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From: barfly on 24 Apr 2008 04:58
American College of Neuropsychopharmacology (ACNP) 46th Annual Meeting

An Update on the Investigational Antipsychotic Iloperidone: An Expert
Interview With Andrew J. Cutler, MD

On behalf of Medscape, Jeffrey R. Bishop, PharmD, spoke with
investigator Andrew J. Cutler, MD, Courtesy Assistant Professor of the
Department of Psychiatry at the University of Florida, and President and
Medical Director of the Florida Clinical Research Center, LLC, who
presented results of an iloperidone study at the ACNP 2007 annual meeting.

Medscape Psychiatry & Mental Health.
�2008 Medscape

Posted 04/16/2008

Editor's Note:
Second-generation antipsychotics (SGAs) are now the mainstay of
treatment for schizophrenia. *Iloperidone* is an investigational agent
not yet approved by the US Food and Drug Administration, but results of
clinical trials are promising. Its profiles of neurotransmitter-receptor
activity and adverse effects have both similarities and differences
compared with currently available SGAs.


Medscape: Can you tell us about the history of the investigational
antipsychotic iloperidone?

Andrew J. Cutler, MD: I don't claim to be an expert on the history of
the drug, and I am not affiliated with any of the companies that have
been involved with ownership or development of it. This agent was
originally developed by Hoechst Marion Roussel, which sold it in 1997 to
Titan Pharmaceuticals, who sold the rights to Novartis in 1998. Finally,
a group of researchers formed Vanda Pharmaceuticals and acquired the
rights to iloperidone in 2004.

One of the questions that people ask is, "Why did these companies sell
it off or give up on it?" The regulatory environment was very different
in the late 1990s and early 2000s than it is now. Other drugs in
development were found to cause prolongation of the QT interval
corrected (QTc), and the US Food and Drug Administration (FDA) was using
that as a proxy for possible cardiac risks. The FDA was being cautious
about this when iloperidone was being developed, and it was found to
*cause some QTc prolongation*. Now we know that this QTc prolongation is
not so great a safety concern, although we do monitor it carefully.

Furthermore, we didn't place as much emphasis then on metabolic issues
as we do now. Ziprasidone and iloperidone, which don't cause a lot of
weight gain, weren't fully appreciated by the drug companies.

Medscape: Second-generation antipsychotics (SGAs) have slightly varied
pharmacologic profiles. Can you tell us about the pharmacology of
iloperidone?

Dr. Cutler: First of all, the property that all SGAs seem to share is
blockade of dopamine D2 and serotonin-2A (5HT2A) receptors. One of the
theories about what makes these antipsychotics special is that the
relative affinity for 5HT2A receptors is greater than the affinity for
D2 receptors, but they differ in binding to other receptors. Iloperidone
is different because of the other serotonin receptors to which it binds.

We know of at least 7 families of serotonin receptors, labeled 5HT1
through 5HT7. Within each family are subtypes, for instance 5HT1A, 1B,
1C, and 1D. *Iloperidone has activity at* 5HT2C, 5HT1A, and 5HT6
receptors. It is an antagonist at the 5HT2C and 5HT6 receptors, and it
is a partial agonist at the 5HT1A receptor, which is favorable.

Iloperidone also has strong affinity for the adrenergic alpha-1 and
alpha-2C receptors. Blocking these receptors causes dizziness or
orthostatic hypotension. However, antagonism at these receptors also
appears to contribute to the efficacy of this drug, particularly in mood
and cognition.

Finally, *iloperidone affects other dopamine receptors*, including the
D3. It has little activity at muscarinic cholinergic receptors, so it is
not likely to have anticholinergic effects. So iloperidone has a unique
pharmacologic fingerprint. Whether this translates into unique clinical
effects has not yet been studied.

Medscape: You were the lead investigator on 1 large recent study of
iloperidone, the results of which you presented at the 2007 American
College of Neuropsychopharmacology meeting in Florida. Can you tell us
about this study and its design?

