Psychiatr News May 19, 2006
Volume 41, Number 10, page 25
© 2006 American Psychiatric Association
Drug Firms Vie to Develop More Effective Antipsychotics
Jim Rosack
A series of articles in a Psychiatric News exclusive discusses
what lies ahead in the psychotropic pipeline. While there may be no front
runner in the different classes of drugs for some time, new options may help
more patients control symptoms and regain and maintain functionality and
quality of life. Part 1 looks at antipsychotic medications.
With each round of results released from the National Institute of Mental
Health's massive CATIE (Clinical Antipsychotic Trials of Intervention
Effectiveness) study, it has become increasingly clear that although each of
the antipsychotic medications studied is generally effective, all have
significant limitations.
And while certain antipsychotics may have a slight edge over others, none
of the six newer antipsychotic medications—the "atypicals,"
or second-generation antipsychotics (SGAs)—remain in contention to win
the race to be the most efficacious or most tolerable.
To the pharmaceutical industry, certainly, and to most psychiatrists and
many of their patients, this is not "breaking news." In fact,
within the pharmaceutical industry, the push has been on for many years to
discover and bring to market new antipsychotic medications that provide
greater efficacy than the drugs currently available and avoid the often
serious and potentially fatal adverse events associated with some of the
current drugs.
"When we talk about the market for schizophrenia medications, we tend
to see it as a very saturated market," said Michelle Grady, a director
with Decision Resources, a Massachusetts-based global research and consulting
firm that follows sectors of the health care industry, including
pharmaceutical markets. But the pharmaceutical industry knows that none of the
five currently patent-protected drugs has the market cornered, Grady told
Psychiatric News.
"Every patient with schizophrenia is prescribed an antipsychotic, as
long as the patient is under the care of a physician. Typically patients start
out on one antipsychotic, and the physician will keep them on it as long as it
seems to work. But then," Grady added, "over time, most patients
tend to rotate through the rest of the available drugs. With schizophrenia, it
isn't as though a patient does well on a specific drug and stays on that drug
for the next 50 years."
About 90 percent of antipsychotic medications prescribed today belong to
the SGA class. While none of the currently available SGAs is perfect, Grady
said, "physicians look at each one of the drugs as options." That
has created considerable competition, not only for squeezing out a bit more
market share for an individual drug (see chart below), but also for developing
new and improved drugs.
"Nearly every atypical antipsychotic that has ever started down the
development pathway has been described as a drug that works as well as
clozapine and has the side-effect profile of Abilify," Grady told
Psychiatric News. "That is a lofty goal. But that is a very
difficult goal to obtain. And I'm skeptical that someone can obtain that,
simply because no one has done it yet."
Development Field Gets Crowded
Along with numerous interviews, an extensive review by Psychiatric
News of documents from numerous sources, including the U.S. Food and Drug
Administration (FDA), industry analysts, and pharmaceutical companies,
revealed that more than two dozen pharmaceutical companies are involved in the
race to develop at least 40 new antipsychotic medications.
However, regulators, analysts, and the pharmaceutical industry agree that
only a handful of those drugs will ever make it all the way through the
"pipeline" to reach the pharmacy shelf. The Pharmaceutical
Research and Manufacturers of America, the professional trade association that
represents U.S. pharmaceutical research and biotechnology companies, estimates
that for every 5,000 new chemical compounds evaluated for possible development
as a human medication, only five go on to enter clinical trials in humans. Of
those five drugs, only one will win the FDA's marketing approval.
The drug development process involves many stages, from discovery and
preclinical testing through phase III clinical trials in patient volunteers
(see chart on page 29.
The process can take 10 to 15 years and cost hundreds
of millions of dollars.
Of the 40 or so developmental antipsychotic medications working their way
through the pipeline, only two are new formulations of existing approved
medications: an intramuscular depot injectable formulation of olanzapine
(Zyprexa) and a sustained-release formulation of quetiapine (Seroquel).
