Focus on 2010: A year of novel pharmacologic agents in review

December 1, 2010

Throughout 2010, Formulary's "Focus on" articles have examined 10 newly approved or investigational drugs of interest to pharmacy and therapeutics (P&T) committee members. Because many readers have said that they frequently refer to this column when making formulary decisions for 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.

Key Points

Many thanks to editorial advisory board members Robert A. Quercia, MS, RPh, and Craig I. Coleman, PharmD, for their invaluable assistance in coordinating and overseeing these articles throughout the year. Mr Quercia is medical editor, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn, and adjunct associate professor, University of Connecticut, School of Pharmacy, Storrs. Dr Coleman is associate professor of pharmacy practice, University of Connecticut, School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

ROFLUMILAST

Phosphodiesterase 4 inhibitor for chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality in adults worldwide affecting approximately 4% to 10% of the population in the United States. Studies have shown that inflammation is a likely physiologic cause of the progressive airflow limitation seen in COPD patients. Although various anti-inflammatory agents are currently available for treating these patients, they do not reduce the likelihood of disease decline. Roflumilast is a novel, orally active phosphodiesterase 4 inhibitor currently under review by FDA for the treatment of patients with moderate-to-severe COPD. During clinical trials, roflumilast was shown to improve markers of lung function including forced expiratory volume in 1 second and forced vital capacity as well as reduce the incidence of COPD exacerbations, particularly in patients with more severe disease. These benefits are seen with monotherapy and when combined with long-acting bronchodilators including anticholinergics (tiotropium) and beta-2 agonists (salmeterol), although they appear to decrease over time. Roflumilast is generally well tolerated; the most common adverse events include nausea, vomiting, weight loss, and headache. Adverse cardiovascular events have not been shown to be of concern with roflumilast use up to 1 year in duration. (Baker EL, Baker WL. Focus on roflumilast: A new phosphondiesterase 4 inhibitor for chronic obstructive pulmonary disease. Formulary. 2010;45;6–13.)

CURRENT STATUS: On September 13, 2010, Forest responded to FDA's complete response letter (CRL) for roflumilast. FDA acknowledged receipt of the resubmission and considers it a complete, class 2 response to its May 17, 2010 CRL, which requested certain additional information and analyses of existing date. No additional patient trials were requested. Forest expects a response from FDA in the first quarter of calendar year 2011. If approved, roflumilast will be the first in a new class of treatment for COPD.

EXENATIDE LAR

Amylin, Lilly, and AlkermesGLP-1 receptor agonist February 2010 issue

A sustained-release formulation of exenatide for the treatment of type 2 diabetes. Despite the availability of multiple classes of glucose-lowering agents to treat type 2 diabetes mellitus, glycemic control often remains inadequate, with glycated hemoglobin values above the treatment goal of 7%. One newer class of agents, the glucagon-like peptide (GLP-1) receptor agonists, targets the incretin system to increase insulin secretion in response to glucose stimuli, while also inhibiting glucagon secretion, slowing gastric emptying and inducing satiety. Currently, exenatide is the only FDA-approved GLP-1 receptor agonist and its use is limited by the need for twice-daily injections. A long-acting release (LAR) formulation of exenatide is being evaluated in clinical trials to assess effects on glucose control and patient quality of life. Data from published clinical trials of exenatide LAR show that a dose of 2 mg given by subcutaneous injection once weekly is associated with reductions in glycated hemoglobin, fasting plasma glucose, and body weight. When compared to twice-daily exenatide, the LAR formulation appears to offer slightly increased efficacy. Exenatide LAR has been well tolerated in phase 2 and 3 clinical trials. Mild-to-moderate nausea is the most commonly reported adverse drug event. Long-term safety and efficacy data have not yet been published and more information is needed before exenatide LAR finds its place in therapy. Currently, once-weekly exenatide LAR is awaiting approval by FDA. (Krause A, Kirwin J. Focus on exenatide LAR: A sustained-release formulation of exenatide for the treatment of type 2 diabetes. Formulary. 2010;45:43–51.)

