Forest Laboratories, Inc. Announces Publication in The Lancet of Pivotal Phase III Hypertension Trial of the Fixed-Dose Combination of Nebivolol/Valsartan

Forest Laboratories, Inc. (NYSE:FRX) today announced the publication of data from its pivotal Phase III Study of an Investigational Fixed-Dose Combination (FDC) of nebivolol and valsartan in the May 30, 2014 issue of The Lancet. In the study, the combination of nebivolol and valsartan met its primary and key secondary endpoints, demonstrating statistically significant reductions from baseline in diastolic and systolic blood pressure vs. both nebivolol alone and valsartan alone at 8 weeks in patients with hypertension.

“These data indicate that the combinations of nebivolol and valsartan were effective at lowering blood pressure in patients with hypertension,” said Thomas Giles, M.D., Professor of Medicine, Tulane University School of Medicine. “To our knowledge, this is the first study to assess the efficacy and safety of a fixed-dose combination consisting of a beta-blocker and angiotensin II receptor blocker in hypertensive patients. The data from this trial show that the combination provided significantly greater blood pressure reductions vs. nebivolol monotherapy and vs. valsartan monotherapy with treatment-emergent adverse events that were similar across all treatment groups, including placebo.”

The mean change in trough seated diastolic blood pressure from baseline to week 8 for FDC 20/320 mg was significantly greater vs. valsartan 320 mg, the highest approved valsartan dose (-15.7 ± 9.6 mmHg vs. -11.2 ± 9.3 mmHg; least squares mean difference (LSMD) [95% CI]: -4.4 [-5.4, -3.3] mmHg, P<0.001) and significantly greater vs. nebivolol 40 mg, the highest approved nebivolol dose (-15.7 ± 9.6 mmHg vs. -14.4 ± 9.4 mmHg; LSMD [95% CI]: -1.2 [-2.3, -0.1] mmHg, P=0.030). All other comparisons to protocol-specified monotherapy arms at 8 weeks were also significant (FDC 10/320 mg and FDC 10/160 mg), favoring the fixed-dose combinations (all p<0.0001).

The baseline-to-endpoint decrease in trough seated systolic blood pressure was significantly greater FDC 20/320 mg vs. valsartan 320 mg: -17·8 ± 15·8 mmHg vs. -14.8 ± 15.1 mmHg; LSMD [95% CI]: -3.1 [-4.9, -1.4] mmHg, P<0.001 and FDC 20/320 mg vs. nebivolol 40 mg: -17.8 ± 15.8 mmHg vs. -15.1 ± 16.5 mmHg; LSMD [95% CI]: -2.9 [-4.7, -1.1] mmHg, P=0.001. All other FDC doses were also significantly better than monotherapies at week 8, (all p<0.01). Other nebivolol and valsartan fixed-dose combinations examined (FDC 5/80 mg, FDC 5/160 mg) resulted in significantly greater reductions from baseline in diastolic and systolic blood pressure at week 4, except for FDC 5/160 mg vs. valsartan 160 mg on systolic blood pressure.

Across all FDC doses the most common adverse reactions (incidence ≥ 2% and greater than that observed in the placebo group) were fatigue (0.9% to 2.3% vs. 1.1% in placebo), and dizziness (1.6% to 2.3% vs. 0.4% in placebo).

Study Design

This pivotal 8-week randomized, double-blind, placebo-controlled clinical trial in 4,161 hypertension patients studied nebivolol 5, 10, 20, and 40mg and valsartan 80, 160, and 320mg alone and in various fixed-dose combinations. The study consisted of a 1-week screening period, followed by 6 weeks of placebo wash-out, an 8-week double-blind treatment period, and a 1-week down-titration period. During the double-blind treatment period, patients were initially randomized to one of eight treatment groups: FDC nebivolol/valsartan 5/80, 5/160, or 10/160mg; nebivolol 5 or 20mg; valsartan 80 or 160mg or placebo. After four weeks, all dosages were doubled.

About Nebivolol and Valsartan

Nebivolol/valsartan (5/80mg, 5/160mg, 10/160mg, 10/320mg, and 20/320mg) is an investigational fixed-dose combination. It combines two U.S. Food and Drug Administration (FDA) approved, once daily, blood pressure lowering agents with different mechanisms of action. It is being evaluated as a potential treatment for hypertension in patients who need combination therapy. Forest recently submitted a New Drug Application to the FDA for the nebivolol/valsartan FDC for the treatment of hypertension

Nebivolol (marketed in the US as Bystolic) is cardioselective up to and including the 10mg dose and in extensive metabolizers. While nebivolol’s mechanism of action has not been definitively established, possible factors include vasodilation and decreased peripheral vascular resistance, reduced heart rate and myocardial contractility, suppression of renin, and reduced sympathetic activity. Nebivolol is indicated for the treatment of hypertension and is effective at lowering blood pressure when taken alone or in combination with other antihypertensive agents.

Valsartan is an angiotensin II receptor blocker that blocks the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland, thereby preventing its vasoconstrictor and aldosterone-secreting effects. Valsartan has been well studied in many different patient populations and is an effective antihypertensive agent.

About Hypertension

According to the CDC, hypertension has been called the “silent killer” because it often has no warning signs or symptoms and has been associated with serious cardiovascular (CV) risks, such as stroke and myocardial infarction. Hypertension represents a significant public health issue with high prevalence. According to the National Institute for Health Statistics, approximately 30% of adults in the United States have hypertension. Inadequate control of hypertension is a significant public health problem, with nearly half of all patients still not achieving target goals. Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce CV morbidity and mortality, and it can be concluded that it is BP reduction that is largely responsible for those benefits. Two-thirds of hypertensive patients will require more than one drug to achieve blood pressure goals.

About Forest Laboratories

Forest Laboratories (NYSE:FRX) is a leading, fully integrated, specialty pharmaceutical company largely focused on the United States market. Forest markets a portfolio of branded drug products and develops new medicines to treat patients suffering from diseases principally in five therapeutic areas: central nervous system, cardiovascular, gastrointestinal, respiratory, and anti-infective. Forest’s strategy of acquiring product rights for development and commercialization through licensing, collaborative partnerships and targeted mergers and acquisitions allows Forest to take advantage of attractive late-stage development and commercial opportunities, thereby managing the risks inherent in drug development. In January 2014, Forest acquired Aptalis Pharmaceuticals for $2.9 billion in cash in order to gain access to its GI and Cystic Fibrosis products, including treatments for Ulcerative Proctitis, Duodenal Ulcers, H. Pylori, Anal Fissures, and Pancreatic Insufficiency. In February 2014, Forest and Actavis plc announced an agreement where Forest would be acquired for about $25 billion in cash and stock. The acquisition of Forest by Actavis is contingent upon regulatory and shareholder approvals.

Forest is headquartered in New York, NY. To learn more, visit www.frx.com.

Except for the historical information contained herein, this release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements involve a number of risks and uncertainties, including the difficulty of predicting FDA approvals, the acceptance and demand for new pharmaceutical products, the impact of competitive products and pricing, the timely development and launch of new products, and the risk factors listed from time to time in Forest Laboratories' Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and any subsequent SEC filings. Forest assumes no obligation to update forward-looking statements contained in this release to reflect new information or future events or developments.