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This article reviews the 10 newly improved or investigational agents evaluated in this year's "Focus on" column and includes an update on the regulatory status of each drug.
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 clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Connecticut, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs. Dr Coleman is assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.
Pegylated anti-TNF-alpha antibody fragment for the treatment of Crohn's disease. Despite the variety of medications available to treat Crohn's disease (CD), many patients' symptoms are not adequately controlled with available therapies. Two tumor necrosis factor-alpha (TNF-alpha) inhibitors, infliximab and adalimumab, are approved by FDA for the treatment of moderate-to-severe CD in patients who have an inadequate response to conventional therapies. Certolizumab is a pegylated TNF-alpha inhibitor being investigated for the treatment of moderate-to-severe CD. Because certolizumab is pegylated, it is able to be administered less frequently than other CD therapies. In addition to a once-monthly dosing schedule, certolizumab could offer patients the conveniences of subcutaneous (SC) administration. Infliximab requires intravenous (IV) administration and a more frequent induction dosing schedule than certolizumab. Adalimumab is administered via SC injection but requires a more frequent dosing schedule during induction and maintenance compared with certolizumab. Certolizumab has been demonstrated in clinical trials to induce a clinical response and maintain remission in patients with CD; however, the agent has not been demonstrated to adequately induce remission. A BLA for certolizumab was originally filed by UCB in February 2006. FDA requested an additional phase 3 trial to assess the drug's ability to induce remission. (Schlesselman LS. Focus on certolizumab pegol: A pegylated anti-TNF-alpha antibody fragment for the treatment of Crohn's disease. Formulary. 2008;43:22–28.)
CURRENT STATUS: On April 22, 2008, FDA approved certolizumab pegol for reduction of the signs and symptoms of CD and for the maintenance of clinical response in adult patients with moderate-to-severe active disease who have an inadequate response to conventional therapy.
Basilea/Johnson & JohnsonAnti-MRSA cephalosporin antibioticFebruary 2008 issue
The first anti-MRSA cephalosporin antibiotic for the treatment of complicated skin and skin-structure infections. Serious infections caused by resistant gram-positive cocci continue to increase in prevalence and significance. An NDA for ceftobiprole, an investigational novel broad-spectrum cephalosporin antibiotic, was submitted on May 18, 2007, for the treatment of complicated skin and skin-structure infections (cSSSIs), including diabetic foot infections. Ceftobiprole has demonstrated in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S aureus (VISA), vancomycin-resistant S aureus (VRSA), multidrug-resistant Streptococcus pneumoniae, Enterococcus faecalis, and some gram-negative bacteria, including Enterobacteriaceae that do not produce extended-spectrum beta-lactamases (ESBLs) and ceftazidime/cefepime-susceptible Pseudomonas aeruginosa. In clinical trials, ceftobiprole has demonstrated noninferiority to vancomycin monotherapy and vancomycin plus ceftazidime for the treatment of cSSSIs. Phase 3 clinical trials have also been conducted to assess ceftobiprole's efficacy in the treatment of community- and hospital-acquired pneumonia; full results have not yet been released. Ceftobiprole was well tolerated in clinical trials, with patients experiencing only mild adverse events (most commonly a caramel taste alteration after administration). If approved, ceftobiprole's in vitro activity against resistant gram-positive bacteria, particularly MRSA, combined with its demonstrated clinical efficacy for the treatment of cSSSIs and its mild adverse event profile, will likely make the drug an attractive addition to the antimicrobial armamentarium. (Kontou P, Kuti JL, Nicolau DP. Focus on ceftobiprole: The first anti-MRSA cephalosporin antibiotic. Formulary. 2008;43:66–78.)
CURRENT STATUS: In September 2008, Basilea and Johnson & Johnson announced that FDA accepted for review the manufacturers' complete response to the agency's March 2008 approvable letter regarding ceftobiprole.
