| The
schizophrenia market was worth over $5 billion in
1999, and IMS HEALTH's Pharmacast
& Beyond forecasting service predicts a 10-year
(2000-2009) compound annual growth rate of 6.0% for
the antipsychotic (N5A) therapy class in the eight
markets covered:
*For
the USA, UK, Canada, France, Germany, Italy, Japan
and Spain combined, converted from local currencies
to US$ using the exchange rate on January 30 2001
As the graph above shows, the schizophrenia market
has seen strong growth since the mid-1990s. This was
due to the introduction of new, or atypical, antipsychotics.
The market is currently dominated by two such drugs
- Eli Lilly's Zyprexa (olanzapine) and Johnson & Johnson's
Risperdal (risperidone). Between them, these two drugs
control more than 65% of the antipsychotic market.
According to IMS HEALTH's Monthly
MIDAS system, Zyprexa and Risperdal had 39.0%
and 27.4% respectively of the N5A market in the 12
months to September 2000. AstraZeneca's Seroquel was
in third place, with 6.7%, followed by Novartis' Clozaril
(clozapine), which had 4.0% of the schizophrenia market:
Source:
Monthly MIDAS
*Retail pharmacy markets in the US, Canada, Germany,
Italy, France, Spain, UK, Brazil, Mexico, Argentina,
New Zealand and Japan
Two drugs not yet launched are already attracting
significant attention: Pfizer's Zeldox (ziprasidone)
has been deemed 'approvable' by the FDA, and Bristol-Myers
Squibb's aripiprazole, licensed from Otsuka, is in
Phase III clinical trials.
Lilly
focuses on Zyprexa
Now facing the patent expiry of its blockbuster antidepressant
Prozac,
Lilly is keen to make up any deficit through Zyprexa,
first launched in 1996. It had a strong start, and
overtook Prozac to become Lilly's top-selling drug
in the fourth quarter of 2000 - total sales for the
full year 2000 amounted to $2.35 billion.
Lilly is already working on enhancements to prolong
Zyprexa's lifecycle: an intramuscular formulation
is scheduled for launch in mid-2001, and could be
of use in the management of acute agitation in people
with schizophrenia, while a disintegrating formulation
- useful in non-compliant patients - was launched
in September 2000. A long-acting injectable version
is also in the pipeline.
Zyprexa has also received a number of new indications,
the latest being long-term schizophrenia therapy and
maintenance of treatment response, in November 2000.
In March 2000, the FDA approved Zyprexa for the treatment
of acute mania associated with bipolar disorder: trials
showed it was superior to Depakote (valproate) in
this indication (though Abbott later said Depakote
produced fewer side-effects and led to lower out-patient
costs).
Zyprexa is also being studied for the reduction of
behavioural and psychotic symptoms in Alzheimer's
disease. A small trial is, moreover, in progress
to see if Zyprexa can prevent the development of schizophrenia
in at-risk teenagers.
Fighting off the competition
Lilly is keen to differentiate Zyprexa from its rivals.
Noting that Pfizer's Zeldox might also be available
in an intramuscular version, a Lilly researcher said
Zyprexa was likely to benefit from its reputation
for safety - Zeldox has been linked with a prolonged
QTc interval (irregular heart beat). However, Zeldox
does not appear to be associated with the weight gain
seen with Zyprexa.
Lilly has been even more aggressive when it comes
to the competition from Johnson & Johnson's Risperdal,
publishing the results of a head-to-head study with
the two drugs in May 2000. Findings in Zyprexa's favour
included:
- Higher
likelihood of maintaining treatment response
- Lower
use of medication to control movement disorder side-effects
- No
increased cost of care for out-patient or in-patient
services
- 36%
lower per-patient medical costs over the study interval
Risperdal
keeps up the pressure...
Naturally, J&J has not been slow to defend its own
antipsychotic - Risperdal was the company's second
biggest drug in 2000 with sales of $1.6 billion -
up 21% from 1999. J&J believes the oral solution of
Risperdal is as effective as an intramuscular injection
of the older antipsychotic haloperidol at reducing
the symptoms of psychotic agitation. The company is
also seeking to have Risperdal approved for use in
the manic phase of bipolar disorder, and it has already
received Canadian approval for the treatment of the
behavioural disturbances of dementia.
