Since I last wrote about antipsychotics in development in the December 2007 issue,1 some important changes have occurred. Here is an update on what recently has been FDA approved, what might be next in line, and what to keep an eye on.
Iloperidone. In my previous article, I predicted that asenapine and iloperidone were “next at bat” for FDA approval. On May 6, Vanda Pharmaceuticals, Inc., announced FDA approval to market iloperidone (Fanapt), a mixed dopamine D2/serotonin 5-HT2a receptor antagonist-an atypical antipsychotic-for the treatment of persons with acute schizophrenia.
In a 593-patient, 4-week trial leading to FDA approval, iloperidone matched ziprasidone (Geodon) in improving symptoms, and both drugs were significantly better than placebo. The recommended target dose range is 12 to 24 mg/day.
Forbes noted that the FDA's decision 10 months after the agency deemed the medication “not approvable” may be evidence of “an easier FDA.”2Forbes reported that Sandy Walsh of the FDA explained that “Vanda provided the FDA with additional data and arguments that led us to reinterpret results of several of their studies, thus convincing the agency that there was sufficient data to support an approval action based on the existing clinical trials.” Speculation has arisen about improved chances for FDA approval of Wyeth's antipsychotic bifeprunox which, like iloperidone, has a good safety profile but questionable efficacy and seemed doomed.
Next in line for approval?
Asenapine. Schering-Plough's asenapine has been moving along in the FDA regulatory process, and the company is hopeful that approval may occur by the end of the year. Asenapine is a serotonin and dopamine (5HT/D2) antagonist like other available agents in the second-generation antipsychotic class, such as clozapine, risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone, and paliperidone (Invega).
Schering-Plough has released recent information about asenapine, notably a report on its effectiveness in bipolar disorder. In essence, the clinical trial data suggest that the drug will treat acute schizophrenic and bipolar symptoms, and the risks of metabolic problems seem low.
If approved, asenapine will be introduced as a fast-dissolving sublingual tablet, which helps to eliminate the possibility of patients “cheeking” the medication and spitting it out when unobserved. Asenapine would enter a crowded field of second-generation antipsychotics, and the early signals that we get from clinicians ultimately will determine its market success.
Sertindole. Sertindole was the subject of an FDA advisory panel review in April, which voted to recommend FDA approval for sertindole (Serdolect) to treat schizophrenia but only for a subgroup of patients yet to be defined. The advisory group reviewed trials from the sponsor involving more than 10,000 patients. The panel's hesitancy about this compound stems in part from studies showing that patients taking sertindole were more than 4 times as likely to die suddenly compared with risperidone. Nevertheless, expert reviewers felt that the compound should be available as a treatment option. Sertindole is manufactured by Lundbeck and currently marketed in other countries. My guess is that this drug will be a welcomed tool for the treatment of patients with nonresponsive or refractory forms of schizophrenia.
Long-acting antipsy-chotics. Long-acting anti-psychotics are underutilized tools for treating schizophrenia in the United States.3 Janssen's long-acting Consta (risperidone) has not caught on as much as it should have since its release several years ago. Now two more long-acting second-generation antipsychotics are getting close to release for clinical use.
Janssen's paliperidone palmitate and Lilly's olanzapine pamoate are headed for approval in the FDA review process, and it is expected that both agents will be available by the end of the year. The entry of two long-acting injectable antipsychotics will be welcomed, not only because they will fill a clinical need but also because the companies' marketing efforts undoubtedly will raise awareness among clinicians about the huge problem of treatment nonadherence in populations with psychotic illnesses.
Further down the line
Lurasidone. This compound is a 5-HT2/D2antagonist but, unlike others in this class, it appears to have “a unique receptor binding profile with high affinity at the 5-HT7 receptor site,” according to Antony Loebel, MD, vice-president of clinical development at Dainippon Sumitomo Pharma. This binding activity may mean that the agent has a unique effect on cognition. Thus far, both the safety and efficacy data look promising-there is little weight gain or other adverse metabolic effects.
In addition to standard efficacy and safety measures, the company has been focusing its studies on the compound's cognition-improving aspects. Cognitive defects are common in schizophrenia, and there is a huge need to find medications that can improve defects in this area. Lurasidone has been compared to ziprasidone in a 3-week, double-blind trial and according to Emory University's Philip Harvey, PhD, the lead author on the trial, the results are “close to favoring lurasidone” in the area of cognitive functioning. The company also is comparing lurasidone to risperidone. The company is expected to initiate the review cycle with the FDA in December.
I'm hopeful about two “un-dopamine” antipsychotics.