Focus on 2007: A year of novel pharmacologic agents in review; arformoterol, pramipexole, CERA, sitaxsentan, bifeprunox, vernakalant, telavancin, maraviroc, and rotigotine

Throughout 2007, Formulary's "Focus on" articles have examined 9 newly approved or investigational drugs of interest to pharmacy and therapeutics committee members. Because many readers have said that they frequently reference this column when making formulary decisions for their hospitals, health systems, or managed care organizations, the editors have compiled this review of these agents, along with updates on the regulatory status of each. Of the 9 agents reviewed in 2007, 4 have received final FDA approval; the remaining 5 agents have not yet been approved by FDA.

Key Points

Throughout 2007, Formulary's "Focus on" articles have examined 9 newly approved or investigational drugs of interest to pharmacy and therapeutics committee members. Because many readers have said that they frequently reference this column when making formulary decisions for their hospitals, health systems, or managed care organizations, the editors have compiled this review of these agents, along with updates on the regulatory status of each. Of the 9 agents reviewed in 2007, 4 have received final FDA approval; the remaining 5 agents have not yet been approved by FDA.

ARFORMOTEROL

A nebulized long-acting beta2-adrenergic agonist for the treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD). Bronchodilators play an important role in the management of stable COPD. Although bronchodilators do not prevent the decline in lung function in patients with COPD, their efficacy in improving disease-related symptoms, reducing the frequency and severity of disease exacerbations, and improving patients' quality of life has been demonstrated in clinical trials. Arformoterol, the (R,R)-enantiomer of the selective beta2-agonist formoterol, is a potent, highly specific, nebulized long-acting beta2-adrenergic agonist approved by FDA for the long-term maintenance treatment of bronchoconstriction in patients with COPD, including chronic bronchitis and emphysema. In 2 large, 12-week, phase 3 studies, arformoterol demonstrated an efficacy superior to that of placebo and comparable to that of salmeterol in patients with COPD. In these trials, arformoterol was well tolerated, with a safety profile similar to that of other inhaled long-acting beta2-agonists when used at the FDA-approved dose. Arformoterol is the only long-acting beta2-adrenergic agonist available as an inhalation solution for use with a nebulizer, thus providing a new option for patients who are unable to use a dry-powder inhaler. Evaluation of the long-term safety and efficacy of arformoterol in patients with COPD is currently under way. (Abdelghany O, Merl M-Y. Focus on arformoterol: The first nebulized long-acting beta2-adrenergic agonist. Formulary. 2007;42:99–109.)

CURRENT STATUS: FDA approved arformoterol on October 6, 2006.

PRAMIPEXOLE

Mirapex, Boehringer IngelheimNonergot-derived dopamine agonistMarch 2007 issue

A nonergot-derived dopamine agonist for the treatment of moderate-to-severe restless legs syndrome (RLS). Drugs that act to increase dopamine activity are the mainstay of pharmacologic treatment for RLS, a sensomotor disorder that usually manifests as an urge to move the legs, with or without other uncomfortable sensations. Pramipexole, a nonergot-derived dopamine agonist previously approved by FDA for the treatment of Parkinson disease (PD), received FDA approval for the treatment of moderate-to-severe RLS in November 2006. In placebo-controlled clinical trials, treatment with pramipexole improved RLS symptom scores and measures of sleep quality. Common adverse events included nausea, fatigue, headache, and somnolence. Sudden onset of sleepiness has also been reported rarely in patients being treated with pramipexole for RLS. Augmentation, a change in or worsening of symptoms after initiation of treatment, may occur in up to one-third of patients treated with this agent. More data are needed to better characterize the relative efficacy of pramipexole compared with other treatments for RLS and to clarify the rates of less common adverse events. (Kirwin J. Focus on pramipexole: A nonergot-derived dopamine agonist for the treatment of restless legs syndrome. Formulary. 2007; 42:165–174.)

CURRENT STATUS: Pramipexole was approved by FDA for the treatment of moderate-to-severe RLS on November 7, 2006.

