So far this year, Formulary has examined 10 newly approved or investigational drugs of interest to pharmacy and therapeutics committee members through our "Focus on" articles. Because many readers have expressed that this information is useful when making formulary decisions for their hospitals, health systems, or managed care organizations, Formulary has compiled this late-year review of these new and emerging agents, along with updates on the regulatory status of each.
Half of the 10 therapeutic agents reviewed during 2006 have now been cleared for marketing by FDA, and the remaining half are nearing potential approval dates. These drugs include 9 new molecular entities and 1 new biologic. Five are first-in-class agents, for the treatment of chronic idiopathic constipation, smoking cessation, refractory rheumatoid arthritis, type 2 diabetes, and obesity. The remaining drugs were developed to treat resistant gram-positive pathogens, osteoporosis, insomnia, Candida infections, and type 2 diabetes. Of the 10 agents, 6 are administered orally and 4 are injectable.
Many thanks to editorial advisory board members Robert A. Quercia, MS, RPh, and Craig I. Coleman, PharmD, for their valued assistance in coordinating and overseeing the "Focus on" articles throughout the year. Mr Quercia is clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn. Dr Coleman is assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director of the Pharmacoeconomics and Outcomes Studies Group at Hartford Hospital.
Zeven, PfizerLipoglycopeptide antibioticFebruary 2006 issue
A lipoglycopeptide antibiotic for the treatment of resistant gram-positive pathogens. Dalbavancin (Zeven, Pfizer) is a new lipoglycopeptide antibiotic under FDA review for the treatment of resistant gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). This agent exerts its bactericidal activity by binding to the terminal D-alanyl-D-alanine moiety of peptidoglycan precursors, thus blocking enzymes involved in the final stages of peptidoglycan synthesis and cell wall formation. Peak concentrations of dalbavancin occur immediately following infusion and increase in proportion to the dose given. After infusion, there is a rapid decline in plasma concentrations due to distribution of the drug into bodily tissues and fluids (Vss=0.52 L/kg). This initial rapid decline in plasma concentration is followed by a slower terminal, log-linear elimination phase, in which dalbavancin exhibits an elimination half-life ranging from 149 to 198 hours. Current data suggest that dalbavancin is well tolerated by patients, with most adverse events being described as mild. Dalbavancin may offer advantages over other antibiotics used in the treatment of resistant gram-positive pathogens because of its excellent tolerability and potency. Due to the long elimination half-life of dalbavancin, once-weekly dosing may be an option. The drug is also being studied for the treatment of catheter-related bloodstream infections. (Blostica TM, Klepser ME. Focus on dalbavancin: A novel long-acting lipoglycopeptide antibiotic. Formulary. 2006;41:59–73.)
CURRENT STATUS: According to Pfizer, FDA issued an approvable letter for dalbavancin on June 21, 2006. The drug had been granted priority review. The company is working with FDA to resolve an issue involving the chemistry, manufacturing, and controls section of the NDA, which was filed by the agent's original developer.
Amitiza, Sucampo/TakedaSpecific chloride channel activatorMarch 2006 issue
A specific chloride channel activator for the treatment of chronic idiopathic constipation. Lubiprostone (Amitiza, Sucampo/Takeda) was approved on January 31, 2006, for the treatment of chronic constipation in adults when the cause of the condition is unknown. The agent has a unique mechanism of action compared with other therapies on the market. It locally activates specific chloride channels (ClC-2) in the lining of the small intestines after oral administration, thereby increasing intestinal fluids and softening bowel movements. In double-blind, placebo-controlled trials, lubiprostone demonstrated efficacy in improving the frequency of spontaneous bowel movements and other related constipation symptoms. Lubiprostone was reported to be well tolerated in clinical trials; the most common adverse effects were mild-to-moderate nausea and headache. The agent is also being investigated for use in constipation-predominant irritable bowel syndrome and postoperative ileus. (Orr KK. Focus on lubiprostone: A novel chloride channel activator for the treatment of constipation. Formulary. 2006;41:118–129.)
CURRENT STATUS: Lubiprostone was approved on January 31, 2006.
PARATHYROID HORMONE (rDNA ORIGIN) FOR INJECTION
Preos, NPS PharmaceuticalsParathyroid hormone (rDNA origin) for injectionMay 2006 issue
A full-length human recombinant parathyroid hormone for the treatment of osteoporosis. Full-length or intact parathyroid hormone (rDNA origin) for injection (PTH [1-84], Preos, NPS Pharmaceuticals) is under FDA review for the treatment of postmenopausal osteoporosis. If approved, parathyroid hormone (1-84) will join teriparatide (PTH [1-34], Forteo, Lilly), the truncated N-terminal (1-34) form of the hormone, as the only anabolic therapies available for osteoporosis treatment. There are currently no published head-to-head trials comparing teriparatide and intact parathyroid hormone, though the effects of each on bone mineral density and fracture rate reduction appear comparable. The adverse effects of the 2 formulations are similar, including injection site reactions, headache, dizziness, nausea, and hypercalcemia. More studies are needed to determine when and if parathyroid hormone monotherapy should be used, whether and how it should be used in conjunction with antiresorptive therapies, and which patient populations would benefit most from parathyroid hormone treatment. (Cheng CM, El-Ibiary SY. Focus on full-length human recombinant parathyroid hormone for the treatment of osteoporosis. Formulary. 2006;41:214–226.)