TibotecNon-nucleoside reverse transcriptase inhibitorMarch 2008 issue
Non-nucleoside reverse transcriptase inhibitor for the treatment of resistant HIV-1 infection. Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that was approved by FDA on January 18, 2008, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in antiretroviral treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to NNRTIs and other antiretroviral agents. Etravirine has a flexible structure that allows multiple binding configurations, making this agent active against wild-type HIV-1 viral strains and against viral strains with known NNRTI resistance mutations. In clinical trials, etravirine has been associated with significant reductions in HIV-1 RNA viral loads in antiretroviral-naïve and antiretroviral-experienced patients. Etravirine is generally well tolerated. The most common adverse event is a mild rash that usually occurs during the second week of therapy and resolves with continued therapy. Although rare, etravirine has been associated with severe skin reactions, including Stevens-Johnson syndrome. Etravirine's broad spectrum of activity and twice-daily dosing schedule help make this agent a valuable treatment option for patients with HIV-1 infection who have developed resistance to other NNRTIs. (Kehr HA, Olin JL, Love BL. Focus on etravirine: A non-nucleoside reverse transcriptase inhibitor for the treatment of resistant HIV-1 infection. Formulary. 2008:43:105–114.)
CURRENT STATUS: Etravirine was approved by FDA on January 18, 2008, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in antiretroviral treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to NNRTIs and other antiretroviral agents.
KyowaAdenosine receptor antagonistMay 2008 issue
Adenosine receptor antagonist for the adjunctive treatment of Parkinson disease. Parkinson disease (PD) is a chronic and progressive neurologic disorder with a prevalence that may be as high as 329 cases per 100,000 population. This movement disorder involves a gradual decline in the neurotransmitter dopamine, which is responsible for facilitating smooth muscle and coordinated muscle movement. Istradefylline, a highly selective adenosine A2A receptor antagonist, is a new agent being investigated for the adjunctive treatment of the motor signs and symptoms of idiopathic PD. A2A receptors, which are abundant in the striatonigral outflow pathway from the basal ganglia, are the proposed target region for therapeutic intervention. An NDA for istradefylline was submitted in April 2007; in February 2008, FDA issued a nonapprovable letter for the agent, asking for additional information. The manufacturer has stated it will work closely with the agency to provide this information. The clinical trials available to date suggest that istradefylline is safe and effective in helping to reduce the symptoms of PD while maintaining overall patient tolerability. (Pomfret TC, Gagnon J, Pietarinen J. Focus on istradefylline: An adenosine receptor antagonist for the treatment of Parkinson disease. Formulary. 2008:43:157–165.)
CURRENT STATUS: Kyowa is awaiting the results of phase 2b clinical trials that are under way in Japan; once the trials are complete, the manufacturer will re-assess the potential development pathway for istradefylline.
VandaAtypical antipsychoticJune 2008 issue
Novel atypical antipsychotic for the treatment of schizophrenia. Iloperidone, a new-generation atypical antipsychotic, is currently under investigation for the treatment of schizophrenia. In 4 separate phase 3 trials, iloperidone has demonstrated efficacy in treating schizophrenia, with total Positive and Negative Symptom Scale (PANSS) scores decreasing by 8 to 14 points depending on the iloperidone dose. The most common adverse events associated with iloperidone treatment include dizziness, dry mouth, dyspepsia, sedation, orthostatic hypotension, and weight gain. Studies have also demonstrated that, similar to ziprasidone, iloperidone is associated with a risk of corrected QT (QTc) prolongation. Currently, iloperidone does not appear to offer any unique chemical properties that separate it from the other atypical antipsychotics. The manufacturer is hoping to determine specific reliable genetic markers for predictive response to this medication. Six polymorphisms demonstrating an association with iloperidone response have been identified. However, until genotyping patients becomes cost effective, iloperidone is not likely to drastically affect current clinical practice. (Ehret MJ, Sopko MA Jr, Levine A. Focus on iloperidone: A novel atypical antipsychotic for the treatment of schizophrenia. Formulary. 2008:43:190–203.)
CURRENT STATUS: On July 25, 2008, Vanda received a nonapprovable letter for iloperidone. In the letter, FDA expressed concern about the efficacy of iloperidone compared with the efficacy of risperidone. The agency stated that an additional trial comparing iloperidone with placebo and with an active comparator such as olanzapine or risperidone would be required. The agency also requested additional safety data on 20- to 24-mg/d doses of iloperidone. On September 10, 2008, Vanda met with FDA to discuss the nonapprovable letter, and the manufacturer agreed to provide a complete response to the letter.
OtsukaOral vasopressin V2 receptor antagonistJuly 2008 issue
Novel oral vasopressin V2 receptor antagonist for the treatment of acute decompensated heart failure and hyponatremia. Arginine vasopressin (AVP) is a nonapeptide hormone responsible for mediating serum sodium and serum osmolality by increasing water retention in the kidney. Tolvaptan is an oral selective vasopressin V2 receptor antagonist that works to produce aquaresis (water diuresis without electrolyte excretion) by blocking the effects of AVP. This effect makes tolvaptan a viable treatment option for patients with acute decompensated heart failure (ADHF) and hyponatremia. Current studies of tolvaptan in patients with ADHF indicate that this agent is safe and effective in relieving the signs and symptoms of this condition without affecting mortality. Data from these trials also indicate that tolvaptan does not adversely affect renal function, blood pressure, or serum potassium in this patient population. This inert effect on mortality, renal function, and electrolytes sets tolvaptan apart from other therapies for heart failure, which are known to deleteriously affect these parameters. Tolvaptan has also been demonstrated to be effective in correcting hyponatremia in patients with heart failure, cirrhosis, or syndrome of inappropriate antidiuretic hormone. Tolvaptan is also being studied for the treatment of autosomal dominant polycystic kidney disease. In December 2007, FDA accepted an NDA for tolvaptan for the treatment of ADHF and hyponatremia. If approved, tolvaptan will be a new option for patients with these conditions. (Jennings DL, Kalus JS. Focus on tolvaptan: A novel oral vasopressin V2 receptor antagonist for the treatment of acute decompensated heart failure and hyponatremia. Formulary. 2008;43:236–249.)
CURRENT STATUS: On June 25, 2008, the Cardiovascular and Renal Drugs Advisory Committee recommended approval of tolvaptan for the treatment of hyponatremia. A response from FDA is expected in the fourth quarter of 2008.
Roche/ChugaiHumanized anti-IL-6 receptor monoclonal antibodyAugust 2008 issue
Humanized anti-IL-6 receptor monoclonal antibody for the treatment of rheumatoid arthritis. Despite the numerous medications available to control the signs and symptoms and prevent the progression of rheumatoid arthritis (RA), many patients' symptoms are not adequately controlled with available therapies. Six immunomodulating agents are currently approved by FDA for the treatment of moderate-to-severe RA in patients who have an inadequate response to conventional therapies. These agents are tumor necrosis factor (TNF)-blocking agents, selective T-cell costimulation modulators, CD20 antigens, and interleukin-1 (IL-1) receptor antagonists. Tocilizumab, an investigational agent for the treatment of moderate-to-severe RA, is a humanized anti-IL-6 receptor monoclonal antibody. Because tocilizumab contains a mouse monoclonal antibody grafted onto human immunoglobulin, the grafted antibody is less antigenic and has a longer half-life than the mouse antibody. When administered, tocilizumab inhibits IL-6 activity by competing for both the membrane-bound and soluble types of IL-6 receptors, thus eliminating IL-6 transduction into the cell. Tocilizumab's dosing interval is longer than subcutaneously administered immunomodulating agents for RA and similar to that of other intravenously administered agents. Phase 3 trials have demonstrated tocilizumab's efficacy in allowing patients to achieve improvement in American College of Rheumatology (ACR) criteria and in slowing radiographic change, including patients who were refractory to anti-TNF treatment. A BLA for tocilizumab was filed in 2007; the agent is pending approval. (Schlesselman LS, Hussey AP. Focus on tocilizumab: A humanized anti-IL-6 receptor monoclonal antibody for the treatment of rheumatoid arthritis. Formulary. 2008;43:272–279.)
CURRENT STATUS: On July 29, 2008, the Arthritis Advisory Committee recommended approval of tocilizumab for the treatment of moderate-to-severe RA. In September 2008, FDA issued a complete response letter for tocilizumab. In the letter, FDA requested additional information regarding the manufacturing of this agent; the agency did not request any additional safety or efficacy data.
TakedaDipeptidyl peptidase-IV inhibitorSeptember 2008 issue
Dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are a promising new class of drugs that may potentially play an important role in the management of type 2 diabetes mellitus. These agents improve glycemic control by preventing the rapid inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), leading to stimulation of insulin release from the pancreas, inhibition of glucagon secretion, and potentially an improvement in pancreatic beta-cell function. Alogliptin is a highly selective DPP-IV inhibitor under investigation for the treatment of type 2 diabetes. Alogliptin's efficacy as monotherapy or in combination with other antidiabetic agents has been demonstrated in several randomized, placebo-controlled trials. Treatment with alogliptin for 26 weeks resulted in a significant reduction in hemoglobin A1c (HbA1c) in patients with diabetes inadequately controlled with their current regimen. In these trials, alogliptin was well tolerated, with a negligible incidence of hypoglycemia and no significant changes in weight. However, the safety of long-term therapy is currently unknown. If approved, alogliptin will compete with sitagliptin, the only DPP-IV inhibitor currently approved by FDA, and with other agents under review by FDA (vildagliptin and saxagliptin). (Glode A, Abdelghany S. Focus on alogliptin: A dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Formulary. 2008;43:317–325.)
CURRENT STATUS: On October 10, 2008, Takeda announced that the company had been notified that FDA would be unable to complete its review of the alogliptin NDA by the action date of October 27, 2008.
GlaxoSmithKline/LigandTPO receptor agonistOctober 2008 issue
TPO receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder that can become a chronic refractory problem in adult patients who develop this disease. To date, therapies have targeted immunosuppression and inhibition of platelet destruction. Eltrombopag is a thrombopoietin (TPO) receptor agonist that is currently pending FDA approval for the treatment of ITP. Studies of eltrombopag have demonstrated that the agent is effective in increasing platelet counts in patients with refractory ITP; this increase in platelet counts is generally observed within 1 week of treatment initiation. In clinical studies, eltrombopag has been well tolerated, with headache reported as the most common adverse event. If approved, eltrombopag will compete with romiplostim, another TPO receptor agonist that was approved by FDA in August 2008 for the treatment of ITP. (Skirvin JA. Focus on eltrombopag: A TPO receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. Formulary. 2008;43:356–365.)
CURRENT STATUS: On May 30, 2008, the Oncology Drugs Advisory Committee voted that eltrombopag demonstrated a favorable risk:benefit profile for the short-term treatment of ITP. On September 19, 2008, GlaxoSmithKline announced that FDA extended the action date for eltrombopag, which was originally set as September 19.
Daiichi Sankyo/LillyThienopyridine prodrug November 2008 issue
Thienopyridine prodrug for the treatment of acute coronary syndrome. Prasugrel is a thienopyridine prodrug under FDA review for the treatment of acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI). This agent inhibits platelet aggregation with a rapid onset of effect and long duration of action, allowing for once-daily dosing. Clinical trials have demonstrated statistically significant inhibition of platelet aggregation with prasugrel relative to placebo and clopidogrel. Prasugrel has also demonstrated a statistically significant decrease compared with clopidogrel in the composite end point of death related to cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. However, this improved efficacy outcome comes with a significantly increased rate of bleeding. Prasugrel is otherwise well tolerated and has an adverse event profile similar to that of clopidogrel. If approved, prasugrel will be an effective antiplatelet agent for the treatment of ACS with PCI, but its benefit will have to outweigh its increased risk of bleeding, and dosing guidelines for specific patient populations will be warranted. An additional phase 3 study currently under way should help to determine if dose adjustments in patient subgroups reduce the risk of bleeding while still maintaining efficacy. (Schillig JM, Kalus JS. Focus on prasugrel: A novel thienopyridine prodrug for the treatment of acute coronary syndrome. Formulary. 2008;43:402–408.)
CURRENT STATUS: In June 2008, FDA was expected to make a decision on prasugrel; the agency pushed the action date back to September 26, 2008. On that date, however, FDA announced that the agency had not completed its review.