Constella® (linaclotide) Approved in Europe for the Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Adults

  Constella® (linaclotide) Approved in Europe for the Treatment of Irritable
  Bowel Syndrome with Constipation (IBS-C) in Adults

  *Constella^® (linaclotide) is the first and only medicine approved by the
    European Commission for the symptomatic treatment of moderate to severe
    IBS-C in adults, that improves abdominal pain/discomfort, bloating and
    constipation
  *First launches in Europe are expected in the first half of 2013
  *IBS-C is a functional gastrointestinal disorder affecting approximately 15
    million adults across the European Union^1

Business Wire

BARCELONA, Spain & CAMBRIDGE, Mass. -- November 28, 2012

Almirall, S.A. (ALM:MC) and Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD)
announced today that the European Commission has granted marketing
authorization to Constella^® (linaclotide 290mcg) for the symptomatic
treatment of moderate to severe Irritable Bowel Syndrome with Constipation
(IBS-C) in adults. This approval follows the positive recommendation received
from the European Committee for Medicinal Products for Human Use (CHMP) in
September.

Constella^® is an oral, once-daily medication. Linaclotide, the active
ingredient in Constella^®, is a guanylate cyclase-C agonist (GCCA) with
visceral analgesic and secretory activities, as stated in the product label
for European use. In non-clinical studies, linaclotide has been shown to
reduce visceral pain by decreasing pain-fiber activity and to accelerate
gastrointestinal transit by increasing intestinal fluid secretion. Linaclotide
acts locally in the intestine with minimal systemic exposure.

“Despite affecting more than 10% of the population in the EU there are few
effective treatment options for IBS. Approximately one third of IBS patients
suffer from the IBS-C form of the disease and the approval of Constella^®
provides physicians with an innovative medication, for improving the lives of
patients whose quality of life is impaired,” said Professor Jan Tack, Head of
Clinic in the Department of Gastroenterology, and Professor in Internal
Medicine at the University Hospital Gasthuisberg of the University of Leuven,
Belgium.

IBS is a functional gastrointestinal disorder impacting over 10% of the
European population, and it is estimated that one-third of IBS patients suffer
from IBS-C^1, which means that approximately 15 million adults across the
European Union might be affected. Symptoms associated with IBS-C include
abdominal pain and discomfort, bloating, and constipation resulting in a
significant impact on affected individuals. There are few prescription
treatment options for this condition approved in the European Union.
Constella^® is the first and only prescription medicine approved by the
European Commission for the symptomatic treatment of moderate to severe
Irritable Bowel Syndrome with Constipation (IBS-C) in adults.

“Almirall is delighted with the approval of Constella^®, the first
prescription medicine approved by the European Commission for the treatment of
IBS-C in adults. This new medicine has the potential to improve some of the
hallmark symptoms of IBS-C patients who up until now have had few treatment
options. Furthermore the approval of Constella^® is an important growth
opportunity for Almirall and will strengthen our gastrointestinal franchise,”
said Eduardo Sanchiz, Chief Executive Officer at Almirall.

Almirall expects to begin launching Constella^® in Europe in the first half of
2013.

“Linaclotide was discovered by Ironwood scientists, and obtaining marketing
authorization for Constella^® in Europe is important progress towards our goal
of translating knowledge into medicines that make a difference for patients,”
said Peter Hecht, Ironwood’s Chief Executive Officer. “We look forward to
continuing to work closely with our partner Almirall in their efforts to bring
Constella^® to adult IBS-C patients in Europe, and we will continue
collaborating with our global network of partners with the goal of bringing
this medicine to appropriate patients worldwide.”

In April 2009, Almirall signed a license agreement with Ironwood, under which
Almirall holds exclusive marketing rights for linaclotide in all European
Union member states, plus Russia, the CIS (Commonwealth of Independent States
of the former USSR), Switzerland, Norway and Turkey, as well as other
countries in Europe, including the countries of former Yugoslavia. In
September 2012, Almirall also signed an agreement by which Forest Laboratories
sublicensed its commercialization rights for linaclotide in Mexico to
Almirall.

Notes to editors

About Constella^® (linaclotide)^1

Linaclotide is a Guanylate Cyclase-C receptor agonist (GCCA) with visceral
analgesic and secretory activities.