CONTINUOUS ERYTHROPOIESIS RECEPTOR ACTIVATOR (CERA)

Mircera, RocheErythropoiesis-stimulating agent (ESA)April 2007 issue

An ESA for the treatment of anemia in patients with chronic kidney disease (CKD). CKD affects 20 million Americans, and an additional 20 million are at increased risk for developing CKD. Anemia is a common complication in patients with CKD. The predominant cause of anemia in this patient population is a deficiency in erythropoietin. CERA is a new ESA that is undergoing FDA review for the treatment of anemia in patients with CKD, including in those undergoing dialysis. CERA has an extended half-life and a mechanism of action that promotes increased stimulation of erythropoietin receptors compared with other ESAs. In clinical trials, CERA dosed every 3 to 4 weeks has demonstrated efficacy similar to that of epoetin alfa and darbepoetin alfa in maintaining hemoglobin concentrations within the target hemoglobin range. CERA has generally been well tolerated in clinical trials. Further studies are needed to determine what the role of CERA may be in the hospital and outpatient settings. (O'Mara NB, Kapoian T. Focus on continuous erythropoiesis receptor activator [CERA]: An erythropoiesis-stimulating agent for the treatment of anemia in patients with chronic kidney disease. Formulary. 2007;42:233–244.)

CURRENT STATUS: FDA issued an approvable letter for CERA on May 21, 2007, along with draft labeling for the agent. Additional safety information regarding dosing and monitoring may be added to the label as a result of the recommendations of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, which were issued for the entire class of ESAs in September 2007.

SITAXSENTAN

Thelin, EncysiveEndothelin (ET)-receptor antagonistMay 2007 issue

ET-receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Elevated blood pressure in the pulmonary vasculature, known as PAH, stresses the right side of the heart and can increase the risk for functional disability and death. In advanced disease, several drugs can be employed, including calcium-channel blockers, phosphodiesterase-5 inhibitors, prostacyclin analogues, and ET-receptor antagonists. ET is an endogenous peptide vasoconstrictor that is present in excessive concentrations in patients with PAH. Sitaxsentan, an ET-receptor antagonist undergoing FDA review, is selective for the ETA receptors. By selectively antagonizing the ETA receptors, sitaxsentan causes pulmonary arterial vasodilation and allows normal functioning of the ETB receptor, thus reducing the effects of ET. Clinical trials have demonstrated that orally administered sitaxsentan improves both 6-minute walking distance and World Health Organization functional class in patients with PAH. Trials have also demonstrated that sitaxsentan is relatively safe, although cases of hepatotoxicity have been reported. Further studies are necessary to better demonstrate the adverse event profile of this agent and to determine how sitaxsentan could be integrated into therapy for patients with PAH. (Reinhart K, White CM. Focus on sitaxsentan: A new endothelin-receptor antagonist for the treatment of pulmonary arterial hypertension. Formulary. 2007;42:295–301.)

CURRENT STATUS: After receiving 3 approvable letters from FDA (March 24, 2006; July 24, 2006; and June 15, 2007) and beginning the formal dispute resolution process with the agency, Encysive has decided to conduct an additional phase 3 trial to assess the efficacy of sitaxsentan in improving 6-minute walking distance. FDA requested this additional trial in response to Encysive's request for formal dispute resolution. Encysive is working with FDA to finalize the study protocol and, as a result, will not continue with the formal dispute resolution process.

BIFEPRUNOX

Solvay/WyethPartial dopamine-receptor agonistJune 2007 issue

A partial dopamine-receptor agonist for the treatment of schizophrenia. Schizophrenia is a chronic psychiatric disorder that affects an estimated 1% of the population. This disorder may be treated with typical (first-generation) or atypical (second-generation) agents; a recognized concern regarding these agents is that long-term use has been associated with increased risks of serious side effects, either neurologic or metabolic in nature. Bifeprunox is a partial dopamine-receptor agonist under investigation for the treatment of patients with schizophrenia. As a partial dopamine-receptor agonist, bifeprunox acts as a dopamine-system stabilizer. This proposed mechanism of action is similar to that of aripiprazole but different from that of the other currently marketed antipsychotic medications. Available clinical and safety data are limited but describe positive effects in treating acute psychotic symptoms and prolonging time to deterioration, with a generally tolerable side-effect profile. (Watanabe MD. Focus on bifeprunox: A partial dopamine-receptor agonist for the treatment of schizophrenia. Formulary. 2007;42:371–377.)

