The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No 1433 1455 Volume 56 November 10, 2014 IN THIS ISSUE Two New GLP-1 Receptor Agonists for Diabetes p 109 A Combination of Ledipasvir and Sofosbuvir (Harvoni) for Hepatitis C p 111 Contrave – A Combination of Bupropion and Naltrexone for Weight Loss p 112 Obinutuzumab (Gazyva) for Chronic Lymphocytic Leukemia online only Pembrolizumab (Keytruda) for Metastatic Melanoma online only Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 (Issue 1455) ISSUE ISSUE No 1433 1455 Volume 56 ▶ November 10, 2014 Take CME Exams ALSO IN THIS ISSUE A Combination of Ledipasvir and Sofosbuvir (Harvoni) for Hepatitis C p 111 Contrave – A Combination of Bupropion and Naltrexone for Weight Loss p 112 Obinutuzumab (Gazyva) for Chronic Lymphocytic Leukemia online only Pembrolizumab (Keytruda) for Metastatic Melanoma online only Two New GLP-1 Receptor Agonists for Diabetes levels of cyclic AMP and potentiation of insulin secretion GLP-1 receptor agonists also lower serum glucagon concentrations, slow gastric emptying, and promote satiety Two new injectable GLP-1 (glucagon-like peptide-1) receptor agonists, dulaglutide (Trulicity [trū li si tee] – Lilly) and albiglutide (Tanzeum [tan' zee um] – GSK), have been approved by the FDA for once-weekly treatment of type diabetes Other available GLP-1 receptor agonists include exenatide, which is approved for injection twice daily (Byetta) or once weekly (Bydureon), and liraglutide (Victoza), which is injected once daily Class Adverse Effects – Gastrointestinal effects and injection-site reactions are the most common adverse effects of GLP-1 receptor agonists; the rates, severity, and duration of these effects vary within the class GLP-1 receptor agonists have been shown to cause thyroid C-cell tumors in animals, and thyroid C-cell hyperplasia has been reported in humans; they are contraindicated for use in patients with a personal or family history of medullary thyroid carcinoma and in those with Multiple Endocrine Neoplasia syndrome type These drugs have rarely been associated with acute pancreatitis GLP-1 receptor agonists are classified as category C (developmental toxicity in animals; no adequate studies in women) for use during pregnancy GLP-1 RECEPTOR AGONISTS — When metformin alone fails to control hyperglycemia, addition of a GLP-1 receptor agonist is an option These drugs are less likely than sulfonylureas or insulin to cause hypoglycemia and usually cause weight loss, but they are expensive and long-term safety data are lacking.1 Mechanism of Action – Released by cells in the gastrointestinal tract in response to food, GLP-1 activates receptors in pancreatic beta cells, resulting in increased Drug Interactions – Since they slow gastric emptying, GLP-1 receptor agonists may decrease the rate Table GLP-1 Receptor Agonists Drug Formulations Albiglutide – Tanzeum (GSK) 30, 50 mg single-dose pen Dulaglutide – Trulicity (Lilly) 0.75 mg/0.5 mL, 1.5 mg/0.5 mL single-dose pen or syringe 0.75 or 1.5 mg SC once/wk3 488.30 250 mcg/mL (1.2, 2.4 mL prefilled pen) or 10 mcg SC bid4 427.10 mg single-dose pen or powder for injectable suspension2 mg/mL (3 mL prefilled pen) mg SC once/wk3 440.00 1.2 or 1.8 mg SC once/d3 392.40 Exenatide – immediate-release Byetta (AstraZeneca) extended-release Bydureon (AstraZeneca) Liraglutide – Victoza (Novo Nordisk) Usual Maintenance Dosage Cost1 30 or 50 mg SC once/wk $326.00 Approximate WAC for 30 days’ treatment at the lowest usual maintenance dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly October 5, 2014 Reprinted with permission by First Databank, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Requires reconstitution before injection Can be given at any time of day, with or without food Should be given within 60 minutes before morning and evening meals (or before the two main meals of the day, approximately hours or more apart) 109 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter and extent of absorption of oral medications taken concomitantly The risk of hypoglycemia increases when these drugs are used