J&J believes Risperdal is significantly cheaper than
Zyprexa: in its own head-to-head trial, J&J found
that Risperdal led to savings of $2.80 per patient
per day - equivalent to over $1,000 per year. The
patients were also discharged from hospital sooner
than those on Zyprexa.
...while Seroquel makes its mark
Currently in third place in the antipsychotic market
is AstraZeneca's Seroquel, introduced in 1997, which
has overtaken Novartis' Clozaril over the course of
2000. AstraZeneca claims that Seroquel, which is in
Phase III trials for bipolar disorder:
- is
safe and tolerable in the long-term treatment of
psychosis in the elderly
- is
as effective as conventional antipsychotics, while
controlling side-effects
- improves
cognitive skills in schizophrenia and Parkinson's
disease
- has
minimal weight gain, extrapyramidal, and sexual/hormonal
side-effects
- is
more effective than haloperidol in the short-term
treatment of acute schizophrenia
- treats
depressive symptoms in patients with psychotic disorders
- and
improves psychotic symptoms in Parkinson's and Alzheimer's
diseases
Zeldox
nears the US market
The next new antipsychotic due on the market, Pfizer's
Zeldox, had a major setback in 1998 when the FDA rejected
it because of the aforementioned heart rhythm disturbances
(also seen in a number of other drugs, including the
withdrawn Propulsid and Seldane).
Pfizer conducted further safety trials, and in July
2000 an FDA advisory panel recommended Zeldox's approval.
It will probably carry a warning label, but Pfizer
described the risks as "modest". The panel noted that
the all-cause mortality was no higher for Zeldox than
the other three atypical antipsychotics.
Zeldox is aimed at a wide range of symptoms, and is
not associated with the weight gain seen with the
other antipsychotics - a point Pfizer is sure to emphasize
in its marketing; it is also associated with a low
incidence of abnormal movements and sexual dysfunction.
The drug has not yet received its final FDA or EU-wide
approval, but was launched in Sweden in October 2000
according to IMS HEALTH's Drug
Launches service. Both the oral and short-acting
intramuscular formulations were launched, making Pfizer
the first company to market an intramuscular atypical
antipsychotic.
Aripiprazole due in 2002?
With an NDA scheduled for filing by the end of 2001,
Bristol-Myers Squibb's aripiprazole (possibly to be
called Abilitat) is already being highlighted by B-MS
as a potential 'best in class'. Developed by Otsuka,
aripiprazole:
- improves
both positive and negative symptoms
-
is associated with a very low incidence of extrapyramidal
side-effects, sedation and weight gain
- has
not caused any cardiotoxicity in clinical trials
- and
is also being studied for psychosis in Alzheimer's
and Parkinson's diseases
The
drug has already been shown to be better tolerated than
haloperidol, while having comparable efficacy. The companies
say it has a "unique" mechanism of action.
As schizophrenia is believed to affect 1% of the population,
there appears to be plenty of room for new entrants
on the market, especially those that can demonstrate
increased efficacy or reduced side-effects - important
for compliance. The following table shows a selection
of pipeline antipsychotics:
| Antipsychotics
(N5A) in development
|
| Compound
|
Trade
Name |
Companies
|
MOA
|
Phase |
| aripiprazole
|
Abilitat
|
Otsuka/B-MS
|
D2
antagonist/ autoreceptor agonist |
III |
| iloperidone
|
Zomaril
|
Titan/Novartis
|
D2/5-HT2
antagonist |
III |
| DTA
201A |
-
|
Knoll
(BASF) |
D3
antagonist |
II |
| DU
127090 |
- |
Solvay/Lundbeck
|
D2/5-HT1a
antagonist |
II |
| ORG
5222 |
-
|
Organon
(Akzo Nobel) |
D2/5-HT2
antagonist |
II |
| Osanetant
|
-
|
Sanofi-Synthelabo
|
neurokinin-3
antagonist |
II |
Source: R&Dfocus |
