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Helsinn Healthcare SA: Palonosetron - The long-lasting antiemetic action finds its basis

Stockholm, Sweden (ots)

New data on the mechanism of action of the second generation 5-HT3
antagonist palonosetron presented today at the 33rd ESMO Congress in
Stockholm, Sweden
New data presented today at the 33rd
ESMO (European Society of Medical Oncology) Congress in Stockholm may
contribute to explain the reason why palonosetron, a second
generation 5-HT3 receptor antagonist, demonstrates in clinical trials
and clinical practice a unique long-lasting action in the prevention
of chemotherapy-induced nausea and vomiting (CINV) in patients with
cancer. A single intravenous dose of palonosetron (0.25 mg) provides
better protection from CINV than first-generation 5-HT3 receptor
antagonists, such as ondansetron and granisetron, throughout a 5-day
post-chemotherapy period*. This means that a single administration of
palonosetron also grants protection during the delayed phase of
CINV*.
Compared to other 5-HT3 receptor antagonists, palonosetron has a
unique chemical structure and exhibits high binding affinity for the
5-HT3 receptor. Since the beginning its structural differences have
been investigated to understand whether they may lead to a different
interaction of the compound with the 5-HT3 receptor. All 5-HT3
receptor antagonists bind to the same site as serotonin, thus
preventing the neurotransmitter from causing emesis. Palonosetron
exhibits allosteric binding and positive cooperativity, unlike
granisetron and ondansetron which exhibit simple bimolecular binding
and no cooperativity. This suggests that palonosetron interacts with
the 5-HT3 receptor at sites distinct to granisetron and ondansetron
and induces a conformational change in the receptor.
"The binding mode and the high receptor affinity of palonosetron
make it a more efficient receptor antagonist compared to agents such
as ondansetron and granisetron, as palonosetron may be less likely to
be displaced by serotonin", said Dr. Matti Aapro, Dean of the
Multidisciplinary Oncology Institute, Genolier, Switzerland.
"However, the efficacy of palonosetron during the delayed phase of
CINV* cannot be explained solely by this higher affinity and its
longer half-life", he added.
Some in vitro studies have shown that palonosetron exhibits a
long-lasting inhibition of 5-HT3 receptor function. Thus, it has been
hypothesized that the drug's mechanism of action may also be
associated to a decrease in the number of overall receptor sites
available to serotonin.
Actually, the findings presented today by Dr. Aapro at the ESMO
conference visualize, via a special microscopy investigation
(confocal fluorescence microscopy), that the binding of palonosetron
is also associated to another conformational change of the receptor,
which is internalized into the cell and therefore "hidden" to
serotonin. "The receptor internalization is a differentiating
pharmacological feature which may account for the effect of
palonosetron, persisting beyond its binding to the 5-HT3 receptor",
Dr. Aapro commented. Chemotherapy-induced nausea and vomiting (CINV)
is among the most dreaded side effects following therapy in patients
with cancer. Despite prophylaxis, on the day of chemotherapy, up to
30-45 percent of patients experience nausea or vomiting or require
rescue therapy following administration of certain types of
emetogenic chemotherapy.
The 5-HT3 receptor plays a pivotal role in the process of emesis,
and agents that antagonise these receptor subtypes are the basis for
control of this effect. Following the development of the first
generation 5-HT3 receptor antagonists, such as ondansetron and
granisetron, in the late '80s and early '90s, in the recent years new
compounds have been made available for preventing CINV, including
palonosetron.
Palonosetron has been developed by Helsinn Healthcare SA of
Switzerland and today it is marketed in more than 40 countries
world-wide as Aloxi®, Onicit®, and Paloxi®. According to the IMS rank
of the Top New Chemical Entities registered world-wide in the years
2003-2007, palonosetron is the 25th best selling compound, accounting
for over 300 million dollars in audited world sales in 2007.
Palonosetron, marketed as Aloxi®, is the leading brand in the USA
within the CINV Day of Chemo segment, and it is steadily growing in
the European markets. Its approval in Japan is expected during 2009.
"This result of palonosetron, a compound indicated in a 'niche'
market, is an outstanding one and demonstrates the commitment of our
company and all our partners in highlighting palonosetron intrinsic
value", commented Dr. Riccardo Braglia, CEO of Helsinn Healthcare.
"We expect soon more key achievement for palonosetron, to further
provide important benefits to the medical community and cancer
patients", he said.
About Palonosetron (Aloxi®, Onicit®, Paloxi®)
Palonosetron (palonosetron hydrochloride) is a selective
5-HT3-receptor antagonist, developed for the prevention of CINV, with
a long half-life of 40 hours and at least 30 times higher receptor
binding affinity than currently available compounds. Several clinical
trials demonstrated that palonosetron covers up to 5 days following
chemotherapy in comparison with single doses of other  competitor
products*. Since its availability in USA in September 2003, there
have been over 7 million administrations of palonosetron. The product
has shown to be effective in preventing both acute and delayed CINV
in patients receiving moderately emetogenic chemotherapies.
Palonosetron 0.075 mg IV is also approved by FDA as a single
intravenous dose administered immediately before the induction of
anaesthesia for the prevention of postoperative nausea and vomiting
(PONV) for up to 24 hours following surgery. Palonosetron is
contraindicated in patients known to have hypersensitivity to the
drug or any of its components. The most commonly reported adverse
reactions (incidence *2 %) in CINV trials with palonosetron were
headache (9 %) and constipation (5 %), and they were similar to the
comparators. In PONV trials, the most commonly reported adverse
reactions were QT prolongation (5 %), bradycardia (4 %), headache (3
%), and constipation (2 %), similar to placebo. For more information
about palonosetron, please visit the website: www.aloxi.com.
About Helsinn Healthcare
Helsinn Healthcare is a privately owned pharmaceutical group with
headquarters in Switzerland and is the worldwide licensor of
palonosetron. Helsinn's core business is the licensing of
pharmaceuticals in therapeutic niche areas. The company's business
strategy is to in-license early stage new chemical entities and
complete their development from the performance of
pre-clinical/clinical studies and CMC development to the attainment
of market approvals in U.S. and Europe. Helsinn's products are
eventually out-licensed to its marketing partners for distribution.
The active pharmaceutical ingredients and the finished dosage forms
are manufactured at Helsinn's cGMP facilities and supplied worldwide
to its customers.
*These sentences refer to Moderately Emetogenic Chemotherapy (MEC)
setting
For more information about Helsinn Healthcare, please visit the
company's website at www.helsinn.com.

Contact:

Helsinn Healthcare SA
Paolo Ferrari
Head of International Marketing
Tel: +41/91-985-21-21.
E-Mail: info-hhc@helsinn.com

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