Analysts expect a new drug application (NDA) to be filed with the FDA later
this year for the sustained-release quetiapine, while an NDA for the depot
olanzapine is likely at least a year to 18 months out. Little information was
available in the public domain for either product. However, analysts question
how well a once-a-month injectable olanzapine will fare, given the drug's
side-effect profile.
The remaining candidates under development are all what the FDA designates
as "new chemical entities" (NCEs). While several of the NCEs are
related to or derived from approved medications, all NCEs possess unique
chemical structures that have not previously been approved for human use.
Nevertheless, analysts agreed, all of the antipsychotics in late stages of
development are "me-too" drugs—their mechanisms of action
are the same as existing drugs.
To date, only one NDA for an NCE antipsychotic medication has been filed
with the FDA. That NDA, for Johnson & Johnson's paliperidone ER
tablets—a derivative of the company's risperidone (Risperdal)— was
submitted November 29, 2005, and is expected to be ruled on by FDA regulators
by the end of 2006. An NDA for a paliperidone depot injectable is expected to
be filed this year.
Company documents and analysts describe paliperidone as a metabolite of
risperidone that possesses at least equal efficacy while boasting an improved
safety profile.
The extended-release formulation of paliperidone uses the patented OROS
technology of sustained release, resulting in more consistent blood levels of
medication over the 24 hours between daily dosings. The depot formulation,
Grady commented, "is said to be every six- to 12-week dosing. We're
bullish on that; we think that would be very attractive." But, Grady
added, a dosing interval of that length could also be a liability. The profile
of the drug, she said, "will have to be just right. Physicians are going
to have to be able to not be scared of [depot paliperidone]."
Two Front Runners Appear
"Key [antipsychotics] to watch out for in the near future,"
said Emma Travis, a senior CNS analyst with Datamonitor, "are the launch
of Solvay/Wyeth's bifeprunox and Organon/Pfizer's asenapine" (see
chart page 25.
Bifeprunox is a partial dopamine agonist/antagonist and serotonin agonist,
similar to aripiprazole (Bristol-Myers Squibb's Abilify).
"This one is interesting," Grady said, "because it is
only the second drug with this mechanism of action to get to the market. That
is clearly an opportunity."
Solvay, which developed the drug and licensed U.S. marketing rights to
Wyeth, said in a November 29, 2005, press release, that "additional
phase III comparative clinical work" would be required "to satisfy
European Union requirements." The company said the European regulatory
filing is now planned for 2008. However, in the same press release, the
company said "Solvay and U.S. partner Wyeth Pharmaceuticals are
continuing to assess and analyze the clinical study data with respect to a
U.S. filing in 2006." Incidentally, Solvay has three additional
antipsychotics in earlier stages of clinical development.
The second highly anticipated drug is asenapine, which was developed by
Organon and licensed to Pfizer. An Organon statement on the asenapine
development program noted in March that phase III clinical trials were on
target to be completed in late 2006, with an expected NDA in early 2007.
Asenapine is described as an "atypical antipsychotic with a unique
receptor signature" involving antagonism at serotonin, dopamine type 2,
and adrenergic receptors. The drug's interaction with serotonin receptors is
said to be stronger than any of the currently marketed antipsychotics, with
only minimal interaction with muscarinic receptors.
"What is interesting about asenapine— which has specifically
been referred to as `clozapine-like, without the side effects'— is that
Organon developed the drug, then Pfizer signed on to market it," Grady
told Psychiatric News. Considering that Pfizer already markets
ziprasidone (Geodon), and the market is already highly competitive with
well-established drugs, Grady added, "what is it about asenapine that
made Pfizer so interested?"
Further Down the Pipeline
Several other antipsychotics appear to be in late-stage development, two of
which have been available in other countries for years.
Lundbeck's sertindole (Serdolect), a serotonin/dopamine/alpha-adrenergic
antagonist, was reintroduced in the European market in December 2005. The drug
was pulled from the market in 1998 after reports of QTc prolongation and
subsequent sudden cardiac death. Lundbeck completed additional safety testing
of the drug in 5,000 patients after the drug was pulled off the market,
bringing the total clinical trial database to 17,000 patients.
