Almirall Announces Regulatory Filing of linaclotide for the Treatment of Irritable Bowel Syndrome With Constipation in Europe

BARCELONA, Spain, September 29, 2011 /PRNewswire/ –

– Linaclotide has demonstrated statistically significant improvement in
abdominal pain/discomfort and global relief of IBS-C symptoms in Phase III
clinical trials [1,2]

– IBS-C is a debilitating disease associated with reduced quality of
life and considerable socio-economic and psychological consequences [3,4]

Almirall, S.A. (ALM.MC) announced today that it has submitted a
Marketing Authorisation Application (MAA) to the European Medicines Agency
(EMA) for linaclotide, an investigational guanylate cyclase-C (GC-C)
receptor agonist for the treatment of irritable bowel syndrome with
constipation (IBS-C). Once approved, linaclotide will be marketed in Europe
under the trademark Constella(R).

“IBS is associated with significant reduction in quality of life and
intensive consumption of healthcare resources. In particular, people
suffering from IBS-C currently have very limited treatment options available
to them. Patients and physicians are frustrated because of this lack of
specific therapy for IBS-C”, said Bertil Lindmark, Chief Scientific Officer
at Almirall. “The results of clinical trials are extremely encouraging and,
with this regulatory submission of linaclotide in IBS-C, we look forward to
bringing this novel first in class medicine to patients in Europe.”

The submission includes efficacy and safety data from a Phase III
program comprising two double-blind placebo-controlled trials[1,2] and two
open-label long term safety studies. A total of more than 1,600 subjects
received an once-daily dose of either linaclotide or placebo across the two
placebo-controlled studies in patients with IBS-C. Full results of these two
studies will be presented at the European Gastroenterology Week (UEGW)
congress in Stockholm in October 23rd-26th, 2011.

This MAA follows the submission of an NDA for linaclotide to the US Food
and Drug Administration (FDA) in August 2011 by Ironwood Pharmaceuticals
Inc. and its US partner, Forest Laboratories Inc.

Almirall licensed from Ironwood the rights to develop and commercialize
linaclotide in Europe.

About the Phase III studies

The efficacy and safety of linaclotide in IBS-C has been evaluated in
two large double-blind placebo-controlled Phase III studies.[1,2] In both
trials, linaclotide was shown to be significantly superior to placebo for
improving pain/discomfort, degree of relief, complete spontaneous bowel
movement frequency, stool consistency, severity of straining and bloating.
These improvements were sustained over the entire treatment periods (12 and
26 weeks). Diarrhoea was the most prevalent adverse event (linaclotide 20%,
placebo 3%), mainly mild to moderate in intensity, that only led to
discontinuation in 5% of linaclotide-treated patients.

About Linaclotide

Linaclotide, a first-in-class investigational drug, is an agonist of the
guanylate cyclase type-C (GC-C) receptor located on the luminal surface of
the intestine. In preclinical models, linaclotide reduced visceral
hypersensitivity, increased fluid secretion, and accelerated intestinal
transit. The effects on secretion and transit are mediated through cyclic
guanosine monophosphate (cGMP), which is also believed to modulate the
activity of local nerves to reduce pain. Linaclotide is an orally delivered
peptide that acts locally in the gut with no measurable systemic exposure at
therapeutic doses and is intended for once-daily administration.

Ironwood Pharmaceuticals, Inc. and Forest Laboratories, Inc. are
co-developing and, if approved, will co-promote linaclotide in the United
States. Ironwood has out-licensed linaclotide to Almirall for European
development and commercialisation and to Astellas Pharma Inc. for
development and commercialisation in Japan, Indonesia, Korea, the
Philippines, Taiwan and Thailand.

About Irritable Bowel Syndrome with Constipation (IBS-C)

IBS is defined as ‘a functional bowel disorder in which abdominal pain
or discomfort is associated with defecation or a change in bowel habit and
with features of disordered defecation’.[5]

The Rome III Diagnostic Criteria for Functional Gastrointestinal
Disorders includes criterion for the diagnosis of IBS,[6] as:

        - Recurrent abdominal pain or discomfort at least three
          days/month, in the last three months, associated with two or more of the
          following:
        - improvement with defecation
        - onset associated with a change of frequency of stool
        - onset associated with a change in form (or appearance) of stool

The estimated prevalence of IBS at 10-15% of the European population
puts it in line with higher profile conditions such as migraine (12%) and
asthma (11%).[7] It leads to a substantial reduction in quality of life,
accompanied by considerable socio-economic and psychological consequences[
3,4] and represents a major proportion of gastrointestinal workload in both
primary and secondary care[8].

Owing to the complex, multimodal nature of the condition there is no
cure for IBS and no ‘gold standard’ of treatment.[8] Irritable bowel
syndrome with constipation (IBS-C) is one of four clinically different
subtypes of IBS. One third of patients with IBS are thought to have
IBS-C,[4,5,9]and therefore live with both abdominal pain and constipation.

About Almirall

Almirall is an international pharmaceutical company based on innovation
and committed to health. Headquartered in Barcelona, Spain, it researches,
develops, manufactures and commercialises its own R&D and licensed drugs
with the aim of improving people’s health and wellbeing.

Almirall focuses its research resources on therapeutic areas related to
the treatment of asthma, COPD (Chronic Obstructive Pulmonary Disease),
gastrointestinal disorders, psoriasis and other dermatological conditions.

Almirall’s products are currently present in over 70 countries while it
has direct presence in Europe and Latin America through 12 affiliates.

For further information please visit the website at:

http://www.almirall.com.

References

1. Rao S. et al. – Efficacy and Safety of Once Daily Linaclotide in
Patients With Irritable Bowel Syndrome With Constipation: A 12-Week,
Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial Followed by a
4-Week Randomized Withdrawal Period. Digestive Disease Week, May 7-10 2001,
Chicago Abstract#: 845

2. Chey, W. et al. – Efficacy and Safety of Once-Daily Linaclotide
Administered Orally for 26 Weeks in Patients With IBS-C: Results From a
Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial. Digestive
Disease Week, May 7-10 2001, Chicago Abstract#: 837

3. Maxion-Bergemann S, Thielecke F, Abel F, Bergemann R. – Costs of
irritable bowel syndrome in the UK and US. Pharmacoeconomics 2006;24:21-37

4. Davis RH. – Overcoming barriers in irritable bowel syndrome with
constipation (IBS-C). J Fam Pract 2009;58:S3-S7

5. Longstreth GF, Thompson WG, Chey WD et al. – Functional Bowel
Disorders. Gastroenterology 2006; 130: 1480-1491

6. Rome III Diagnostic Criteria for Functional Gastrointestinal
Disorders

7. P. S. Hungin et al – The prevalence, patterns and impact of irritable
bowel syndrome: an international survey of 40,000 subjects – Aliment
Pharmacol Ther 2003; 17: 643-650.

8. Camilleri M, Chang L. – Challenges to the therapeutic pipeline for
irritable bowel syndrome: end points and regulatory hurdles.
Gastroenterology 2008;135:1877-1891

9. American College of Gastroenterology Task Force on Irritable Bowel
Syndrome. An evidence-based position statement on the management of
irritable bowel syndrome. Am J Gastroenterol 2009; 104 Suppl 1:S1-35

Constella(R) is a trademark owned by Ironwood Pharmaceuticals, Inc. and
its use in Europe is pending approval from the appropriate regulatory
authorities.

SOURCE Almirall, S.A.