (risperidone), Pfizer's Geodon (ziprasidone) - and one conventional antipsychotic, perphenazine (Schering's Trilafon and generics).

The CATIE study results also raised questions about the relative efficacy of second-generation drugs over the first-generation products.

Although Zyprexa faired best on the primary endpoint of discontinuation of treatment for any reason, the difference between the olanzapine group and the perphenazine group was "not significant after adjustment for multiple comparisons," the study notes.

Further, when Zyprexa was excluded, "there was no significant difference in effectiveness" between perphenazine and the atypicals.

In the 1,493-patient study, all-cause treatment discontinuation rates were 64% for the olanzapine group (n=330), 74% for the risperidone group (n=333), 75% for the perphenazine group (n=257), 79% for the ziprasidone group (n=183) and 82% for the quetiapine group (n=329).

In general, the study had 85% power to identify an absolute difference of 12% in the rates of discontinuation between two atypical agents.

However, the statistical power was lower for comparisons involving perphenazine (76%) and ziprasidone (58%). Geodon was not added to the study until its approval in January 2002; the study began in January 2001 and continued through December 2004.

Duration of successful treatment was significantly longer in the olanzapine group than in the quetiapine group (hazard ratio, 0.53; p<0.001), the risperidone group (hazard ratio, 0.69; p=0.002), or the perphenazine group (hazard ratio, 0.73; p=0.013).

Duration was also significantly longer for Risperdal versus Seroquel (hazard ratio, 0.77; p=0.021).

The time to discontinuation of treatment for lack of efficacy was longer in the olanzapine group than in the other groups, but "after adjustment for multiple comparisons," the study adds, "the difference between olanzapine and ziprasidone...was not significant."

In the study, the rates of therapy discontinuation due to lack of efficacy were 15% for olanzapine, 24% for ziprasidone, 25% for perphenazine, 27% for risperidone and 28% for quetiapine.

In terms of time to discontinuation due to intolerable side effects, the study found no significant differences between groups. Discontinued treatment rates due to intolerability were highest for Zyprexa (10% for risperidone, 15% for ziprasidone, 15% for quetiapine, 16% for perphenazine and 19% for olanzapine).

Zyprexa also had the highest rates of discontinuation due to weight gain or metabolic effects (9% vs. 1% for perphenazine, 2% for Risperdal, 3% for Geodon, 4% for Seroquel).

Weight gain is a significant differentiation point for antipsychotic marketing. Lilly said in December that its promotional efforts for the product would seek to "demystify" weight problems associated with the treatment (¹ (Also see "Cymbalta “Mood” And “Pain” Claims May Include Fibromyalgia And Anxiety" - Pink Sheet, 20 Dec, 2004.), p. 19).

Patients in the olanzapine group gained more weight than patients in any other group with an average gain of two pounds per month, the study notes.

The quetiapine group gained 0.5 pounds per month, and the risperidone group gained 0.4 pounds. The perphenazine group lost 0.2 pounds per month, and the ziprasidone group lost 0.3 pounds.

In CATIE, a larger proportion of patients in the olanzapine group than in the other groups gained 7% or more of their baseline body weight (30% vs. 7% for ziprasidone, 12% for perphenazine, 14% for risperidone, 16% for quetiapine).

"Olanzapine had effects consistent with the potential development of the metabolic syndrome and was associated with greater increases in glycosylated hemoglobin, total cholesterol and triglycerides after randomization than the other study drugs, even after adjustment for duration of treatment," the study states.

"Ziprasidone was the only study drug associated with improvement in each of these metabolic variables."

The atypicals carry a class warning regarding potential risk of diabetes mellitus-related events; however, Geodon's label includes several caveats to the claim (² (Also see "Pfizer Geodon Label Adds Bipolar Claim, Modified Class Diabetes Warning" - Pink Sheet, 30 Aug, 2004.), p. 13).

A 2004 American Diabetes Association "consensus" statement on antipsychotics concluded that patients taking Geodon and Bristol-Myers Squibb/Otsuka's Abilify (aripiprazole) are not at increased risk for developing diabetes whereas patients on Zyprexa and clozapine are (³ (Also see "Geodon, Abilify Have Low Diabetes Risk, ADA Says; Lilly Disagrees" - Pink Sheet, 2 Feb, 2004.), p. 31).

CATIE did not substantiate other safety concerns associated with the atypical class - the authors report that "concerns about potential prolongation of the corrected QT interval with ziprasidone and of cataracts with quetiapine were not realized in this study."

In 2004, Pfizer said that Geodon's acceptance in the U.S. has been held back by warnings about QT interval prolongation associated with the drug (⁴ (Also see "Geodon, Abilify Have Low Diabetes Risk, ADA Says; Lilly Disagrees" - Pink Sheet, 2 Feb, 2004.), p. 31).

The study also notes that there were "no significant differences among the groups in the incidence of extrapyramidal side effects, akathisia or movement disorders as reflected by rating-scale measures of severity." These concerns are generally attributed to the conventional antipsychotics.

"The use of low-dose perphenazine appears to have diminished the frequency of extrapyramidal side effects," the study states.

The authors note that dose "could have been a factor in the performance of the various agents studied."

"The fact that a higher proportion of patients assigned to quetiapine and ziprasidone received the maximal dose allowed in the study suggests that these agents are either less effective or require higher doses," the authors note (see chart: " ⁵ CATIE Dosing ").

Although the results were highly anticipated on Wall Street, the release of the study did not greatly affect any of the atypical manufacturers' stock prices.

Abilify, which cleared FDA in November 2002, was not included in the study. The drug's mechanisms "move beyond" those of the atypicals and thus could have differential efficacy, Freedman said.

With $834 mil. in sales from January to July, Abilify was the fourth leading antipsychotic based on U.S. sales, according to IMS Health.

During the same period, Zyprexa had sales of $1.5 bil.; Seroquel had sales of $1.4 bil.; Risperdal had sales of $1.3 bil.; and Geodon had sales of $367 mil. Year-over-year growth ranged from -15% for Zyprexa to 58% for Abilify. Zyprexa was the only drug with a decrease in sales from 2003 to 2004 (-9%).