With approval of Forest/Mylan's Bystolic (nebivolol) - the newest member of a crowded beta blocker class - the company is gearing up to launch with an experienced sales force, data to differentiate the drug, and a price in line with one of the most commonly used drugs in the class.

Pricing for Bystolic will be comparable to AstraZeneca's Toprol (metoprolol), Forest VP-Investor Relations Charles Triano told "The Pink Sheet." According to AstraZeneca, the average wholesale price for 25 mg and 50 mg of Toprol is about $1 per pill (data from FirstDataBank). Generics of Toprol XL are available (starting in November 2006 with 25 mg, with the highest doses launching in August 2007), with an average AWP of 78 cents per pill, according to Elsevier subsidary Gold Standard's pricing database ProspectoRx.

On Dec. 17 Bystolic became the 19th beta blocker to clear FDA, charging Forest with the task of differentiating the selective beta-1 blocker from its competitors, including generic versions of several established drugs. Forest plans to highlight nebivolol's "placebo-like" rates of adverse events and efficacy in black patients, a subgroup that typically does not respond well to beta blockers.

Triano stressed the points of differentiation as "basically tolerability, [that] a broader range of patients may respond well to Bystolic [compared to] other beta blockers, and that this is a highly selective compound for beta-1 that is also vasodilating."

Forest has been proactive about preparing for nebivolol's introduction to the market. The firm initiated postmarketing studies (still ongoing) prior to Bystolic's approval in order to further highlight potential differences from existing beta blockers (¹ Also see "Nebivolol Education Efforts Will Tout Performance In Hypertension Subgroups" - Pink Sheet, 9 July, 2007., p. 10).

Commercial activities for Bystolic have already begun, and Forest will roll out the full 2,000-rep sales force by late January. Triano said there will be a broad physician education effort behind the brand, but no traditional direct-to-consumer advertising.

Nebivolol was approved based on three randomized, double-blind, placebo-controlled monotherapy trials that ran for up to three months. A fourth placebo-controlled clinical trial demonstrated additional blood-pressure lowering effects when nebivolol was given with up to two other antihypertensive medications in patients with inadequate blood pressure control.

Results showed efficacy similar to that of other marketed beta blockers. The most common side effects reported by patients taking nebivolol in clinical trials were headache, fatigue, dizziness and diarrhea.

Bystolic is indicated for the treatment of hypertension as monotherapy or in combination with other antihypertensive agents. Triano noted that the firm expects the drug to be used mostly as combination therapy in accordance with the JNC7 guidelines; it was in the trial of nebivolol as combination therapy that the differentiating attribute of effectiveness in black subjects was seen. Labeling includes the statement that "Effectiveness was established in Blacks, but as monotherapy the magnitude of effect was somewhat less than in Caucasians."

NitroMed has somewhat paved the way for marketing a cardiovascular therapy for black patients. Its heart failure combo BiDil (isosorbide dinitrate/hydralazine) was approved in June 2005 specifically for African- American patients. Sales have been weak, in part due to initial difficulties with formulary placement (² Also see "NitroMed Aims To Revive BiDil With CEO Change, Managed Care Push" - Pink Sheet, 27 March, 2006., p. 14). The firm is working with Elan on a once-daily formulation.

Mylan licensed U.S. rights to nebivolol from Johnson & Johnson in 2001, and submitted the NDA in 2004. In January 2006 Forest assumed development, sales, and marketing of nebivolol.

FDA issued two "approvable" letters for the drug. In response to the first, from 2005, two additional preclinical studies and one pharmacokinetic study were submitted in May 2007. The second letter, issued in early December, cited deficiencies at a backup manufacturing facility in Belgium.

Though at various points during nebivolol's long FDA review Mylan and Forest announced intentions to pursue a supplemental indication for the drug in congestive heart failure, Triano said Forest now has "not committed one way or another" to the additional indication. A single trial investigating nebivolol for CHF has been conducted by Menarini, an Italian company that holds marketing rights to the drug in non-U.S. markets (³ [A#00670250017], p. 25). Triano said Forest will meet with FDA in 2008 to discuss the regulatory pathway for the CHF indication.

- Jamie Hammon (j.hammon@elsevier.com)

Forest Hopes Efficacy In Blacks And Tolerability Will Set Bystolic Apart

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