in combination with insulin secretagogues, such as sulfonylureas, or insulin DULAGLUTIDE CLINICAL STUDIES — In randomized, controlled trials in patients with type diabetes, use of dulaglutide, alone and in combination with metformin, a sulfonylurea, pioglitazone, or insulin, lowered HbA1c (A1C) and reduced weight (Table 2) Table Some Dulaglutide Clinical Trials Study Drug Regimen November 10, 2014 Vol 56 (1455) ® A1C Weight Change Change (%)1 (kg)1 upper arm, which can be increased to a maximum of 1.5 mg once weekly Dulaglutide does not require reconstitution prior to administration It should be stored in a refrigerator in its original carton to keep the drug protected from light (it can be stored at room temperature for up to 14 days) ALBIGLUTIDE CLINICAL STUDIES — In randomized, controlled trials, use of albiglutide alone and in combination with other antihyperglycemic drugs led to modest reductions in A1C and weight in patients with type diabetes (Table 3) Table Some Albiglutide Clinical Trials Drug Regimen A1C Weight Change Change (%)1 (kg)1 Albiglutide 30 mg/wk Albiglutide 50 mg/wk Placebo -0.7 -0.9 +0.2 -0.4 to -0.9 -0.4 to -0.9 -0.7 B Ahrén et al.3 104 weeks (n=999) Metformin + Albiglutide 30 mg/wk4 + Sitagliptin 100 mg/d + Glimepiride 2-4 mg/d + Placebo -0.6 -0.3 -0.4 +0.3 -1.2 -0.9 +1.2 -1.0 J Reusch et al.5 52 weeks (n=299) Metformin ± pioglitazone + Albiglutide 30 mg/wk + Placebo -0.8 -0.1 +0.3 +0.5 52 weeks2 (n=657) Metformin + glimepiride -0.6 + Albiglutide 30 mg/wk4 + Pioglitazone 30-45 mg/d -0.8 + Placebo +0.3 -0.4 +4.4 -0.4 RE Pratley et al.6 32 weeks (n=805) Current oral antihyperglycemic therapy + Albiglutide 30 mg/wk4 + Liraglutide 1.8 mg/d -0.8 -1.0 -0.6 -2.2 PN Weissman et al.7 Metformin ± sulfonylurea 52 weeks + Albiglutide 30 mg/wk4 (n=735) + Insulin glargine -0.7 -0.8 -1.1 +1.6 J Rosenstock et al.8 Insulin glargine 26 weeks + Albiglutide 30 mg/wk4 (n=563) + Insulin lispro -0.8 -0.7 -0.7 +0.8 -0.8 -0.5 -0.8 -0.2 Monotherapy Dulaglutide 0.75 mg/wk -0.7 Dulaglutide 1.5 mg/wk -0.8 Metformin 1500-2000 mg/d -0.6 -2.3 -2.3 -2.2 Study Metformin + Dulaglutide 0.75 mg/wk + Dulaglutide 1.5 mg/wk + Sitagliptin 100 mg/d -0.9 -1.1 -0.4 -2.6 -3.0 -1.5 Add-on Therapy Metformin + pioglitazone + Dulaglutide 0.75 mg/wk + Dulaglutide 1.5 mg/wk + Exenatide 10 mcg bid + Placebo -1.3 -1.5 -1.0 -0.5 +0.2 -1.3 -1.1 +1.2 52 weeks5 (n=807) Metformin + glimepiride + Dulaglutide 0.75 mg/wk + Dulaglutide 1.5 mg/wk + Insulin glargine -0.8 -1.1 -0.6 -1.3 -1.9 +1.4 26 weeks5 (n=884) Insulin lispro ± metformin + Dulaglutide 0.75 mg/wk + Dulaglutide 1.5 mg/wk + Insulin glargine -1.6 -1.6 -1.4 +0.2 -0.9 +2.3 Metformin + Dulaglutide 1.5 mg/wk + Liraglutide 1.8 mg/d -1.4 -1.4 -2.9 -3.6 G Umpierrez et al.2 26 weeks (n=807) Add-on Therapy M Nauck et al.3 52 weeks (n=1098) C Wysham et al 26 weeks (n=976) KM Dungan et al.6 26 weeks (n=599) Mean change from baseline G Umpierrez et al Diabetes Care 2014; 37:2168 M Nauck et al Diabetes Care 2014; 37:2149 C Wysham et al Diabetes Care 2014; 37:2159 Summarized in the package insert KM Dungan et al Lancet 2014; 384:1349 ADVERSE EFFECTS — According to pooled data from placebo-controlled trials, the most common adverse effects of dulaglutide 1.5 mg were nausea (21%), diarrhea (13%), vomiting (13%), abdominal pain (9%), decreased appetite (9%), dyspepsia (6%), and fatigue (6%); these effects were considered mild in 48% of patients, moderate in 43%, and severe in 11%, and occurred more frequently than with the 0.75-mg dose Injection-site reactions occurred in only 0.5% of patients treated with the drug DOSAGE AND ADMINISTRATION — The recommended dosage of dulaglutide is 0.75 mg once weekly, injected subcutaneously in the abdomen, thigh, or 110 Monotherapy 52 weeks2 (n=296) LA Leiter et al.9 26 weeks (n=486) Current oral antihyperglycemic therapy + Albiglutide 30 mg/wk4 + Sitagliptin 25-100 mg/d Mean change from baseline Summarized in the package insert B Ahrén et al Diabetes Care 2014; 37:2141 Dose could be increased to 50 mg/week J Reusch et al Diabetes Obes Metab 2014 August 23 (epub) RE Pratley et al Lancet