Vanda Pharmaceuticals said recently that it has validated pharmacogenetic markers of efficacy and safety for its schizophrenia drug iloperidone with the aim of helping physicians avoid the trial-and-error method of treating patients with the disease.
Vanda conducted a market analysis before it began moving on iloperidone, which was originally developed by Novartis, to “understand the reaction of physicians,” Vanda CEO Mihael Polymeropoulos said last week during a conference call announcing that the company had confirmed Phase III efficacy and safety results for the drug.
The findings are noteworthy because treatments for schizophrenia, like most psychological disorders, offer very narrow therapeutic windows that are difficult, costly, and time consuming to identify. The resulting trial-and-error treatment, typically marked by side effects and poor efficacy, forces patients to jump from one drug to the next, and often, to quit their regimens in frustration.
“What we heard was nothing but tremendous excitement to put an end to the trial-and-error method in psychiatry today,” Polymeropoulos said. “Handing them tools that can predict for them who are the right patients for the drug adds tremendous value.”
Vanda evaluated iloperidone’s efficacy and safety in patients with certain specific genetic profiles, the company said. The firm did not reveal specific trial data or discuss which genetic markers it was targeting or which diagnostic test it was using in its clinical trials. However, Vanda said it is in the process of drafting a plan to publish and present the Phase III data in the near future.
Genetics May Reduce Drug Switching
The Rockville, Md.-based biopharmaceutical company characterized the genetic component of the clinical trials as “part of [its] commitment to give physicians and patients information to help specialize anti-psychotic therapy.”
According to Polymeropoulos, “iloperidone will have the safety and efficacy necessary to meet unmet medical need in the schizophrenia market where as many as 50 percent of the patients switch their drugs within a given year.” The company said it has not yet calculated the dropout rate in Phase III trials when genetic data were used to determine treatment, but is confident that the rate was lower than in trials without pharmacogenomic components.
“With these results in hand we have increased our efforts to file iloperidone in [the] fourth quarter [of] 2007,” Polymeropoulos said. “We plan to meet with [the US Food and Drug Administration] in the next quarter to reconfirm the structure and content of our filing. After that we may be able to update our guidance.”
In a statement released Dec. 7, Vanda said the confirmed data showed that iloperidone had statistically significant efficacy over placebo. The four-week, 604-patient Phase III study examined 12 mg of iloperidone dosed twice daily, or 24 mg per day.
During the call, Polymeropoulos suggested there may be a dosing advantage with iloperidone over other atypical antipsychotics dosed twice-a-day. “Although with iloperidone we studied twice-a-day, we have long experience with once-a-day [dosing]. The half-life of iloperidone is 24 hours, so we can use it as the physicians please, once-a-day or twice-a-day,” Polymeropoulos said.
The company did not say whether incorporating genetic data into iloperidone therapy may help hone in on which patient populations are right for once-a-day versus twice-a-day dosing. Meanwhile, there are several studies and ongoing regulatory discussions to determine how pharmacogenetics can guide dosing regimens for the anticoagulant warfarin [see PGx Reporter 11-29-06].
The primary endpoint of the study was efficacy versus placebo on the Positive and Negative Symptom Scale. The secondary endpoint was efficacy in the genetic subpopulation.
The PANSS evaluates patients’ psychopathological symptoms using a 30-item questionnaire. The three scores obtained using PANSS address three dimensions of schizophrenia: positive, negative, and general psychopathology. Positive symptoms may be characterized as having hallucinations, delusions, and racing thoughts. Negative symptoms may include moodiness, anhedonia, loss of interest, disturbed eating and sleeping, and difficulty concentrating.
The response to iloperidone in the genetic subpopulation was more statistically significant for PANSS than in the overall population.
“There appears to be about a 20-percent-better efficacy response in the genetic subpopulation as compared to the other responses that were elevated,” Polymeropoulos said. “When we have gone out and asked physicians how big the difference should be to make a difference in their practice, we were told a 10 percent increase will be very clinically meaningful to them.”
Iloperidone’s PGx Future With Vanda
Iloperidone comes to Vanda by way of a sublicense from Titan, who in turn licensed the drug from Novartis. According to Vanda, Titan is entitled to between eight percent and 10 percent of iloperidone royalties.
Vanda Chief Financial Officer Steven Shallcross characterized the forthcoming iloperidone NDA as “one of the most voluminous applications in the history of applications because of the enormity of the data, the legacy data we’ve inherited from the previous sponsors.”