Linaclotide is a 14-amino acid synthetic peptide structurally related to the
endogenous guanylin peptide family. Both linaclotide and its active metabolite
bind to the GC-C receptor, on the luminal surface of the intestinal
epithelium. Through its action at GC-C, linaclotide has been shown to reduce
visceral pain and increase GI transit in animal models and increase colonic
transit in humans. Activation of GC-C results in an increase in concentrations
of cyclic guanosine monophosphate (cGMP), both extracellularly and
intracellularly. Extracellular cGMP decreases pain-fiber activity, resulting
in reduced visceral pain in animal models. Intracellular cGMP causes secretion
of chloride and bicarbonate into the intestinal lumen, through activation of
the cystic fibrosis transmembrane conductance regulator (CFTR), which results
in increased intestinal fluid and accelerated transit.

Constella^® is a trademark owned by Ironwood Pharmaceuticals, Inc.

Clinical efficacy and safety^1

The efficacy of linaclotide was established in two randomised, double-blind,
placebo-controlled Phase 3 clinical studies in patients with IBS-C. In one
clinical study (study 1), 802 patients were treated with Constella^® 290
micrograms or placebo once daily for 26 weeks. In the second clinical study
(study 2), 800 patients were treated for 12 weeks, and then re-randomised for
an additional 4 weeks treatment period. During the 2-weeks pre-treatment
baseline period, patients had a mean abdominal pain score of 5.6 (0-10 scale)
with 2.2% of abdominal pain-free days, a mean bloating score of 6.6 (0-10
scale), and an average of 1.8 spontaneous bowel movements (SBM)/week.

The characteristics of the patient population included in Phase 3 clinical
trials were as follows: mean age of 43.9 years [range 18 - 87 years with 5.3%
≥ 65 years of age], 90.1% female. All patients met Rome II criteria for IBS-C
and were required to report a mean abdominal pain score of ≥ 3 on a
0-to-10-point numeric rating scale (criteria that correspond to a moderate to
severe IBS population), < 3 complete spontaneous bowel movements and ≤ 5 SBMs
per week during a 2-week baseline period.

The co-primary endpoints in both clinical studies were 12-week IBS degree of
relief responder rate and 12 week abdominal pain/discomfort responder rate. An
IBS degree of relief responder was a patient that was considerably or
completely relieved for at least 50% of the treatment period; an abdominal
pain/discomfort responder was a patient that had an improvement of 30% or more
for at least 50% of the treatment period.

For the 12 weeks data, study 1 shows that 39% of the patients treated with
linaclotide compared with 17% of the patients treated with placebo showed
response to IBS degree of relief (p<0.0001) and 54% of the patients treated
with linaclotide compared with 39% of the patients treated with placebo showed
response to abdominal pain/discomfort (p<0.0001). Study 2 shows that 37% of
the patients treated with linaclotide compared with 19% of the patients
treated with placebo showed response to IBS degree of relief (p<0.0001) and
55% of the patients treated with linaclotide compared with 42% of the patients
treated with placebo showed response to abdominal pain/discomfort (p=0.0002).

For the 26 weeks data, study 1 shows that 37% and 54% of the patients treated
with linaclotide compared with 17% and 36% of the patients treated with
placebo showed response to IBS degree of relief (p<0.0001) and abdominal
pain/discomfort (p<0.0001) respectively.

In both studies, these improvements were seen by week 1 and sustained over the
entire treatment periods. Linaclotide has been shown not to cause rebound
effect when the treatment was stopped after 3 months continuous treatment.

Other signs and symptoms of IBS-C including bloating, complete spontaneous
bowel movement (CSBM) frequency, straining, stool consistency, were improved
in linaclotide treated patients vs. placebo (p<0.0001). These effects were
reached at 1 week and sustained over the entire treatment periods.

Treatment with linaclotide also resulted in significant improvements in
validated and disease-specific Quality of Life (QoL) measure (IBS-QoL;
p<0.0001), and EuroQoL (p = 0.001). Clinically meaningful response in overall
IBS-QoL (> 14 points difference) was achieved in 54% of linaclotide treated
patients vs. 39% in placebo treated patients.