CURRENT STATUS: FDA issued a nonapprovable letter for bifeprunox on August 10, 2007. In the letter, FDA indicated that bifeprunox demonstrated efficacy for the maintenance treatment of schizophrenia in stable adult patients but that a second study in this patient population would be needed to support this indication. FDA also stated that the available data for the efficacy of bifeprunox in the acute treatment of schizophrenia were not sufficient for approval of this indication. Solvay and Wyeth are working with FDA to discuss possible study designs to support the maintenance indication. FDA has also requested additional information on the human metabolism of bifeprunox and on the case of a patient who died while participating in a bifeprunox trial.

VERNAKALANT

Astellas/CardiomeAntiarrhythmic agentAugust 2007 issue

An antiarrhythmic agent for the treatment of atrial fibrillation (AF). AF is a disorder that affects >2 million people in the United States. First-line antiarrhythmic agents (per American College of Cardiology/American Heart Association/European Society of Cardiology guidelines) that are currently used to treat recent-onset AF work by indiscriminately blocking various ionic channels, thereby inducing a prolonged ventricular action potential duration or possibly inducing ventricular arrhythmias in the presence of myocardial ischemia because of excessive conduction slowing in diseased cardiac tissue. Vernakalant is an atrial-selective, potassium- and sodium-channel-blocking agent undergoing FDA review for the indication of conversion of recent-onset AF to normal sinus rhythm. This agent offers a novel mechanism of action for the acute conversion of AF, as it specifically targets the potassium channel underlying the ultrarapid delayed rectifier current that is found only in atrial myocytes, along with other potassium channels. Pivotal phase 3 clinical trials have demonstrated that patients with recent-onset AF (≤7 d) who receive intravenous (IV) vernakalant usually convert to normal sinus rhythm within 10 minutes of administration, with response rates of 51% within 90 minutes. Preliminary results from a single phase 3 clinical trial that enrolled patients with recent-onset AF after cardiac surgery demonstrated a conversion rate of 47%. Unlike the commonly used first-line agents, which have been demonstrated to induce polymorphic ventricular arrhythmias, vernakalant appears to be less proarrhythmic, as it has not been demonstrated to induce torsades de pointes. Comparative studies are needed to determine vernakalant's potential role among the agents used in the treatment of AF. (Dia EQ, Rathbun RA, Song JC. Focus on vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation. Formulary. 2007;42:475–483.)

CURRENT STATUS: On August 30, 2007, FDA requested that Astellas and Cardiome participate in a panel review with the Cardiovascular and Renal Drugs Advisory Committee on December 11 and 12, 2007, to discuss the NDA for IV vernakalant. The companies have agreed to submit additional safety and efficacy data to FDA in preparation for this meeting, and the FDA's action date for vernakalant has been extended to January 19, 2008.

TELAVANCIN

Theravance/AstellasNovel lipoglycopeptide antibioticSeptember 2007 issue

A lipoglycopeptide antibiotic for the treatment of complicated skin and skin-structure infections. Over the past few decades, resistant bacteria have continued to increase in prevalence and significance. The historical gold standard for the treatment of infections caused by resistant gram-positive pathogens has been vancomycin. Unfortunately, contemporary use of vancomycin has been tempered by increasing rates of resistance, leading researchers to investigate other antimicrobial options. Telavancin is a novel semisynthetic lipoglycopeptide antibiotic undergoing FDA review for complicated skin and skin-structure infections; this agent is also in phase 3 clinical trials for the treatment of hospital-acquired pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant Streptococcus pneumoniae. Telavancin exerts its antibacterial action via a dual mode of action involving both inhibition of peptidoglycan synthesis and disruption of the bacterial cell membrane; the latter of these effects is believed to improve the rate of killing observed with telavancin compared with other glycopeptides. In vitro, telavancin exhibits good activity against a variety of gram-positive organisms, including drug-resistant S pneumoniae, MRSA, vancomycin intermediate-susceptible and vancomycin-resistant S aureus, and vancomycin-resistant enterococci. Clinical data have demonstrated that telavancin is at least as effective as comparator agents for a variety of infectious processes. In general, this agent appears to be well tolerated, with patients typically experiencing relatively mild adverse events. Telavancin has the potential to become a much-needed addition to the antimicrobial arsenal. (Knechtel SA, Jacobs C, Klepser ME. Focus on telavancin: A novel lipoglycopeptide antibiotic with dual mechanisms of action. Formulary. 2007;42:545–557.)

