| After
first being submitted for clearance in 2001, on August 4 2004
Lilly's Cymbalta (duloxetine) finally received marketing
approval from the FDA and was due to be widely available in
the US by the end of the month. Cymbalta, a dual serotonin
and noradrenaline (norephinephrine) inhibitor, is indicated
for major depressive disorder.
Duloxetine
is also in development for the treatment of stress urinary
incontinence and diabetic neuropathic pain. In November
2002, Lilly began an alliance with Boehringer Ingelheim
for the development and commercialisation of duloxetine,
but in the US, this will be focusing on the SUI indication.
As Yentreve/Ariclaim, duloxetine received EU approval
for SUI later in August 2004.
The
battle for top spot
While
many of Lilly's other products have performed well, since
the loss
of exclusivity for
Prozac (fluoxetine) in the US in 2001, other companies
have taken its place in the depression market. This is notable
for the changing fortunes of the top products: GlaxoSmithKline's
Seroxat/Paxil (paroxetine) assumed the top spot in
the N6A (antidepressants and mood stabilisers) rankings
once generic fluoxetine became available.
Then, despite GSK's efforts,
in September 2003, generic paroxetine was launched in the
US. This vaulted Pfizer's Zoloft (sertraline) to
first position, closely followed by Wyeth's Effexor/XR
(venlafaxine). Unbranded paroxetine became more widely available
in the US from March 2004, so sales of GSK's brand will
continue to fall over 2004 (down 41% in the second quarter);
in 2002, it launched a once-daily version developed by SkyePharma,
Paxil CR, in the US.
N6A
antidepressant market share
*Manufactured
by Par and Apotex
Source: IMS
MIDAS
Most
of the leading antidepressants are selective serotonin reuptake
inhibitors, or SSRIs. They have become a controversial class,
however, following widespread media coverage of potential
side-effects such as the risk of suicide and withdrawal
symptoms, and are now generally not recommended for use
in younger patients. In March 2004, the FDA told manufacturers
to strengthen the suicide risk warnings for 10 antidepressants,
and the agency is examining their effects on children.
Indeed,
doubts were raised about the approval of Cymbalta following
the suicide of a trial participant at Lilly's Laboratory
for Clinical Research in February 2004. The FDA, however,
exonerated the drug, saying it could not be linked to the
death of 19 year-old Traci Johnson. She had been a 'healthy
volunteer' in a study examining the effects of high doses
of duloxetine; following her death, by hanging, Lilly extended
the "weaning period" of the trial from four days to eight.
It was later reported that Johnson had suffered some psychiatric
problems when younger, but Lilly would not comment.
Nevertheless,
19 million Americans are believed to suffer from depression,
and the SSRIs do have many fewer adverse effects in general
than the older tricyclic antidepressants. Two other leading
antidepressants from different chemical groups are GSK's
Wellbutrin/XL (bupropion), a noradrenaline and dopamine
reuptake inhibitor, and Akzo Nobel's Remeron (mirtazapine),
a noradrenaline and specific serotonin antagonist (NaSSA).
Dual
action benefits
Effexor
has performed well partly as it too inhibits both serotonin
and noradrenaline. Wyeth released an analysis in September
2003 demonstrating that Effexor/XR helped significantly
more patients achieve remission and resolution of both emotional
and physical symptoms than SSRIs. Lilly has made similar
claims for Cymbalta, stating that at present, only 25-35%
of patients with depression experience relief from all their
symptoms. Brokers Merrill Lynch believe Cymbalta could be
a more potent and selective reuptake inhibitor, offering
a more rapid onset and a better response/remission rate.
Lilly has said the selectivity of duloxetine for its receptor
leads to a better tolerability profile, with lower potential
for cardiovascular side-effects than Effexor.
Quoted
in the Lilly press release announcing the FDA approval of
Cymbalta, a UCSD professor of psychiatry commented: "Depression
is a whole-body illness, but most modern antidepressants
treat the emotional symptoms, such as crying and sadness,
better than they treat the physical symptoms of depression.
Because of its dual action on serotonin and norepinephrine,
Cymbalta offers physicians a new opportunity to help patients
with depression, particularly those who experience the common
physical symptoms of the disease, such as vague aches and
pains."
Manufacturing
problems overcome
Cymbalta,
which most analysts believe has blockbuster potential (Effexor
had global sales of $2.7 billion in 2003), is seen as crucial
to Lilly's future. While it eventually weathered the loss
of Prozac's exclusivity, the company has now become reliant
on atypical
antipsychotic Zyprexa (olanzapine), which
accounted for 40.5% of the company's total sales in the
12 months to March 2004, according to IMS MIDAS.
