Santarus and VeroScience Announce Publication of Positive Data from Pivotal CYCLOSET® (bromocriptine mesylate) Efficacy Study

CYCLOSET add-on therapy provided significant improvement in glycemic control versus placebo in patients with type 2 diabetes poorly controlled on one or two oral anti-diabetes medications

SAN DIEGO & TIVERTON, R.I.--(BUSINESS WIRE)--Santarus, Inc. (NASDAQ: SNTS) and VeroScience, LLC today announced publication of positive data from a double-blind, placebo-controlled, multi-center pivotal study with CYCLOSET^® (bromocriptine mesylate) tablets. Patient groups in the evaluable per protocol (EPP) population that added CYCLOSET to their treatment regimen achieved a 0.60% to 0.70% reduction in HbA1c (p<0.0001) relative to placebo after 24 weeks, the primary endpoint of the study. These results appear in the November/December 2012 print edition of Endocrine Practice, a peer-reviewed medical journal.

“The results of this pivotal study show that the addition of CYCLOSET to the treatment regimen in this poorly controlled type 2 diabetes patient population produces significant and clinically relevant improvements in glycemic control markedly increasing the percent of patients reaching the HbA1c goal of ≤ 7.0 vs. placebo”

Additionally, among the EPP population with no concomitant change in diabetes medication, treatment with CYCLOSET resulted in:

• Reductions in HbA1c levels of 0.69% to 0.83% (CYCLOSET vs. placebo between group difference, p<0.0001)
• Five to seven times more subjects reaching the goal of HbA1c ≤7.0 in the CYCLOSET treated groups compared with placebo (32%-42% vs 5%-7%, respectively) (p<0.0001).

CYCLOSET is a unique, quick release form of bromocriptine, a dopamine receptor agonist that is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The study included 515 patients with type 2 diabetes with baseline HbA1c of ≥7.5% and ≤10.0% (average baseline HbA1c: 8.3) taking one or two oral anti-diabetes medications (metformin, sulfonylurea and/or thiazolidinediones). These poorly controlled patients were randomized 2:1 to CYCLOSET add-on (1.6 mg/day to 4.8 mg/day) or placebo add-on for a 24-week treatment period. Study investigators were allowed to adjust patient anti-diabetes medications during the study to attempt to achieve glycemic control in case of glycemic deterioration. The impact of CYCLOSET treatment was assessed in patients taking: (1) one or two oral anti-diabetes medications, (2) metformin with or without another oral anti-diabetes medication, or (3) metformin plus a sulfonylurea. The study was conducted in a cohort of patients imbedded in a larger randomized safety study.

The results of the primary endpoint analysis for the intent-to-treat (ITT) and EPP populations are summarized in the table below.

Effect of CYCLOSET Versus Placebo on Change from Baseline HbA1c (%)^a
and Odds Ratio of Achieving Goal of HbA1c ≤ 7.0
	ITT	EPP	EPP
Any one or two oral anti-diabetes			No concomitant change
medications			in diabetes medication
	N=515	N=379	N=272
Between group difference HbA1c	-0.51 (-0.70, -0.31)^b	-0.60 (-0.83, -0.38)^b	-0.69 (-0.97, -0.41)^b
Odds ratio of achieving HbA1c ≤ 7.0	3.48 (1.96, 6.18)^b	5.80 (2.93, 11.47)^b	6.50 (2.67, 15.84)^b
	ITT	EPP	EPP
Metformin with or without another			No concomitant change
oral anti-diabetes medication			in diabetes medication
	N=356	N=262	N=198
Between group difference HbA1c	-0.56 (-0.78, -0.34)^b	-0.68 (-0.93, -0.42)^b	-0.81 (-1.12, -0.51)^b
Odds ratio of achieving HbA1c ≤ 7.0	3.98 (1.98, 7.98)^b	6.69 (2.98, 15.04)^b	12.03 (3.53, 40.99)^b
	ITT	EPP	EPP
Metformin plus a sulfonylurea			No concomitant change
			in diabetes medication
	N=245	N=179	N=129
Between group difference HbA1c	-0.49 (-0.75, -0.24)^c	-0.70 (-1.00, -0.40)^b	-0.83 (-1.18, -0.48)^b
Odds ratio of achieving HbA1c ≤ 7.0	3.77 (1.72, 8.30)^d	7.26 (2.92, 18.01)^c	11.45 (3.19, 41.12)^c
^aValues are based on mean (95% Confidence Interval), adjusted by baseline HbA1c
^bp < 0.0001
^cp < 0.0002
^dp < 0.001

The most frequent adverse events in the study for CYCLOSET and placebo were, respectively, nausea (33% vs. 6%), fatigue (11% vs. 8%), dizziness (14% vs. 11%), headache (12% vs. 8%), constipation (7% vs. 3%), back pain (6% vs. 3%) and vomiting (6% vs. 2%). The discontinuation rate due to any adverse event was 20% for CYCLOSET-treated and 9% for placebo-treated patients.

“The results of this pivotal study show that the addition of CYCLOSET to the treatment regimen in this poorly controlled type 2 diabetes patient population produces significant and clinically relevant improvements in glycemic control markedly increasing the percent of patients reaching the HbA1c goal of ≤ 7.0 vs. placebo,” stated Aaron I. Vinik, M.D., Ph.D, Strelitz Diabetes Center and Neuroendocrine Unit, Norfolk, Virginia and lead author of the paper.

