The FDA recently approved iloperidone (Fanapt, Vanda Pharmaceuticals) for the treatment of schizophrenia, reversing a July 2008 determination that the New Drug Application (NDA) was “not approvable.” An FDA spokesperson explained in an interview in Forbes (May 8), “Vanda provided the FDA with additional data and arguments that led us to reinterpret results of several of their studies.”
The favorable judgment culminated a circuitous product development path. The compound had been developed by Hoechst Marion Roussel, but the rights were sold to Titan Pharmaceuticals in 1997, and then to Novartis in 1998, before Vanda Pharmaceuticals acquired them in 2004. Vanda succeeded in garnering regulatory approval, in large part by redesigning the clinical trials supporting the NDA.
Rather than comparing the efficacy of iloperidone with risperidone(Drug information on risperidone) and haloperidol(Drug information on haloperidol), which had not previously favored iloperidone, the new trials compared iloperidone with placebo and used ziprasidone(Drug information on ziprasidone) as an active control. In this design, the active agents were shown to have comparable efficacy in improving symptoms measured on the 30-item Positive and Negative Syndrome Scale (PANSS) and were both statistically superior to placebo.
Although the FDA was apparently unconvinced by the studies in July 2008, their reversal could reflect not only successful arguments by Vanda but also how the field has come to view risks and benefits of new antipsychotics. Andrew Cutler, MD, an investigator in the Vanda-sponsored iloperidone trials, opined in an April 2008 Medscape.com interview that the initial assessment of iloperidone had been colored by concern over QTc prolongation. That concern has been somewhat allayed by how well ziprasidone has been tolerated despite potential for QTc prolongation. In addition, concern about the metabolic adverse effects of antipsychotics has grown, along with an appreciation of differences between the agents in liability for those adverse effects.
In the 4-week trial involving 593 patients randomized to either iloperidone (24 mg/d), ziprasidone (160 mg/d), or placebo, QTc prolongation occurring with the agents was reported as comparable and moderate.1 The mean QTc(F) interval prolongation measured 2 weeks from baseline was 11.4 milliseconds with iloperidone and 11.4 milliseconds with ziprasidone; these intervals dropped to 7.0 and 5.7 milliseconds, respectively, at day 28. Mean weight gain with iloperidone was approximately 2.8 kg over the 4-week study period, which was characterized as “modest” in the poster presentation of the data at the 161st Annual Meeting of American Psychiatric Association on May 8 by Jennifer Hamilton, Clinical Research Scientist at Vanda. Mean weight gain with ziprasidone was approximately 1.1 kg, and 0.05 kg with placebo. There were no clinically relevant increases reported in levels of serum glucose, triglycerides, or cholesterol.
Efficacy in the study population was measured against a baseline PANSS total score of more than 90.2 Both iloperidone and ziprasidone were associated with a reduction of approximately 12 points—significantly better than placebo. The active agents were also found to be comparable and significantly better than placebo in reducing PANSS Positive and Negative Symptom subscale and Brief Psychiatric Rating Scale (BPRS) scores.
The approved dosing for iloperidone is initially 1 mg twice daily, with titration to between 6 and 12 mg twice daily. The potential for QTc prolongation increases at higher drug levels, and the approved labeling indicates that dosage should be reduced by half if iloperidone is used concurrently with inhibitors of cytochrome P-450 (CYP) 2D6 isoenzyme (such as fluoxetine(Drug information on fluoxetine) and paroxetine(Drug information on paroxetine)) or inhibitors of CYP3A4 (such as ketoconazole(Drug information on ketoconazole) and clarithromycin(Drug information on clarithromycin)).
Increasing therapeutic options
The change in the FDA stance on iloperidone could bode well for 2 other antipsychotics that were not deemed approvable last year: bifeprunox from Wyeth and asenapine from Schering-Plough. While additions to this therapeutic class expand treatment options, there is increasing criticism when they fail to demonstrate improved efficacy and safety, and concern that “second-generation” antipsychotics are not fulfilling their promised advantage over first-generation neuroleptics.
An invited commentary in the January 2009 issue of the Lancet titled “The Spurious Advance of Antipsychotic Drug Therapy”3 accompanied a meta-analysis of the effectiveness of second-generation antipsychotics. Peter Tyrer, MD, and Tim Kendall, MD, of the Imperial College London argue that this therapeutic category is a heterogeneous mix of compounds, with “no special atypical characteristics” that clearly distinguish it from the group of older agents.
“As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective,” the correspondents declare.
Their opinions follow from the findings of a meta-analysis conducted by John Davis, MD, Maryland Psychiatric Research Center, Baltimore, and colleagues in Germany and China.4 The researchers included 150 double-blind, mostly short-term studies with 21,533 participants in comparing 9 second-generation antipsychotic drugs with first-generation agents for overall efficacy, as well as efficacy specifically for positive, negative, and depressive symptoms; relapse; quality of life; extrapyramidal side effects; weight gain; and sedation.
Davis and colleagues determined that 4 of the 9 second-generation agents (amisulpride, clozapine, olanzapine(Drug information on olanzapine), and risperidone) demonstrated better overall efficacy than older agents, within a small to medium efficacy effect size. The effects on overall symptoms of the other 5 studied (aripiprazole, quetiapine(Drug information on quetiapine), sertindole, ziprasidone, and zotepine(Drug information on zotepine)) were not significantly different from those of the neuroleptic antipsychotics. The authors also noted that while all second-generation agents were associated with fewer extrapyramidal side effects than was haloperidol, this advantage was not apparent for most second-generation agents in comparison with the low-potency older agents.
“Importantly for the notion of atypicality,” Davis and colleagues point out, “the other 5 second-generation antipsychotic drugs were not more effective than first-generation drugs for treatment of negative symptoms. The drugs were also no more efficacious than first-generation antipsychotic drugs for positive symptoms, and quetiapine was less efficacious.”
Davis and colleagues as well as commentators Tyrer and Kendall suggest that it is no longer helpful to classify these agents as first- and second-generation, because each category is heterogeneous for pharmacological action, therapeutic efficacy and side-effect profiles. A newly approved antipsychotic, then, should not necessarily be assumed to be superior to older agents or even on par with contemporaneous agents.
Differences in activity and side effect are important in how an individual patient responds to and tolerates a drug, however. Tyrer and Kendall set aside the quest for overall greater efficacy in acknowledging that “individual responses vary, and so a range of drugs is needed for clinical practice.”
With the approval of additional antipsychotics more likely to be based on distinguishing characteristics than superiority, Tyrer and Kendall caution, “it is prudent to remember that although science rules during a drug’s development, the market usurps control once the drug is released for care of patients.”