CURRENT STATUS: In October 2010, Amylin, Lilly, and Alkermes announced FDA issued a second complete response letter regarding the new drug application (NDA) for exenatide extended-release for injectable suspension (Bydureon). In the CRL, FDA requested a thorough QT (tQT) study with exposures of exenatide higher than typical therapeutic levels of Bydureon. The tQT protocol will be agreed to by FDA prior to study initiation. Additionally, FDA has now requested the results of the DURATION-5 study to evaluate the efficacy, and the labeling of the safety and effectiveness, of the commercial formulation of Bydureon. This letter did not cite any manufacturing processes referenced in the FDA's March 15 CRL. REMS and product labeling discussions will continue following submission of the additional data. The companies' goal is to submit their reply to the CRL by the end of 2011, pending discussions with FDA. Based on the requirements for additional data, this likely will be considered a class 2 resubmission requiring a 6-month review.

ETRAVIRINE

Intelence/Tibotec (a division of Centocor Ortho Biotech/Johnson & Johnson)HIV-1 specific, non-nucleoside reverse transcriptase inhibitorMarch 2010 issue

HIV-1 specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by FDA (January 2010) for treatment-experienced adult patients with HIV-1 strains resistant to an NNRTI and other antiretroviral agents. Etravirine is an HIV-1 specific, non-nucleoside reverse transcriptase inhibitor that was FDA approved for treatment-experienced adult patients with HIV-1 strains resistant to an NNRTI and other antiretroviral agents. In phase 3 trials etravirine versus placebo both in combination with darunavir/ritonavir, a background of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with or without enfurvitide demonstrated potent antiviral activity that was sustained through 48 weeks. Specifically, the patients in the etravirine group were more likely to achieve the primary outcome of viral load of <50 copies/mL at 24 weeks, which was sustained through 48 weeks. The most common adverse effects reported in phase 3 studies were rash, diarrhea, nausea, nasopharyngitis, headache, and injection site reaction. Although many patients continued therapy despite the rash, 2.2% of total patients in the phase 3 studies discontinued the trial due to the rash. Additionally, post-marketing reports have described cases of toxic epidermal necrolysis and hypersensitivity reactions. Like many antiretroviral agents, etravirine has many drug interactions. It's a known substrate of CYP3A, 2D6, and 2C19 as well as an inducer of CYP 3A, 2C9, 2C19, and P-glycoprotein. Because of the drug interactions, etravirine should not be given in combination with any NNRTI, a protease inhibitor without ritonavir, or with tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, or ritanavir (except as a boosting agent). (Girotto JE. Focus on etravirine: A unique non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1. Formulary. 2010;45;78–83;101–103.)

CURRENT STATUS: The manufacturer is expecting to launch a 200-mg tablet in 2011 since the recommended initial dose of the drug is 200 mg taken twice daily with food. Currently, etravirine is available only as a 100-mg tablet.

NAPROXCINOD

NicOxA cyclooxygenase-inhibiting nitric oxide donor for knee and hip osteoarthritis painApril 2010 issue

A cyclooxygenase-inhibiting nitric oxide donor pending FDA approval for the indications of knee and hip osteoarthritis pain. Treating osteoarthritis pain can be challenging because many agents commonly used for this indication carry potential risk for increased cardiovascular events including increased blood pressure, increased upper gastrointestinal (GI) bleeding, and increased hepatotoxicity. Naproxcinod combines the action of the parent drug, naproxen, with nitric oxide, to minimize potential hypertensive and GI adverse effects while maintaining the analgesic effects. Available clinical trial data indicates that naproxcinod has superior efficacy for pain compared to placebo, does not increase blood pressure, but has not been shown to lower the incidence of gastroduodenal ulcer compared with naproxen therapy. The most commonly reported adverse effects include headache, back pain, arthralgia, nausea, dyspepsia, and upper abdominal pain. Unresolved issues include gastroprotective effects of naproxcinod, recommended dosing in chronic kidney disease patients, and the drug interaction profile of this agent. (Diep K, Bussard L, Song JC. Focus on naproxcinod: A first-in-class cyclooxygenase-inhibiting nitric oxide donor for osteoarthritis pain. Formulary. 2010;45:116–122.)