Cymbalta
was submitted for FDA approval in November 2001, but its
clearance was delayed by problems at Lilly's manufacturing
plant and FDA requests for further data: 'approvable' letters
for the depression indication were issued in September 2002
and October 2003, then the FDA extended the review period
by three months in June. Cymbalta's approval thus marked
a red letter day for Lilly.
Market
developments
In an
interview with IMS
Company Profiles in June 2004,
Claus Braestrup, President and CEO of Lundbeck, said it
was hard to predict the impact of Cymbalta. Lundbeck developed
Cipramil (citalopram) and the second-generation version
Cipralex (escitalopram), which are marketed in the
US by Forest as Celexa and Lexapro respectively.
Braestrup saw at least two possible scenarios following
the launch of Cymbalta:
- it
could take market share from Lexapro, or
- the
high level of 'noise' created by its introduction could
boost sales of branded antidepressants in general
Overall,
Braestrup did not see Cymbalta having a significant impact
on Lexapro (Celexa is expected to lose US exclusivity in
2004). Lundbeck, however, has some strategies in place,
including possible head-to-head trials of Lexapro against
Cymbalta.
According
to IMS, the US N6A market was worth $13.2 billion in 2003.
IMS
Therapy Forecaster
predicts that this will rise to $22.9 billion in 2013, with
a compound annual growth rate of 5.7%. This may appear to
be lower than expected, but the period will see the loss
of exclusivity for Celexa, Zoloft and Effexor, and thus
a higher volume of lower-priced generics. The US market
in general will see some changes, with the Medicare prescription
drug benefit likely to boost sales; however, cost-containment
measures will likely encourage the prescribing of generic
alternatives where possible.
Lilly
will therefore have to demonstrate the improved efficacy
and value of Cymbalta to compete, and is planning a major
marketing blitz for its launch. In general, experts interviewed
by IMS were positive about Cymbalta's performance, and thought
it might replace Effexor if better tolerated. The most common
side-effect is nausea, affecting 20% of patients, but it
tends to subside after the first few days of use.
Looking
further ahead
A
number of products are in development for the treatment
of depression, with some of the later-stage compounds detailed
below.
Antidepressants
in late-stage development
| Compound |
Mechanism
of action |
Developer |
Status |
| Emsam
(selegiline patch) |
Monoamine
oxidase inhibitor |
Somerset
(Watson & Mylan) |
Pending
final approval |
| Valdoxan
(agomelatine) |
Melatonin
agonist |
Servier |
III |
| desvenlafaxine |
SNRI |
Wyeth |
III |
| SR
58611 |
phenylethanolaminotetraline
& beta3 adrenergic agonist |
Sanofi-Synthelabo |
III |
| AAG
561 |
corticotropin-releasing
factor 1 antagonist |
Novartis |
II |
| AR
A2 |
serotonin
(5-HT1b) antagonist |
AstraZeneca |
II |
| AVE
7398 |
GABA-B
antagonist |
Aventis |
II |
| 353162 |
dopamine
& noradrenaline reuptake inhibitor |
GSK |
II |
| vestipitant
(597599) |
neurokinin
1 antagonist |
GSK |
II |
| Org
34517 |
glucocorticoid
antagonist |
Akzo
Nobel |
II |
| saredutant |
neurokinin
2 antagonist |
Sanofi-Synthelabo
|
II |
Source:
IMS
LifeCycle R&D
One
potential competitor for Cymbalta has disappeared: after it
was rejected by the FDA in June 2004, Akzo Nobel withdrew
the NDA for gepirone ER, a serotonin (5-HT1a) antagonist.
Just one day after Cymbalta's approval, however, Merck &
Co launched itself into the depression arena again through
a $300m+ licensing deal with DOV; it gained exclusive worldwide
rights to DOV 21,947, one of the smaller firm's novel triple
uptake inhibitors (noradrenaline, serotonin and dopamine),
currently in Phase I studies for depression, plus a related
compound, DOV 216,303.
This article was written by Selena Class, Deputy Executive
Editor of IMS Company Profiles.
Much
of the information was sourced from IMS Knowledge
Link, which integrates detailed data from a number
of publications covering sales, R&D, news, patents and
strategic issues on a single website. The extensive coverage
includes more than 100 of the top pharmaceutical and biotechnology
companies as well as 300 therapeutic areas and 36 countries.
For more information, visit imsknowledgelink.com or contact Rupesh
Chudasama via
or +44 207 393 5000. |