CURRENT STATUS: FDA issued an approvable letter for full-length parathyroid hormone (rDNA origin) for injection on March 9, 2006. At press time, NPS Pharmaceuticals was evaluating how to address FDA concerns about the benefit/risk profile of the hormone with approval strategies other than an additional clinical trial.
Chantix, PfizerPartial nicotine receptor agonistJune 2006 issue
A partial nicotine receptor agonist for smoking cessation. Varenicline (Chantix, Pfizer) is the first oral medication approved for smoking cessation since bupropion and brings a novel mechanism of action. Varenicline is a partial nicotine receptor agonist with a high affinity for the alpha-4 beta-2 nicotinic acetylcholine receptors, modulating dopamine levels associated with nicotine addiction and aiding in smoking cessation. Clinical studies have demonstrated favorable cessation rates compared with placebo and sustained-release bupropion, with an encouraging safety profile. The most common adverse effect seen in clinical trials was mild-to-moderate nausea. An NDA was submitted for varenicline in November 2005, and the drug was subsequently granted a 6-month priority review. (Feret B, Orr K. Focus on varenicline: An oral partial nicotine agonist for smoking cessation. Formulary. 2006;41:265–272.)
CURRENT STATUS: Varenicline was approved on May 10, 2006.
Neurocrine BiosciencesSelective non-benzodiazepine sedative hypnoticJuly 2006 issue
A selective non-benzodiazepine sedative hypnotic for the treatment of insomnia. A number of clinical approaches are utilized in managing insomnia. Indiplon (Neurocrine Biosciences) is a selective non-benzodiazepine sedative hypnotic under consideration by FDA for this indication. Like other agents in its class, indiplon binds selectively to the GABA-A receptors in the brain, promoting sleep. However, indiplon may have several competitive advantages. Clinical trials have demonstrated that the agent has minimal potential for adverse effects and tolerance. Other trials have demonstrated that, in addition to improved efficacy in sleep initiation and sleep maintenance, indiplon is effective in managing nighttime awakenings and difficulty returning to sleep after middle-of-the-night dosing without any residual daytime impairment. The developer submitted an NDA for immediate-release capsules in April 2005 and for modified-release tablets in May 2005, both for the treatment of insomnia in adults and elderly patients. (In June 2006, Pfizer returned all co-development and co-marketing rights to Neurocrine Biosciences.) (Gryskiewicz KA, Semanco M. Focus on indiplon: A short-acting GABA-A receptor agonist sedative hypnotic for the treatment of insomnia. Formulary. 2006;41:316–321.)
CURRENT STATUS: On May 15, 2006, FDA issued an approvable letter for indiplon capsules and a nonapprovable letter for indiplon tablets. Neurocrine Biosciences plans to amend both applications to respond to the stipulations requested by FDA. The developer will initiate a clinical trial to supplement the pharmacokinetic/food effect profile of indiplon capsules to include several meal types, and at press time, the company had plans to meet with FDA in late October to discuss the requirements for the approval of indiplon tablets.
Orencia, Bristol-Myers SquibbT-lymphocyte co-stimulation modulatorJuly 2006 issue
A T-lymphocyte co-stimulation modulator for the treatment of refractory rheumatoid arthritis. Abatacept (Orencia, Bristol-Myers Squibb) is the first T-lymphocyte co-stimulation modulator to be approved by FDA. The agent is indicated for use in patients with moderate-to-severe, active rheumatoid arthritis who have not had an adequate response to methotrexate, tumor necrosis factor (TNF)-alpha inhibitors, or other disease-modifying antirheumatic drugs (DMARDs). Abatacept inhibits the immune and inflammatory response by blocking the activation of helper T-cells. Abatacept 10 mg/kg intravenously at weeks 0, 2, and 4, and then every 4 weeks thereafter, decreases inflammation and pain in 2 to 4 weeks. The agent may be used as the only DMARD or in combination with other DMARDs except TNF-alpha inhibitors. The most common adverse effects associated with abatacept are headache, upper respiratory symptoms or infection, and gastrointestinal disturbance. Abatacept is also being investigated for the treatment of juvenile rheumatoid arthritis and systemic lupus. (Boyce EG. Focus on abatacept: The first T-lymphocyte co-stimulation modulator; for use in rheumatoid arthritis. Formulary. 2006;41:322–326.)
CURRENT STATUS: Abatacept was approved on December 23, 2005.