Lundbeck has said it intends to launch the product in the United States;
however, the company's president and CEO, Claus Braestrup, noted in May 2005
that the company would "have to wait a couple of years before we will be
in a position [to address previously discussed FDA concerns], and we have not
made any predictions or expectations" regarding when an NDA might be
filed.
A second drug, also available in Europe and available in Japan since 1982,
is Orion Pharmaceutical's zotepine (Zoleptil). As of last summer, analysts
said the company was exploring a U.S. market launch, however this could not be
confirmed.
A third drug in late-stage development is Corcept Therapeutics'
glucocorticoid type II receptor (GR-II) antagonist, mifepristone (Corlux).
The drug is better known for its ability to block estrogen and its
controversial marketing as the "morning-after pill" method of
contraception. The drug is currently in phase III testing in patients with
psychotic major depression, and because no other drug is marketed as an
approved treatment for psychotic depression, the FDA has designated
mifepristone for psychotic depression as an "orphan drug" and
granted Corcept's request for designation of fast-track status. Once an NDA is
filed, fast-track status commits the FDA to an accelerated approval
timeline.
The remaining drug known to be in late-stage development is iloperidone,
which was developed by Novartis Pharmaceuticals in the early 1990s. Said to
have longer occupancy and higher affinity for serotonin receptors than
dopamine receptors, iloperidone was expected to have moderate efficacy while
offering a lower liability for extrapyramidal symptoms.
Similar to ziprasidone, however, the drug appeared to be associated with
potential prolongation of the QTc interval. Novartis discontinued development
of the compound and later sold the rights to Titan Pharmaceuticals. Titan then
licensed the drug to Vanda Pharmaceuticals for phase III clinical testing. If
or when an NDA might be filed with the FDA is unknown.
At least four other NCEs are in mid-stage development and show promise for
final approval. Each drug is in phase II clinical trials; therefore, none is
likely to be the subject of an NDA filing before the end of 2007 or into 2008.
Organon is developing an AMPAkine modulator, designated ORG 24448, which was
given the generic name farampator. Japan's Dainippon Sumitomo Pharmaceuticals
is testing blonanserin (Lonasen), a new serotonin/dopamine/adrenergic
antagonist, and has partnered with Merck in the United States on another
developmental antipsychotic, lurasidone, a serotonin/dopamine antagonist SGA.
Finally, ocaperidone, another risperidone derivative on which Johnson &
Johnson discontinued development in 1994, has been licensed to Neuro3D for
further development.
Long-Term Promise Unclear
A number of other putative antipsychotics that appear to be truly novel
compounds are in early development. Some interact with the tachykinin receptor
NK3, while others target melatonin receptors or are CRF modulators. Drugs are
also in the pipeline targeting cannabinoid receptors, nicotinic acetylcholine
receptors, glutamate and NMDA receptors, and highly specific subsets of
dopamine, serotonin, and/or noradrenergic receptors.
In addition, one company (Acadia Pharmaceuticals) is specifically chasing
the efficacy of clozapine with a direct metabolite of the drug, known as
ACP-104 or N-desmethylclozapine. The compound is said to maintain clozapine's
relatively higher efficacy, but is less likely to mirror its well-documented
adverse effects.
Overall, however, it is difficult at best to guess which—if
any—of these drugs in the earlier stages of development has significant
potential.
"There are certainly a lot of drugs in development," concluded
Grady. Any that come to market, she added, provide another option to help
patients. "But honestly, as far as late-stage products," she said,
"there isn't anything that is really impressive—and when I say
that, what I mean is nothing that is truly novel, different, or has the
potential to change the face of treatment for schizophrenia." 
Related Article:
-
New Brands May Help Offset Generic Competition
Psychiatr News 2006 41: 25-29.
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