The article, titled Effect of Bromocriptine-QR on Glycemic Control in Subjects with Uncontrolled Hyperglycemia on One or Two Oral Anti-Diabetes Agents can be found online at http://www.ncbi.nlm.nih.gov/pubmed/23186965.

Important Safety Information

CYCLOSET is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications

CYCLOSET is contraindicated in:

• Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in CYCLOSET.
• Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during a migraine may reflect dopamine receptor hypersensitivity. CYCLOSET is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.
• Women who are nursing their children. CYCLOSET may inhibit lactation. There are postmarketing reports of stroke in this patient population although causality has not been proven.

Warnings and Precautions

• Hypotension: Can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use caution in patients taking anti-hypertensive medications. Assess orthostatic vital signs prior to initiation of CYCLOSET and periodically thereafter. Advise patients during early treatment to avoid situations that could lead to injury if syncope was to occur.
• Psychosis: May exacerbate psychotic disorders or reduce the effectiveness of drugs that treat psychosis. Use in patients with severe psychotic disorders is not recommended.
• Somnolence: May cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur.
• Interaction with dopamine antagonists: Concomitant use with dopamine antagonists such as neuroleptic agents may diminish the effectiveness of both drugs. Concomitant use is not recommended.
• Other dopamine receptor agonists: Effectiveness and safety are unknown in patients already taking dopamine receptor agonists for other indications. Concomitant use is not recommended.
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET or any other anti-diabetes drug. CYCLOSET does not increase the risk of macrovascular events.

Adverse Reactions

In controlled clinical trials, adverse reactions reported in ≥5% of patients treated with CYCLOSET and reported more commonly than in patients treated with placebo, included nausea, fatigue, dizziness, vomiting, and headache.

Postmarketing reports with higher doses of bromocriptine used for other indications include psychotic disorders, hallucinations, and fibrotic complications.

Drug Interactions

• May increase the unbound fraction of highly protein-bound therapies, altering their effectiveness and safety profiles.
• May increase ergot-related side effects or reduce ergot effectiveness for migraines if co-administered within 6 hours of ergot-related drugs.
• Extensively metabolized by CYP3A4. Use caution when co-administering strong inhibitors, inducers, or substrates for CYP3A4.

The Important Safety Information does not include all the information needed to use CYCLOSET safely and effectively. See Full Prescribing Information for CYCLOSET for additional information, available at www.cycloset.com or by contacting Santarus at [phone].

About VeroScience

VeroScience is a privately held biotechnology and healthcare product development company with main offices and laboratories in Tiverton, R.I. VeroScience holds the New Drug Application and related technology for CYCLOSET and has a large patent portfolio that supports its preclinical and clinical development programs and product pipeline in the areas of metabolism, immunology and oncology. VeroScience leverages its intellectual property and products in out-licensing and collaborative arrangements with appropriate industry partners.

About Santarus

Santarus, Inc. is a specialty biopharmaceutical company focused on acquiring, developing and commercializing proprietary products that address the needs of patients treated by physician specialists. The company's current commercial efforts are focused on GLUMETZA^® (metformin hydrochloride extended release tablets) and CYCLOSET^® (bromocriptine mesylate) tablets, which are indicated as adjuncts to diet and exercise to improve glycemic control in adults with type 2 diabetes, and on FENOGLIDE^® (fenofibrate) tablets, which is indicated as an adjunct to diet to reduce high cholesterol. In March 2013, the company plans to begin promoting UCERIS^™ (budesonide) extended release tablets for the induction of remission of active, mild to moderate ulcerative colitis and ZEGERID^® (omeprazole/sodium bicarbonate) for the treatment of certain upper gastrointestinal disorders. Safety information and full prescribing information for Santarus’ products are available at www.santarus.com.

Santarus’ product development pipeline includes the investigational drug RUCONEST^® (recombinant human C1 esterase inhibitor) for treatment of acute attacks of hereditary angioedema. The company expects to submit a biologics license application (BLA) to the U.S. Food and Drug Administration for RUCONEST in the first half of 2013. Santarus is also developing rifamycin SV MMX^®, which is in Phase III clinical testing for treatment of travelers’ diarrhea. In addition, SAN-300, the company’s investigational monoclonal antibody, is in Phase I clinical testing. More information about Santarus is available at www.santarus.com.

Santarus cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. The inclusion of forward-looking statements should not be regarded as a representation by Santarus that any of its plans or objectives will be achieved. Actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in Santarus’ business, including, without limitation: risks associated with the collaboration relating to CYCLOSET, including the potential for termination of the collaboration; competition from other products; unexpected adverse side effects or inadequate therapeutic efficacy of Santarus’ products and product candidates; the scope and validity of patent protection for Santarus’ products and product candidates; and other difficulties or delays relating to the development, testing, manufacturing and marketing of, and obtaining and maintaining regulatory approvals for, Santarus’ products and product candidates; and other risks detailed in Santarus’ prior press releases as well as in prior public periodic filings with the Securities and Exchange Commission.

You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Santarus undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.

Santarus^®, FENOGLIDE^®, UCERIS^™ and ZEGERID^® are trademarks of Santarus, Inc. GLUMETZA^® is a trademark of Biovail Laboratories International S.r.l. licensed exclusively in the United States to Depomed, Inc. CYCLOSET^® is a trademark of VeroScience LLC. MMX^® is a trademark of Cosmo Technologies Limited. RUCONEST^® is a trademark of Pharming Group N.V.