CURRENT STATUS: In July, FDA informed NicOx that it did not approve the naproxcinod application. FDA recommended conducting more long-term studies to assess cardiovascular and gastrointestinal safety of naproxcinod. Additional studies to demonstrate a clinically meaningful therapeutic benefit attributable to the nitric oxide donation also were recommended. NicOx will make no further comment on these recommendations until discussions with FDA are completed. In the European Union, the review of the Marketing Authorization Application file for naproxcinod remains on track, with a Committee on Human Medicinal Products opinion expected by mid-2011.

TICAGRELOR

Brilinta/AstraZenecaDirect-acting P2Y12 receptor antagonist May 2010 issue

Oral, direct-acting P2Y12 receptor antagonist for the reduction of thrombotic events in patients with acute coronary syndromes. Coronary heart disease and acute coronary syndromes (ACS) are a significant cause of morbidity and mortality in the United States. The cornerstone of ACS management is combination oral antiplatelet therapy, usually with aspirin and a thienopyridine. Clopidogrel, the most commonly used thienopyridine, is limited by a high degree of interpatient variability and inconsistent inhibition of platelets. Ticagrelor, a new, oral, direct-acting P2Y12 receptor antagonist, produces a more profound and consistent antiplatelet effect than clopidogrel. Clinical studies of patients with both ST-elevation and non-ST-elevation ACS have shown that ticagrelor, when compared with clopidogrel, reduces the rates of vascular death and myocardial infarction while increasing the rate of non-coronary artery bypass graft-related major bleeding. Ticagrelor was also associated with a higher incidence of dyspnea and ventricular pauses. A new drug application was submitted to FDA for ticagrelor in November 2009. If approved, ticagrelor will be an attractive alternative antiplatelet agent for patients with ACS. (Jennings D. Focus on ticagrelor: An oral, non-thienopyridine P2Y12 receptor antagonist for the treatment of acute coronary syndromes. Formulary. 2010:45;148–154.)

CURRENT STATUS: In September 2010, FDA extended the time for AstraZeneca to complete its review of the NDA for ticagrelor. The manufacturer has announced the initiation of a large, international, clinical outcomes study for ticagrelor in collaboration with the Brigham and Women's Hospital-based Thrombolysis in Myocardial Infarction (TIMI) Study Group. The PEGASUS-TIMI 54 study is scheduled to begin patient enrollment during the fourth quarter 2010. The PEGASUS-TIMI 54 study will examine the long-term efficacy and safety of ticagrelor in patients who have sustained a heart attack from 1 to 3 years prior to enrollment. Such individuals are at substantially increased risk for another cardiovascular event. The study aims to determine in this group of patients if treatment with ticagrelor and aspirin will further reduce the risk of subsequent cardiovascular events compared to aspirin alone (http://www.dicardiology.net/node/37594/3/).

LORCASERIN

Arena and EisaiSelective 5-HT2C-receptor agonist June 2010 issue

Selective 5-HT2C-receptor agonist under development for weight management, including weight loss and maintenance of weight loss, in some patients who are obese (BMI>30) or patients who are overweight (BMI>27) and have at least 1 weight-related comorbid condition. Obesity is a prevalent disease that has reached epidemic proportions in both the developed and developing world. In the United States, it is estimated that 66% of the adult population is overweight or obese. There are several available pharmacologic treatments for obesity used as an adjunct to diet, exercise, and behavioral therapy. However, weight loss with these agents is modest and usually reversible when the drug is discontinued, and novel, more-effective anti-obesity agents are desperately needed. Lorcaserin is a selective 5-HT2C-receptor agonist under development for weight management. This receptor is expressed in the brain, including the hypothalamus, an area involved in the control of appetite and metabolism. Lorcaserin has demonstrated efficacy in 2 pivotal phase 3 clinical trials. Mean weight loss at 1 year was approximately 6 kg in both trials. These trials have also demonstrated that lorcaserin is devoid of the serious adverse reactions that have plagued other weight-loss medications. A new drug application for lorcaserin was submitted in December 2009. (Pauli M, Abdelghany S. Focus on lorcaserin: A novel, selective 5-HT2C-receptor agonist for the treatment of obesity. Formulary. 2010;45;180–186.)

CURRENT STATUS: On October 22, FDA issued a complete response letter for lorcaserin's NDA. FDA completed its review of the NDA and determined that it cannot approve the application in its present form. In the CRL, FDA outlined the non-clinical and clinical reasons for their decision. Arena and Eisai are committed to work with FDA to obtain further clarity on the recommendations and timeline and address the issues of the NDA as quickly as possible.