Dr. Cutler: The primary goal was to accomplish a registration-quality
study. By that I mean a study that fulfills the FDA's requirements to
get the drug approved, which is important to understand because
decisions are made in designing a study for registration that are not
necessarily those one would make in the real world. Registration studies
are done in consultation with the FDA to demonstrate that a drug is
efficacious and safe.

This study had 3 arms, the iloperidone arm at a dose of 24 mg/day, given
in two 12-mg doses. The other active treatment arm was ziprasidone, an
FDA-approved SGA that is well-established to be safe and effective given
at 80 mg twice daily. The third arm was placebo. The 593 participants in
the study were adults with schizophrenia having an acute psychotic
exacerbation requiring hospitalization. They were randomly assigned to 1
of the 3 treatment conditions, to which assignment the patients and
researchers were masked. The duration of the trial was 4 weeks, and
participants remained in hospital for the entire study.

It's worth mentioning why ziprasidone was chosen. Previous studies with
iloperidone used risperidone or haloperidol as active controls, but
those medications tend to have more side effects and it is sometimes
obvious when a patient is taking them. In the earlier trials, because
iloperidone has a different side effect profile and is better tolerated,
if a patient didn't seem to be getting better within the first few days
and had no side effects, the investigator might assume the patient was
on placebo. The patient might then be removed from the study, and
iloperidone was not given a chance to work. Ziprasidone is a better
choice as an active control because its tolerability and side effect
profile are similar to iloperidone, and the 2 medications are
administered in the same manner.

The primary outcome measure was the Positive and Negative Syndrome Scale
(PANSS), which is divided into 3 clusters of symptoms and has 30 items.

Medscape: Can you expand on the demographics and clinical
characteristics of the study participants?

Dr. Cutler: The patients were 18 to 65 years old with a mean age of
about 40 years, and 80% were men. More than half the patients were
African American, 35% were white, and 8.8% were Asian. The typical PANSS
scores at baseline were 80 to 90, so these were fairly sick patients.
The study excluded subjects with alcohol or drug dependence in the
preceding 6 months, prolonged hospitalization, and treatment resistance.

Medscape: Can you tell us about results of this study?

Dr. Cutler: The results of the trial are in line with those of other
marketed SGAs. This study was not designed as a head-to-head comparison
between iloperidone and ziprasidone; ziprasidone was included as an
active control.

At the endpoint, we saw good separation between iloperidone and placebo,
with a decrease on the total PANSS score of 12 points for iloperidone
and only 7 points for placebo, which is a low placebo response.
Furthermore, iloperidone worked for both the positive and negative
clusters of symptoms, and all the secondary rating scales were
statistically better with iloperidone than with placebo. This reflected
a robust and broad efficacy across a wide range of symptoms.

Other important results were in the realm of tolerability and safety.
Although no drug is perfect, iloperidone in this trial was not
associated with some of the things that concern us about SGAs. The most
common side effects for iloperidone included dizziness, sedation, and
increase in weight, but the magnitude of weight gain was not large.
While tachycardia and orthostatic hypotension were expected with this
drug, only 17% of patients complained of dizziness, whereas 13% percent
of patients on ziprasidone complained of dizziness. With ziprasidone,
27% of patients had sedation, whereas 13% of iloperidone patients and 8%
of placebo patients had sedation. We saw virtually no extrapyramidal
signs (EPS) or akathisia with iloperidone: 9% of ziprasidone patients
spontaneously reported EPS, compared with 2% of patients on placebo and
3% on iloperidone. Akathisia occurred in 1% of patients on iloperidone,
in no patients on placebo, and in 7% on ziprasidone.

There was some QTc prolongation, which we expected, and it was the same
as with ziprasidone, which we know is a safe drug. The mean prolongation
from baseline at study midpoint was 11.4 milliseconds with iloperidone
and 11.3 milliseconds with ziprasidone. By day 28, the mean iloperidone
QTc prolongation dropped from 11.4 to 7.2 milliseconds, and the mean
ziprasidone prolongation went from 11.3 to 6.1 milliseconds, so this
effect may be a short-term concern.

In the iloperidone group, mean weight increased during the 4 weeks by
about 2.8 kg. It increased 1.1 kg in the ziprasidone group and 0.05 kg
in the placebo group. As for changes in serum glucose and cholesterol,
there did not appear to be a significant difference. I can't say that
iloperidone is entirely weight neutral or free of any risk of metabolic
concerns, but on those outcomes, it appears to be on the lower end of
the SGA spectrum.

Medscape: Pharmacogenetic research that has also occurred during the
development of iloperidone. Can you comment on this and discuss how
pharmacogenetics may influence the way we treat patients in the years to
come and how it may be relevant to iloperidone?

Dr. Cutler: For a number of years, we have been conducting voluntary
sub-studies involving genetic analyses of drug response and
tolerability. We are trying to identify a common factor in people who
respond well, some genetic marker that we can use prospectively to
predict who might be likely to respond to iloperidone, because we know
that no drug is 100% effective for everyone.

Vanda's research group has developed a panel of markers that may
identify patients who are likely to respond to iloperidone. It is not
yet commercially available, but clinicians should be aware that in the
next few years we are going to have tools like this to help us better
match a specific treatment to a specific patient.

Medscape: Can you comment on what niche you think that iloperidone may
have if it does gain FDA approval and how this may affect clinical practice?

Dr. Cutler: Iloperidone would be an important new treatment option,
although not necessarily a generational shift ahead. Its efficacy will
likely be as good as the other SGAs, and I think it has some potential
advantages in tolerability and safety. Some of the real excitement may
come from the genetic research that I mentioned. Clinicians may find it
helpful to have a test to predict response or tolerability to this drug.

Also, several formulations of this medication are under development. So
I think there may be a number of clinical niches for this agent, but we
need to think responsibly and put it in context.


References

1. 1. Cutler AJ, Kalali AH, Schooler NR, et al. Iloperidone: Placebo-
and ziprasidone-controlled study in patients with schizophrenia. Program
and abstracts of the 46th Annual Meeting of the American College of
Neuropsychopharmacology; December 9-13, 2007; Boca Raton, Florida.
Abstract 20.


Andrew J. Cutler, MD, Courtesy Assistant Professor, Department of
Psychiatry, University of Florida, Maitland, Florida; President and
Medical Director, Florida Clinical Research Center, LLC, Maitland, Florida

Jeffrey R. Bishop, PharmD, BCPP, Assistant Professor, University of
Illinois at Chicago Medical Center, Chicago, Illinois

Disclosure: Andrew J. Cutler, MD, has disclosed that he has received
research grants from Acadia Pharmaceuticals, AstraZeneca
Pharmaceuticals, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli
Lilly & Company, Forest Research Institute, Ortho-McNeil-Janssen
Pharmaceuticals, Johnson and Johnson PRD, McNeil Pharmaceuticals, Memory
Pharmaceuticals, Merck & Company, Novartis Pharmaceuticals, Organon,
Otsuka America Pharmaceuticals, Pfizer, Sanofi, Solvay Pharmaceuticals,
Supernus Pharmaceuticals, Vanda Pharmaceuticals, and Wyeth
Pharmaceuticals. Dr. Cutler has also disclosed that he served as a
consultant to AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli
Lilly & Company, Ortho-McNeil-Janssen Pharmaceuticals, Otsuka America
Pharmaceuticals, Pfizer, Supernus Pharmaceuticals, and Vanda
Pharmaceuticals. Dr. Cutler has also disclosed that he served as a
speaker to AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly
& Company, Ortho-McNeil-Janssen Pharmaceuticals, Otsuka America
Pharmaceuticals, Pfizer, and Vanda Pharmaceuticals.

Disclosure: Jeffrey R. Bishop. PharmD, BCPP, has disclosed that he has
received grants for clinical research from the American College of
Clinical Pharmacy and the National Institutes of Health. Dr. Bishop has
also disclosed that he has served as an advisor or consultant to Eli
Lilly and provided continuing educational materials for Drug Store News.
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