The most frequently reported adverse reaction associated with linaclotide
therapy was diarrhoea, mainly mild to moderate in intensity, occurring in less
than 20% of patients. Other common adverse reactions (>1%) were abdominal
pain, abdominal distension and flatulence.

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 function and
with features of disordered defecation.^2 IBS-C is one of four clinically
different subtypes of IBS. One-third of patients with IBS are thought to have
IBS-C^3 and suffer chronically from both abdominal pain and constipation.

The Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders
includes criterion for the diagnosis of IBS^3 as:

  *Recurrent abdominal pain or discomfort at least three days/month, in the
    last three months with symptom onset at least 6 months prior to diagnosis,
    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 conditions such as migraine (12%) and asthma (11%)^1. IBS can
have a negative impact on daily living with considerable socio-economic and
psychological consequences, and represents a major proportion of
gastrointestinal workload in both primary and secondary care. Due to the
complex, multimodal nature of the condition there is no cure for IBS and there
are minimal therapeutic options.^4

About Almirall

Almirall is an international pharmaceutical company based on innovation and
committed to health. Headquartered in Barcelona, 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 respiratory, gastrointestinal, dermatology and pain. Almirall’s
products are currently present in over 70 countries in the five continents.
With the opening of the Canadian affiliate, Almirall has now direct presence
in Europe, Mexico and Canada through 13 affiliates.

For further information please visit: www.almirall.com

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (NASDAQ: IRWD) is an entrepreneurial pharmaceutical
company dedicated to the art and science of great drugmaking. Ironwood is
located in Cambridge, Mass.

To learn more, visit www.ironwoodpharma.com.

This press release contains forward looking statements. Investors are
cautioned not to place undue reliance on these forward-looking statements,
including, but not limited to, the potential for Constella as a treatment
option for the symptomatic treatment of moderate to severe IBS-C in adult men
and women, the anticipated launch timing of Constella, and the potential for
linaclotide to achieve marketing authorization approval in countries outside
of the European Union. Each forward-looking statement is subject to risks and
uncertainties that could cause actual results to differ materially from those
expressed or implied in such statement. Applicable risks and uncertainties
include the risks that Constella is priced at a point lower than anticipated,
Almirall is unable to secure sufficient reimbursement for Constella in any of
the major E.U. countries, physicians do not view Constella as an effective or
safe treatment option for adult men or women who suffer from moderate to
severe IBS-C, or Almirall is unable to produce an adequate commercial supply
of Constella, as well as risks related to the difficulty of predicting
regulatory approvals, the acceptance of and demand for new pharmaceutical
products, the potential prescribing habits of doctors, the impact of
competitive products and pricing, and whether linaclotide will ever be
commercialized successfully in a given country. Applicable risks also include
those that are listed in Ironwood Pharmaceuticals’ Quarterly Report on Form
10-Q for the quarter ended September 30, 2012, in addition to the risk factors
that are listed from time to time in Ironwood Pharmaceuticals’ Annual Reports
on Form 10-K, Quarterly Reports on Form 10-Q and any subsequent SEC filings.
We undertake no obligation to update these forward-looking statements to
reflect events or circumstances occurring after this press release. These
forward-looking statements speak only as of the date of this press release.
All forward-looking statements are qualified in their entirety by this
cautionary statement.

References

^1 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.

^2 Longstreth GF, Thompson WG, Chey WD et al. - Functional Bowel Disorders.
Gastroenterology 2006; 130: 1480-1491

^3 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

^4 Camilleri M, Chang L. - Challenges to the therapeutic pipeline for
irritable bowel syndrome: end points and regulatory hurdles. Gastroenterology
2008;135:1877–1891

Contact:

Almirall
Media Enquires:
Bianca Daneshfar-Nia, +44 20 76113510
bianca.daneshfar-nia@ketchumpleon.com
or
Investor Relations:
Jordi Molina, +34 93 2913087
jordi.molina@almirall.com
or
Ironwood Pharmaceuticals, Inc.
Media Relations:
Lisa Buffington, 617-374-5103
lbuffington@ironwoodpharma.com
or
Investor Relations:
Meredith Kaya, 617-374-5082
mkaya@ironwoodpharma.com