RIFAXIMIN

Xifaxan/SalixOral antibiotic with negligible systemic absorptionJuly 2010 issue

Oral broad-spectrum antibiotic approved by FDA for the reduction in the risk for recurrence of overt hepatic encephalopathy in patients aged 18 years and older with advanced liver disease. Hepatic encephalopathy is a debilitating disorder caused by the inability of the liver to remove bacterial-derived toxic by-products, specifically ammonia. It is a nonabsorbable antibiotic that provides activity locally in the gut due to its negligible systemic absorption. Rifaximin has a favorable side-effect profile and a low potential for drug interactions. A recent landmark phase 3 trial in patients in remission from recurrent hepatic encephalopathy demonstrated that rifaximin at a dose of 550 mg twice daily is significantly more effective than placebo in maintaining remission and reducing the risk of hospitalization. Rifaximin's approval by FDA in March 2010, offers clinicians the first pharmacologic treatment for hepatic encephalopathy in more than 30 years. (Feret B, Barner B. Focus on rifaximin: A nonabsorbable, broad-spectrum antibiotic for reduction in the risk for recurrence of overt hepatic encephalopathy. Formulary. 2010;45;210–216.)

CURRENT STATUS: On March 23, 2010, FDA granted marketing approval for rifaximin 550-mg tablets for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients 18 years of age or older. This approval was supported by findings from the largest randomized trial of maintenance therapy in HE conducted to date, which assessed the efficacy and safety of rifaximin 550-mg tablets and demonstrated a statistically significant and clinically meaningful reduction in the risk of overt HE recurrence. The labeling for rifaximin tablets includes data on both the risk reduction of overt HE recurrence as well as risk reduction of HE-related hospitalization. On June 7, 2010, Salix submitted an efficacy supplement to NDA 21–361 for rifaximin for the proposed indication of treatment of non-constipation irritable bowel syndrome and IBS-related bloating. FDA granted priority review for this application.

FINGOLIMOD

Gilenya/NovartisSphingosine 1-phosphate receptor modulatorAugust 2010 issue

Fingolimod, a sphingosine 1-phosphate receptor modulator, was approved by FDA for treatment of patients with relapsing-remitting multiple sclerosis (RRMS). The goal of therapy is to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Fingolimod represents a first-in-class sphingosine 1-phosphate receptor modulator as well as the first oral therapy for the treatment of RRMS. In phase 3 trials, fingolimod-treated patients had a significantly lower annualized relapse rate (ARR), a prolonged time to first relapse, were more likely to be relapse-free for the 24-month period, and had fewer new or enlarged lesions compared to placebo. When compared to interferon, fingolimod-treated patients had a lower ARR, prolonged time to disability progression, and fewer new or enlarged lesions at 12 months. The most common adverse events reported in phase 3 trials were fatigue, melanocytic nevus, influenza virus infection, lower respiratory tract or lung infection, back pain, diarrhea, cough, and abnormal liver function tests. Fingolimod is unlikely to interact significantly with other drugs due to its metabolism via CYP4F2, although it may require dose adjustment in patients with hepatic impairment. (Sobieraj DM. Focus on fingolimod: A potential first-in-class oral therapy for the treatment of relapsing-remitting multiple sclerosis. Formulary. 2010;45;245–251.)

CURRENT STATUS: In September 2010, fingolimod was approved by FDA as a first-line treatment to reduce relapses and delay disability progression in patients with relapsing forms of MS. Fingolimod is the first oral treatment indicated for this form of MS available in the United States. Physicians began prescribing fingolimod on October 4, 2010. Fingolimod was submitted to the European Medicines Agency (EMA) for review in December 2009 and the EMA regulatory review and other filings worldwide are ongoing.

