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Synergy Pharmaceuticals Highlights New Data at Digestive Disease Week (DDW) 2018 Linking Uroguanylin Deficiency to Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C)

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Synergy Pharmaceuticals Inc. (NASDAQ:SGYP), a biopharmaceutical company
focused on the development and commercialization of novel
gastrointestinal (GI) therapies, announced today new data presented at
Digestive Disease Week (DDW) 2018 showing chronic idiopathic
constipation (CIC) and irritable bowel syndrome with constipation
(IBS-C) are associated with depressed levels of uroguanylin, a naturally
occurring and endogenous human GI peptide.

"The discovery of uroguanylin deficiency in CIC and IBS-C patients
represents a historic advance towards better understanding and treating
these two complex GI disorders," said Scott A. Waldman, M.D., PhD,
Professor and Chair, Pharmacology & Experimental Therapeutics, Sidney
Kimmel Medical College, Thomas Jefferson University. "This is the first
study to measure circulating uroguanylin responses in humans, and we
observed a significant correlation between chronic constipation and
depressed levels of uroguanylin following food intake. These findings
suggest that chronic constipation syndromes may, in part, reflect an
insufficiency of uroguanylin. In turn, this peptide insufficiency can be
corrected, and the pathophysiology underlying chronic constipation
reversed, by administering oral uroguanylin analogs such as plecanatide."

"This is an exciting day for Synergy and for the broader GI community,"
said Patrick H. Griffin, M.D., Chief Medical Officer at Synergy
Pharmaceuticals Inc. "For more than a decade, Synergy has been committed
to advancing the understanding of uroguanylin and the role this key
peptide plays in human GI physiology. This discovery provides novel
insight into the complex biology of CIC and IBS-C and reinforces our
belief that the best approach to reversing this uroguanylin deficiency
is by administering oral analogs of uroguanylin. This is the foundation
of Synergy's approach and why we see significant potential for our
uroguanylin analog platform to transform the treatment paradigm and
benefit patients suffering from GI conditions."

Study Results

The objective of the study was to evaluate and compare pre- and
postprandial circulating pro-uroguanylin levels in healthy subjects
versus patients with CIC or IBS-C. The study included 60 healthy
subjects and 107 patients with CIC or IBS-C who participated in an
overnight fast, followed by a standardized meal of 750 calories.
Pro-uroguanylin and uroguanylin levels were measured at fasting and then
at 30, 60 and 90 minutes following the meal.

Results showed that pro-uroguanylin concentrations were lower in
patients at fasting and at each time point following the meal compared
to healthy subjects (difference in mean pro-uroguanylin concentrations
was 583 pg/mL, 95% CI: 405, 761; p<0.0001). Mean pro-uroguanylin plasma
concentrations were consistently >30% lower in patients than in healthy
subjects. Similarly, patients also had lower circulating uroguanylin
levels at preprandial and all postprandial time points (the difference
in mean uroguanylin concentration was 112 pg/mL, 95% CI: 74, 150;
p<0.0001).

These results suggest a novel pathophysiological hypothesis in which
chronic constipation may reflect a paracrine hormone insufficiency of
pro-uroguanylin in the small intestine. The correlative therapeutic
hypothesis suggests that this pathophysiology can be reversed by oral
supplementation with a uroguanylin analog such as plecanatide.

Indications and Usage

TRULANCE (plecanatide) 3 mg tablets is indicated in adults for the
treatment of Chronic Idiopathic Constipation (CIC) and Irritable Bowel
Syndrome with Constipation (IBS-C).

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS

TRULANCE® is contraindicated in patients
less than 6 years of age; in nonclinical studies in young juvenile mice
administration of a single oral dose of plecanatide caused deaths due to
dehydration. Use of TRULANCE should be avoided in patients 6 years to
less than 18 years of age. The safety and efficacy of TRULANCE have not
been established in pediatric patients less than 18 years of age.

Contraindications

  • TRULANCE is contraindicated in patients less than 6 years of age due
    to the risk of serious dehydration.
  • TRULANCE is contraindicated in patients with known or suspected
    mechanical gastrointestinal obstruction.

Warnings and Precautions

Risk of Serious Dehydration in Pediatric Patients

  • TRULANCE is contraindicated in patients less than 6 years of age. The
    safety and effectiveness of TRULANCE in patients less than 18 years of
    age have not been established. In young juvenile mice (human age
    equivalent of approximately 1 month to less than 2 years), plecanatide
    increased fluid secretion as a consequence of stimulation of guanylate
    cyclase-C (GC-C), resulting in mortality in some mice within the first
    24 hours, apparently due to dehydration. Due to increased intestinal
    expression of GC-C, patients less than 6 years of age may be more
    likely than older patients to develop severe diarrhea and its
    potentially serious consequences.
  • Use of TRULANCE should be avoided in patients 6 years to less than 18
    years of age. Although there were no deaths in older juvenile mice,
    given the deaths in young mice and the lack of clinical safety and
    efficacy data in pediatric patients, use of TRULANCE should be avoided
    in patients 6 years to less than 18 years of age.

Diarrhea

  • Diarrhea was the most common adverse reaction in the four
    placebo-controlled clinical trials for CIC and IBS-C. Severe diarrhea
    was reported in 0.6% of TRULANCE-treated CIC patients, and in 1% of
    TRULANCE-treated IBS-C patients.
  • If severe diarrhea occurs, the health care provider should suspend
    dosing and rehydrate the patient.

Adverse Reactions

  • In the two combined CIC clinical trials, the most common adverse
    reaction in TRULANCE-treated patients (incidence ≥2% and greater than
    in the placebo group) was diarrhea (5% vs 1% placebo).
  • In the two combined IBS-C clinical trials, the most common adverse
    reaction in TRULANCE-treated patients (incidence ≥2% and greater than
    in the placebo group) was diarrhea (4.3% vs 1% placebo).

Please also see the full
Prescribing Information
, including Box Warning, for
additional risk information.

About Chronic Idiopathic Constipation (CIC)

CIC affects approximately 14 percent of the global population,
disproportionately affecting women and older adults. People with CIC
have persistent symptoms of difficult-to-pass and infrequent bowel
movements. In addition to physical symptoms including abdominal bloating
and discomfort, CIC can adversely affect an individual's quality of
life, including increasing stress levels and anxiety.

About Irritable Bowel Syndrome with Constipation (IBS-C)

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder
characterized by recurrent abdominal pain and associated with two or
more of the following: related to defecation, associated with a change
in the frequency of stool, or associated with a change in the form
(appearance) of the stool. IBS can be subtyped by the predominant stool
form: constipation (IBS-C), diarrhea (IBS-D) or mixed (IBS-M). Those
within the IBS-C subtype experience hard or lumpy stools more than 25
percent of the time they defecate, and loose or watery stools less than
25 percent of the time. It is estimated that the
prevalence of IBS-C in the U.S. adult population is approximately 4 to 5
percent.

About TRULANCE®

TRULANCE® (plecanatide) is a once-daily tablet approved for
adults with CIC or IBS-C. With the exception of a single amino acid
substitution for greater binding affinity, TRULANCE is structurally
identical to uroguanylin, a naturally occurring and endogenous human GI
peptide. Uroguanylin activates GC-C receptors in a pH-sensitive manner
primarily in the small intestine, stimulating fluid secretion and
maintaining stool consistency necessary for regular bowel function.

About Synergy Pharmaceuticals Inc.

Synergy is a biopharmaceutical company focused on the development and
commercialization of novel GI therapies. The company has pioneered
discovery, research and development efforts on analogs of uroguanylin, a
naturally occurring and endogenous human GI peptide, for the treatment
of GI diseases and disorders. Synergy's proprietary GI platform includes
one commercial product TRULANCE® (plecanatide) and a second
product candidate, dolcanatide. For more information, please visit www.synergypharma.com.

Forward-Looking Statement

Certain statements in this press release are forward-looking within the
meaning of the Private Securities Litigation Reform Act of 1995. These
statements may be identified by the use of forward-looking words such as
"anticipate," "planned," "believe," "forecast," "estimated," "expected,"
and "intend," among others. These forward-looking statements are based
on Synergy's current expectations and actual results could differ
materially. There are a number of factors that could cause actual events
to differ materially from those indicated by such forward-looking
statements. These factors include, but are not limited to, substantial
competition; our ability to continue as a going concern; our need for
additional financing; uncertainties of patent protection and litigation;
uncertainties of government or third party payer reimbursement; limited
sales and marketing efforts and dependence upon third parties; and risks
related to failure to obtain FDA clearances or approvals and
noncompliance with FDA regulations. As with any pharmaceutical under
development, there are significant risks in the development, regulatory
approval and commercialization of new products. There are no guarantees
that future clinical trials discussed in this press release will be
completed or successful or that any product will receive regulatory
approval for any indication or prove to be commercially successful.
Investors should read the risk factors set forth in Synergy's Annual
Report on Form 10-K for the year ended December 31, 2017 and other
periodic reports filed with the Securities and Exchange Commission.
While the list of factors presented here is considered representative,
no such list should be considered to be a complete statement of all
potential risks and uncertainties. Unlisted factors may present
significant additional obstacles to the realization of forward-looking
statements. Forward-looking statements included herein are made as of
the date hereof, and Synergy does not undertake any obligation to update
publicly such statements to reflect subsequent events or circumstances.

PP-TRU-US-0784

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