Vanda had previously identified an undisclosed polymorphism that occurs in more than 70 percent of schizophrenia patients. The polymorphism is thought to be implicated in the pathophysiology of schizophrenia, which appeared to correlate with iloperidone response, the company said.
Although Vanda is keeping a tight lid on details surrounding any diagnostic tests for the particular polymorphism, the company suggested that the test may be specifically for iloperidone and would not work across the class of atypical antipsychotic drugs
“We have not examined how this applies across the class, [but] we will not be surprised if it does not apply to other atypical antipsychotics,” Polymeropoulos said. “The reason for that is that while [these drugs] all have the same name — atypical antipsychotics — they [are] very complex. …
“Any individual who has profile binding will actually result to different interplay with the molecular structure of the brain. It is very possible this genotype may be very specific for iloperidone,” he added.
The company did reveal during the call whether it would be ready to scale up a companion diagnostic by the time of iloperidone’s launch. Regardless, “it is very unlikely that FDA will require [in the drug’s label that] the safety genetic testing be done. … We know that because we’ve extensively discussed this with FDA,” Polymeropoulos said. “But it would be good to have.”
An FDA recommendation for genetic testing in iloperidone’s label may place the drug in a more favorable reimbursement environment. According to Russell Teagarden, vice president of clinical practices and therapeutics at the pharmacy benefits manager Medco, payors would feel more comfortable incorporating genetics into clinical decisions if tests were recommended in drug labeling or by credible independent institutions [see PGx Reporter 12-06-06].
The FDA to date has used genotypic data to describe how physicians should modify doses for 6-mercaptopurine in patients with acute lymphatic leukemia, and Pfizer’s colorectal cancer agent Camptosar.
“Iloperidone will have the safety and efficacy necessary to meet unmet medical need in the schizophrenia market where as many as 50 percent of the patients switch their drugs within a given year.”
The ubiquitous anticoagulant warfarin may soon be next. During the most recent meeting of the Clinical Pharmacology Subcommittee on incorporating genetic information in tamoxifen’s label, Lawrence Lesko, director of the Office of Clinical Pharmacology and Biopharmaceutics, said the agency is in the final stages of negotiating the language to include genetic information in warfarin’s label [see PGx Reporter 11-15-06].
PGx in QT Prolongation
As part of its Phase III study of iloperidone, Vanda also measured the drug’s effect on the QT interval, a common side effect associated with atypical antipsychotics. The mean QT prolongation for patients on iloperidone was consistent with other drugs in the class and did not exceed the FDA’s safety threshold of 500 milliseconds, Vanda said in a release.
The company used an additional undisclosed genetic marker to confirm its overall QT prolongation results. Using this genetic marker Vanda was able to identify for which patients the QT prolongation was longer in clinical trials.
According to Polymeropoulos, the majority of patients, about 75 percent, were good iloperidone metabolizers with a QT prolongation of 10.4 milliseconds. The poor-to-intermediate metabolizers, about 20 percent to 25 percent of the patient population, had a QT prolongation of 15 milliseconds.
“This effect of the QT prolongation is modest,” Polymeropoulos said, adding that in clinical trials the genetic data was not used to exclude poor metabolizers from the study. “The application of the genetic marker further informs us of who are the patients who may have a little more of these QT prolongations. But the overall picture on QT is exactly what we expected to see.”
“In Phase III studies, we never excluded a patient just because of being a poor metabolizer, but we are committed to understanding what the specific needs for each patient are and to providing tools to physicians for that,” he said.
Eli Lilly's atypical antipsychotic Strattera was originally labeled by the FDA in 2003 to note that 2D6 testing can identify poor and extensive metabolizers, and that "higher blood levels in [poor metabolizers] lead to a higher rate of some adverse effects of Strattera."
According to Strattera's label, CYP450 2D6 poor metabolizers in clinical trials were either statistically significantly or twice as likely as extensive metabolizers to report the following adverse events: decreased appetite; insomnia; sedation; depression; tremor; early morning awakening; pruritus; and mydriasis [see PGx Reporter 03-22-06].
Other important drugs metabolized by 2D6 include antidepressants Prozac and Paxil, manufactured by Eli Lilly and GlaxoSmithKline, respectively, and known generically as fluoxetine and paroxetine; and anti-psychotic drugs Risperdal and Haldol, made by Janssen Pharmaceutica and Ortho-McNeil, and known generically as risperidone and haloperidol.