DRONEDARONE

Multaq/Sanofi-aventisNoniodinated benzofuran derivativeSeptember/October 2010 issue

A noniodinated benzofuran derivative with characteristics of all 4 Vaughan-Williams antiarrhythmic classes. Atrial fibrillation (AF) is the most common form of arrhythmia, affecting an estimated 2.2 million people in the United States. The goal of treatment is to reduce symptoms through rate or rhythm control and to prevent a cardioembolic event. Dronedarone is a noniodinated benzofuran derivative with characteristics of all 4 Vaughan-Williams antiarrhythmic classes. A search in http://www.clinicaltrials.gov/ for dronedarone phase 3 studies yielded 5 randomized controlled studies that investigated the efficacy and safety of the drug. The ATHENA and EURIDIS/ADONIS clinical trials have shown dronedarone to reduce hospitalizations due to cardiovascular events and AF recurrence, respectively. The ANDROMEDA study was discontinued prematurely due to a significant increase in mortality with dronedarone when compared with placebo, mainly due to progressive heart failure. ERATO showed significant reduction in ventricular rate in patients with permanent AF. DIONYSOS compared dronedarone to amiodarone and demonstrated that amiodarone was more efficacious than dronedarone in preventing AF recurrence but with more premature drug discontinuation. There are 4 ongoing clinical trials, 3 of which have estimated completion dates in 2011. Another ongoing study (PALLAS) will evaluate the efficacy of dronedarone in preventing cardiovascular events, hospitalization, or death in permanent AF patients with additional cardiac risk factors; its estimated completion date is 2013. Although dronedarone has a favorable adverse effect profile when compared with amiodarone, it has a trade off of less efficacy. Its black box warning in heart failure patients is also a limitation. Dronedarone was approved for use by FDA in July 2009 and is considered a possible therapeutic option in AF management. Until long-term efficacy and safety studies are available, the key to dronedarone prescribing is appropriate patient selection to ensure the most effective therapeutic approach. (Draskovich CD, O'Dell KM. Focus on dronedrarone for atrial fibrillation: An update of clinical evidence. Formulary. 2010;45;275–283.)

CURRENT STATUS: Dronedarone was approved by FDA in July 2009. It is an anti-arrhythmic drug indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted. Associated cardiovascular risk factors include age over 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction <40%. Dronedarone is contraindicated in patients with NYHA Class IV heart failure or NYHA Class II-III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.

In May 2010, Sanofi-aventis announced the PALLAS study, which is investigating whether dronedarone can decrease major cardiovascular events as well as cardiovascular hospitalization or death in permanent AF patients. The study commenced in June 2010 and is ongoing. Most recently, dronedarone has come under increased attention as a report from the Institute for Safe Medication Practices has identified several reported cases of heart failure, arrhythmias, drug-drug interactions, and impaired kidney function in patients receiving this agent since its launch in the United States in 2009. Representatives from Sanofi-aventis, the drug's manufacturer, have criticized the report and its methodology.

LURASIDONE

Latuda/Sunovion PharmaceuticalsAtypical antipsychotic November 2010 issue

A new-generation atypical antipsychotic has been approved by FDA for the treatment of schizophrenia and is under investigation for the treatment of bipolar disorder. In 4 separate clinical trials, lurasidone has demonstrated efficacy in treating schizophrenia, with total Positive and Negative Syndrome Scale scores decreasing by a range of 14 to 17 points depending on the lurasidone dosage. In addition to the studies in schizophrenia, ongoing trials in patients with bipolar disorder are being completed. The most common adverse events associated with lurasidone treatment are nausea, vomiting, akathisia, dizziness, and sedation. Lurasidone has similar affinity for the dopamine D2 and serotonin 5-HT2A receptors, but a much greater affinity for 5-HT7, 5-HT1A, and α2C-adrenergic subtype receptors, than other atypical antipsychotics. Experimental data support the theory that antagonism of 5-HT7 can improve cognition, memory, and mood symptoms. This may provide a unique place for lurasidone in the treatment of schizophrenia and bipolar disorder. (Ehret MJ, Sopko M, Lemieux T. Focus on lurasidone: A new atypical antipsychotic for the treatment of schizophrenia. Formulary. 2010;45:313–317.)

CURRENT STATUS: Lurasidone was FDA approved in October 2010 for the treatment of schizophrenia. It's an oral once-daily atypical antipsychotic, that offers a first-line treatment option for patients with schizophrenia. The manufacturer has a comprehensive, global clinical trial program for lurasidone. The ongoing studies for this drug include:

• Schizophrenia

• Bipolar

In addition, the manufacturer has agreed to the following post-marketing commitments: