Tracey Walker, Contributing Editor

to the controversial diabetes drug rosiglitazone (Avandia, 

). The agency made its determination after an FDA Advisory Committee reviewed the drug in June 2013 and voted to lift its restrictions, and new information was released indicating that the drug carries no heightened cardiovascular risk.

	Among its new actions, FDA is calling for modifications to cardiovascular-safety labels and the easing of restrictions connected with the Risk Evaluation and Mitigation Strategy (REMS) program, as well as provision of information updates for prescribers as changes arise in knowledge of cardiovascular risk connected with the drug. GSK will work with FDA to update labeling and to implement its decisions on easing access restrictions to the drug.  

	“The recent FDA decision to remove certain restrictions with regard to the prescribing to Avandia demonstrates the power of clinical trials to provide valuable information. This also has the potential to alter clinical decision-making processes in an effort to improve patient care,” said Abimbola Farinde, PharmD, MS, who serves on the faculty at Columbia Southern University, Orange Beach, Ala.

	Results from the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) clinical trial showed no elevated risk of heart attack or death in patients treated with Avandia when it was compared to standard-of-care diabetes drugs. These data do not confirm the signal of increased risk of heart attacks that was found in a meta-analysis of clinical trials first reported in 2007.

	Once the changes are final, rosiglitazone’s indication for use will no longer be limited to certain patients. FDA expects the new indication to state that the drug may be used along with diet and exercise to improve control of blood sugar in patients with type 2 diabetes mellitus. This is similar to indications for other diabetes drugs currently available.

	Once the changes to the REMS are finalized, healthcare professionals, pharmacists, and patients will no longer be required to enroll in the rosiglitazone REMS program to prescribe, dispense, or receive rosiglitazone medicines. Patients will also be able to receive rosiglitazone through regular retail pharmacies and mail-order pharmacies. 

	The manufacturers of rosiglitazone drugs will be required to ensure that healthcare providers who are likely to prescribe rosiglitazone-containing medicines be provided training based on the current state of knowledge concerning the cardiovascular risk of these medicines.

	FDA is also releasing GlaxoSmithKline from the postmarket requirement to conduct a clinical trial, known as Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE), comparing Avandia to Actos (pioglitazone), the only other approved drug in the thiazolidinedione class, and to standard diabetes drugs. FDA has concluded that this trial is no longer necessary or feasible.

	In 2010, in response to data from a meta-analysis of placebo-controlled randomized trials that suggested an elevated risk of cardiovascular events in association with rosiglitazone use, FDA announced it would restrict use of the drug to patients with type 2 diabetes who could not control their diabetes on other medications. FDA also required GSK to convene an independent group of scientists to reevaluate key aspects of RECORD, which studied the cardiovascular safety of Avandia compared to that of standard diabetes drugs, in order to provide clarity about the integrity of the study findings.

	On June 5 and 6, 2013, the readjudicated results of RECORD, which were consistent with the original findings of the trial, were discussed at a joint meeting of FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Committee members generally agreed that the readjudication was conducted appropriately and provided reassurance that the original study findings were accurate. A majority of the committee members, 13 of the 26, voted to recommend that the REMS for rosiglitazone be eliminated or modified to lessen restrictions to use.

	Rosiglitazone is available in the form of Avandia and in combination with other diabetes medications, including metformin under the brand name Avandamet and glimepiride under the brand name Avandaryl.

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Reevaluation of RECORD trial data fails to uncover elevated cardiovascular risk.

FDA lifts some restrictions on diabetes drug Avandia

	Lurasidone HCl (Latuda) reduces depressive symptoms in adult patients with bipolar depression when used as monotherapy and adjunctive therapy to lithium or valproate. This flexibility is important given the multiple unmet needs of patients with bipolar depression, according to two phase 3 

	In the first study, adult patients with bipolar depression in the double-blind, randomized, placebo-controlled, 6-week monotherapy clinical trial were randomly assigned to receive 6 weeks of treatment with lurasidone flexibly dosed within two dose ranges, 20 mg/day to 60 mg/day (N=166) and lurasidone 80 mg/day to 120 mg/day (N=169), or placebo (N=170). 

	In the monotherapy study, adverse events reported with an incidence ≥5% (and greater than placebo) in at least one of the lurasidone 20 mg/day to 60 mg/day, lurasidone 80 mg/day to 120 mg/day and placebo groups were nausea, headache, akathisia, somnolence, sedation, dry mouth, and vomiting. 

	In the second study, adult patients with bipolar depression in the double-blind, randomized, placebo-controlled, 6-week adjunctive clinical trial were randomized to receive 6 weeks of adjunctive treatment with lurasidone (N=183) or placebo (N=165) (added to background treatment with lithium or valproate). 

	In this adjunctive therapy study, adverse events reported with an incidence ≥5% (and greater than placebo) in patients receiving lurasidone versus placebo were nausea, somnolence, tremor, akathisia, and insomnia. 

	The primary end point in both studies was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6.  The key secondary end point was change from baseline at week 6 in the Clinical Global Impression, Bipolar Severity of Depression (CGI-BP-S) score, which assessed global severity of depressive symptoms.

	Other secondary end points included responder rates; rates of remission; Hamilton Anxiety Rating Scale (HAM-A); Sheehan Disability Scale (SDS); Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and Quality of Life, Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF). 

	“These studies demonstrated that [lurasidone] significantly reduced depressive symptoms in adult patients with bipolar depression, both as monotherapy and as adjunctive therapy with lithium or valproate,” said Antony Loebel, MD, executive vice president and chief medical officer at Sunovion, the manufacturer of Latuda.

	Bipolar disorder is a serious mental illness characterized by severe and debilitating mood swings that affects approximately 10.4 million adults in the United States. Bipolar depression refers to the depressive phase of bipolar disorder. When symptomatic, most people with bipolar disorder spend most time in the depressive phase.

	Major depressive episodes associated with bipolar disorder have been shown to result in significant impairment in work, family, and social function. Bipolar depressive episodes are also associated with increased direct and indirect healthcare costs, as well as an increased risk of suicide.

	“Many of the most commonly used mood stabilizers, antidepressants and antipsychotic agents actually have little data to support their efficacy in treating bipolar depression,” said Dr. Loebel. “The dearth of data means that healthcare providers must often exercise a ‘trial-and-error’ approach to managing their patients’ symptoms.  This can be frustrating, time-consuming, and costly for patients and the healthcare system. Very few medications have been approved as monotherapy treatment and no medications to date have been approved as adjunctive treatment of bipolar depression, despite the fact that mood stabilizers [such as lithium or valproate] are a mainstay treatment for people with bipolar disorder. The last FDA approval of any medication for bipolar depression occurred in 2006; there is a pressing need for additional effective and safe treatment options for this severely disabling and difficult to treat condition.” 

	Latuda was approved by FDA in June 2013 for the treatment of bipolar depression.  

Lurasidone HCl (Latuda) reduces depressive symptoms in adult patients with bipolar depression when used as monotherapy and adjunctive therapy to lithium or valproate. This flexibility is important given the multiple unmet needs of patients with bipolar depression, according to two phase 3 studies published recently in The American Journal of Psychiatry.

Studies: Lurasidone effective for treating depression associated with bipolar disorder

	Once-daily dosing of the investigational drug tiotropium helped to improve lung function over 24 hours in individuals with severe asthma, according to data presented at the 2013 American College of Chest Physicians annual meeting (CHEST 2013) in Chicago.

	Boehringer Ingelheim presented clinical trial data from a phase 3 study of tiotropium delivered via the Respimat inhaler in severe adult asthma patients. Tiotropium is currently being evaluated to determine the efficacy and safety in treating asthma patients.

	Pooled phase 3 data was presented from the PrimoTinA-asthma studies (NCT00772538 and NCT00776984). The PrimoTinA-asthma studies are two replicate randomized, double-blind, placebo-controlled, parallel-group trials that were designed to evaluate the long-term efficacy and safety of once-daily tiotropium 5 µg delivered via the Respimat inhaler, and placebo, as add-on to stable maintenance treatment of high-dose inhaled corticosteroids (ICS)/long-acting beta-2 agonists (LABA) in adult patients with symptomatic severe persistent asthma over 48 weeks.

	A total of 912 patients were randomly assigned to treatment in the paired studies, which included specific inclusion and exclusion criteria to both select patients with asthma and actively exclude patients with COPD. Patients who enrolled had a confirmed diagnosis of severe persistent asthma of at least 5 years duration made prior to age 40 years, documented by confirmatory testing, with a post-bronchodilator FEV

 ≤70% of forced vital capacity (FVC). Patients were never-smokers or ex-smokers for at least 1 year with a history of less than 10 pack-years and symptomatic as measured by an ACQ score ≥1.5 while on at least high-dose ICS/LABA therapy.

	The pre-specified co-primary lung function end points included peak and trough FEV

 at 24 weeks. The third co-primary end point in the pre-specified combined analysis of the 2 trials was the time to first severe exacerbation during the 48-week treatment period. A severe exacerbation was defined as an exacerbation that required treatment with systemic corticosteroids for at least 3 days.

	The data showed that in adult asthma patients who remain symptomatic despite treatment with at least ICS/LABA, treatment with tiotropium 5 µg delivered via the Respimat inhaler as add-on to maintenance therapies reduced the risk of both severe asthma exacerbations and any asthma exacerbation, or asthma worsening.

	An exacerbation was defined as an increase in one or more of a patient’s asthma symptoms and/or decrease in best morning peak expiratory flow rate (PEFR) for two or more consecutive days compared with a patient’s baseline. Severe exacerbations were defined as requiring systemic corticosteroids for at least three days and a decrease in lung function and/or an increase in symptoms.

	In addition, pooled safety data (ie, vital signs and adverse events [AEs]) from the PrimoTinA-asthma studies were presented, which suggest that treatment with once-daily tiotropium 5 µg, delivered via the Respimat inhaler, was comparable to that of placebo in these studies when used as add-on therapy for symptomatic patients with severe persistent asthma on ICS/LABA.

	The overall incidence of AEs reported (including SAEs, drug-related AEs, and AEs resulting in discontinuation) with once-daily tiotropium 5 µg delivered via the Respimat treatment was similar to placebo. A lower percentage of patients in the tiotropium-treated group (73.5%, n=335) reported AEs versus placebo (80.3%, n=336). The most commonly reported AEs by patients were asthma (tiotropium group 39.9%, n=182; placebo group 50.9%, n=232), peak expiratory flow (PEF) rate decrease (tiotropium group 20.4%, n=93; placebo group 26.8%, n=122) and nasopharyngitis (tiotropium group 11.2%, n=51; placebo group 12.3%, n=56). Treatment with tiotropium delivered via the Respimat inhaler was associated with fewer AE reports of asthma compared to placebo.

	“Importantly, both for physicians and their patients, these data increase our understanding of tiotropium’s potential efficacy as an add-on asthma treatment for severe asthma patients who continue to experience symptoms despite current standard treatments,” said Alan Cohen, MD, executive director, clinical development & medical affairs, respiratory, Boehringer Ingelheim. “There is an unmet need in asthma for patients with severe disease . . . Despite current treatment options, approximately 40% of patients with asthma remain symptomatic.”

	According to the Centers for Disease Control and Prevention, in May 2011, about 1 in 12 people (about 25 million) in the United States have asthma, and the numbers are increasing every year.

Once-daily dosing of the investigational drug tiotropium helped to improve lung function over 24 hours in individuals with severe asthma, according to data presented at the 2013 American College of Chest Physicians annual meeting (CHEST 2013) in Chicago.

Investigational tiotropium reduces exacerbations in severe asthma cases

, Genentech, a member of the Roche Group), also known as GA101, in combination with chlorambucil chemotherapy for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

	Obinutuzumab is the first drug approved with FDA’s 

. FDA can designate a drug as breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. FDA also granted obinutuzumab priority review and orphan drug designation.

	CLL is a blood and bone marrow disease that usually gets worse slowly. According to the 

, 15,680 Americans will be diagnosed and 4,580 will die from the disease this year.

	Obinutuzumab works by helping certain cells in the immune system attack cancer cells. It is intended to be used with chlorambucil, another drug used to treat patients with CLL. 

	The approval is based on the outcomes of the CLL11 trial. The trial showed that patients who received obinutuzumab in combination with chlorambucil chemotherapy had significantly reduced risk of disease progression or death (HR=0.16; 

<.0001) and lived significantly longer without their disease getting worse compared to those who received chlorambucil alone (median PFS, 23.0 months vs 11.1 months). The most common Grade 3/4 adverse events for those who received obinutuzumab in combination with chlorambucil compared to chlorambucil alone were infusion-related reactions during the first infusion (21% vs. 0% [chlorambucil is an oral medicine]), thrombocytopenia (11% vs 3%) and neutropenia (34% vs 16%), though this did not result in an increased rate of infections in the obinutuzumab arm. 

	Final data from the CLL11 trial investigating the direct comparison between obinutuzumab in combination with chlorambucil and rituximab (Rituxan) in combination with chlorambucil (stage 2) will be presented at the American Society of Hematology’s (ASH) 55th Annual Meeting in December 2013.

	Obinutuzumab has a boxed warning regarding hepatitis B virus reactivation and a rare disorder that damages the material that covers and protects nerves in the white matter of the brain (progressive multifocal leukoencephalopathy). These are known risks with other monoclonal antibodies in this class and rare cases were identified in participants on other trials of obinutuzumab. Patients should be advised of these risks and assessed for hepatitis B virus and reactivation risk. 

FDA has approved obinutuzumab (Gazyva, Genentech, a member of the Roche Group), also known as GA101, in combination with chlorambucil chemotherapy for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Author | Tracey Walker, Contributing Editor

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