Eraxis, PfizerEchinocandin antifungalAugust 2006 issue
An echinocandin antifungal for the treatment of Candida infection in adults. Anidulafungin (Eraxis, Pfizer) is a new echinocandin antifungal agent approved for the treatment of Candida infection in adults. Like other echinocandins, anidulafungin acts on the fungal cell wall by inhibiting 1, 3 beta-D glucan synthesis. Studies suggest that among the echinocandins, anidulafungin may have more potent in vitro activity against Candida spp and Aspergillus spp. Further, phase 2 and 3 clinical studies with anidulafungin have supported high end-of-therapy success rates for invasive candidiasis, including esophageal candidiasis. Anidulafungin appears to be well tolerated, with headache, nausea, vomiting, phlebitis, neutropenia, and hypokalemia being the most commonly reported adverse effects. Importantly, as anidulafungin is chemically degraded, it has no clinically significant drug interactions and does not require any dose adjustment for renal or hepatic impairment. The agent also is being studied in clinical trials for the treatment of invasive aspergillosis infections. (St. Germain RM, Ellis JM. Focus on anidulafungin: An echinocandin antifungal for the treatment of Candida infection. Formulary. 2006;41:387–403.)
CURRENT STATUS: Anidulafungin was approved on February 17, 2006.
Januvia, MerckDipeptidyl peptidase-IV inhibitorSeptember 2006 issue
A dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. A variety of clinical approaches are utilized in the management of poor glycemic control in patients with type 2 diabetes. Sitagliptin (Januvia, Merck) is the first agent to be approved in a new medication class known as dipeptidyl peptidase-IV (DPP-IV) inhibitors. The drug offers a new mechanism by which to achieve glycemic control. Although stimulation of receptors by the glucagon-like peptide-1 (GLP-1) enhances the body's ability to produce insulin in response to elevated blood glucose concentrations, rapid degradation of GLP-1 by DPP-IV limits its clinical effectiveness. The development of medications to reduce this degradation is being pursued by numerous manufacturers. Clinical data used to support the approval of sitagliptin demonstrated improved glycemic control in patients who had not achieved target glucose levels with diet and oral medications. (Schlesselman LS. Focus on sitagliptin: The first dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Formulary. 2006;41:434–441.)
CURRENT STATUS: Sitagliptin was approved on October 16, 2006.
Galvus, NovartisDipeptidyl peptidase-IV inhibitorOctober 2006 issue
A dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Despite the variety of medications available to treat type 2 diabetes, the disease is inadequately controlled in many patients. To improve glycemic control, manufacturers are pursuing compounds that affect the incretin hormones that stimulate insulin release in response to increased glucose levels. Although stimulation of the incretin receptors by the glucagon-like peptide-1 (GLP-1) enhances the body's ability to produce insulin in response to elevated blood glucose concentrations, the clinical usefulness of GLP-1 is limited by its rapid degradation by dipeptidyl peptidase-IV (DPP-IV). Drug companies have developed compounds intended to act as inhibitors of DPP-IV. Vildagliptin (Galvus, Novartis) is the second DPP-IV inhibitor under investigation by FDA to offer this new mechanism to achieve glycemic control. FDA accepted an NDA for vildagliptin in March 2006, 1 month after the submission of the first DPP-IV inhibitor, sitagliptin. The NDA includes data for use of vildaglilptin as monotherapy and in combination with other anti-diabetic agents. Currently available clinical studies have demonstrated improved glycemic control with vildagliptin therapy in patients who have not achieved target glucose levels with diet and oral medications. (Schlesselman LS. Focus on vildagliptin: A dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Formulary. 2006;41:494–500.)
CURRENT STATUS: FDA accepted the NDA for vildagliptin in March 2006.
Sanofi-AventisSelective CB1 receptor antagonistNovember 2006 issue
A CB1 receptor antagonist for the treatment of obesity. Obesity is on the rise in the United States, with 60.5% of the adult population overweight and 23.9% obese as of 2005. Up to 10% of an industrialized country's healthcare budget often can be spent on obesity and associated comorbidities. Rimonabant (Sanofi-Aventis), a novel CB1 receptor antagonist, is approved in Europe for the treatment of obese or overweight patients with associated risk factors. Clinical trials, in addition to demonstrating efficacy in obesity, also have demonstrated a potential role of rimonabant in cardiovascular disease and type 2 diabetes. Rimonabant 20 mg is to be taken once daily before breakfast. Adverse events are relatively benign, with psychiatric adverse events being the leading cause for discontinuation of treatment. The benefit of continuing rimonabant therapy for a duration of 2 years is evident, but therapy could potentially be continued for a longer duration based on results from future studies. (Shah SA, Coleman CI, White CM. Focus on rimonabant: A novel CB1 receptor antagonist for the treatment of obesity. Formulary. 2006;41:561–569.)
CURRENT STATUS: In February 2006, FDA issued an approvable letter for rimonabant for weight management and a nonapprovable letter for smoking cessation. At press time, Sanofi-Aventis was continuing to work with FDA in resolving the issues required for approval of both NDAs.