CURRENT STATUS: FDA issued an approvable letter for telavancin on October 22, 2007. Therevance and Astellas have stated that they do not anticipate a need for additional clinical trials.

MARAVIROC

Selzentry, PfizerCCR5 antagonistOctober 2007 issue

A CCR5 antagonist approved for the treatment of HIV-1 infection. Maraviroc is the first CCR5 antagonist approved for the treatment of HIV-1 infection. The use of maraviroc is associated with significant decreases in HIV viral load and increases in CD4 counts in antiretroviral treatment-experienced patients with CCR5-tropic virus when used as an add-on to optimized antiretroviral treatment. In clinical trials, patients with dual- or mixed-tropic virus (which can infect cells using CXCR4 and/or CCR5 receptors) who were treated with maraviroc demonstrated no difference in HIV viral load compared with patients who received placebo. A recent study compared maraviroc plus lamivudine/ zidovudine with efavirenz plus lamivudine/zidovudine; maraviroc did not demonstrate noninferiority when undetectable virus was defined as <50 copies/mL; however, maraviroc did meet noninferiority criteria when undetectable virus was defined as <400 copies/mL. Maraviroc is not recommended for patients with CXCR4-tropic, dual-tropic, or mixed-tropic virus; for antiretroviral-naïve patients; or for children aged <16 years. Overall, maraviroc has been well tolerated in clinical trials. The most common adverse events associated with the use of maraviroc are fever, upper respiratory infection, back pain, dizziness, cough, and rash. Hepatotoxicity and cardiovascular ischemic events have also been reported with use of the drug. Maraviroc currently occupies the niche of add-on therapy to optimized combination antiretroviral background therapy in treatment-experienced patients with CCR5-tropic virus; additional studies are needed to determine whether maraviroc's role in treating HIV could potentially be expanded. (Girotto JE. Focus on maraviroc: The first CCR5 antagonist for the treatment of HIV. Formulary. 2007;42:601–608.)

CURRENT STATUS: FDA approved maraviroc on August 6, 2007.

ROTIGOTINE

Neupro, SchwarzNonergot-derived dopamine agonistNovember 2007 issue

A nonergot-derived dopamine agonist for the treatment of the signs and symptoms of early-stage idiopathic Parkinson disease (PD). PD is a chronic, progressive neurodegenerative disorder affecting approximately 1% of people aged >60 years. Levodopa has long been the cornerstone of PD treatment, but many patients receiving long-term levodopa therapy experience dyskinesia and motor fluctuations. Dopamine agonists act directly on dopamine receptors and are associated with a lower incidence of dyskinesias. There are 2 subclasses of dopamine agonists: ergot-derived and nonergot-derived. The use of ergot-derived dopamine agonists has declined in recent years due to the agents' association with valvular heart disease. Nonergot-derived dopamine agonists such as ropinirole and pramipexole are used more widely in the treatment of PD. Rotigotine is a nonergot-derived dopamine agonist that was approved by FDA on May 9, 2007, for the treatment of early-stage idiopathic PD. Rotigotine is the first approved nonergot-derived dopamine agonist that is delivered continuously through a transdermal silicone-based patch that is replaced every 24 hours. In clinical trials, rotigotine was demonstrated to be efficacious and generally well tolerated among patients with early-stage PD; the agent demonstrated a low potential for drug-drug interactions. Because rotigotine is administered via a once-daily continuous transdermal delivery system, there are dosing advantages with this drug compared with ropinirole and pramipexole, which require administration 3 times daily. Rotigotine is also useful in the treatment of patients with swallowing difficulties or those who are unable to take oral medications. The manufacturer intends to submit an sNDA for rotigotine by the end of 2007 for the treatment of advanced-stage PD. Ultimately, the results from ongoing studies and further clinical experience will dictate the clinical utility of this agent.(Talati R, White CM, Coleman CI. Focus on rotigotine: The first transdermal nonergot-derived dopamine agonist for the treatment of Parkinson disease. Formulary. 2007;42:633–646.)

CURRENT STATUS: Rotigotine was approved by FDA on May 9, 2007.