Diabetes Endocrinol 2014; 2:289 PN Weissman et al Diabetologia 2014 September 11 (epub) J Rosenstock et al Diabetes Care 2014; 37:2317 In patients with renal impairment LA Leiter et al Diabetes Care 2014; 37:2723 ADVERSE EFFECTS — According to pooled data from placebo-controlled trials, diarrhea (13%) and nausea (11%) were the most common gastrointestinal adverse effects of albiglutide Injection-site reactions occurred in 11% of patients treated with the drug The Medical Letter ® DOSAGE AND ADMINISTRATION — The recommended dosage of albiglutide is 30 mg once weekly, injected subcutaneously in the abdomen, thigh, or upper arm, which can be increased to 50 mg once weekly Albiglutide should be stored in a refrigerator in its original carton, but it can be stored at room temperature for up to weeks before use Before injecting the drug, the patient must twist the cartridge on the pen to mix the lyophilized albiglutide powder with the diluent and then gently rock the pen side-to-side times To ensure that the reconstituted solution is mixed, the patient must wait for 15 minutes before injecting a 30-mg dose and for 30 minutes before a 50-mg dose CONCLUSION — The two new once-weekly GLP-1 receptor agonists dulaglutide (Trulicity) and albiglutide (Tanzeum) are both effective in lowering A1C, but dulaglutide appears to be superior in reducing weight and less likely to cause injection-site reactions The ready-to-use formulation of dulaglutide is more convenient than albiglutide or once-weekly exenatide (Bydureon), which must be reconstituted before use Once-daily liraglutide (Victoza) and twice-daily exenatide (Byetta) are also ready to use ■ Drugs for type diabetes Treat Guidel Med Lett 2014; 12:17 ▶ A Combination of Ledipasvir and Sofosbuvir (Harvoni) for Hepatitis C The FDA has approved a fixed-dose combination (Harvoni [har voe' nee] – Gilead) of sofosbuvir and ledipasvir (led’ i pas’ vir), two oral direct-acting antiviral agents, for treatment of chronic hepatitis C virus (HCV) genotype infection Genotype is responsible for 70-80% of HCV infections in the US Sofosbuvir (Sovaldi) was approved earlier for use in combination with other antiviral drugs for treatment of HCV infection Ledipasvir is a new drug DRUGS FOR HCV INFECTION — Sofosbuvir is the most effective drug available to date for treatment of chronic HCV infection, and it appears to have a high genetic barrier to resistance In combination with pegylated interferon and/or ribavirin, or with the protease inhibitor simeprevir (Olysio), sofosbuvir has produced higher sustained virologic response (SVR) rates with shorter treatment durations than the previous standard regimen of peginterferon, ribavirin, and a protease inhibitor, and it is better tolerated Vol 56 (1455) November 10, 2014 MECHANISM OF ACTION — Sofosbuvir is a uridine nucleotide analog that is converted to an active metabolite in the liver It inhibits the HCV NS5B RNAdependent RNA polymerase, which is essential for viral replication Ledipasvir inhibits the HCV NS5A protein, which is also essential for viral replication Table Pharmacokinetics Ledipasvir Sofosbuvir Tmax 4-4.5 hrs ~0.8-1 hr Metabolism Oxidation via unknown mechanism Hepatic activation via hydrolysis and phosphoramidate cleavage, followed by phosphorylation; inactivated by dephosphorylation Elimination Feces (~86%); urine (~1%) Urine (~80%); feces (~14%); expired air (~2.5%) Half-life (terminal) 47 hours 0.5 hours CLINICAL STUDIES — A randomized, open-label trial (ION-1) in 865 treatment-naive patients with HCV genotype infection compared use of the fixeddose combination of ledipasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks; 16% of these patients had cirrhosis and 67% had genotype 1a infection, features that have been associated with less successful treatment outcomes An SVR was achieved in 99% of patients treated for 12 weeks and in 98% of those treated for 24 weeks with the combination alone The addition of ribavirin had little effect on SVR rates (97% with 12 weeks of treatment and 99% with 24 weeks) Among patients with cirrhosis, SVR rates ranged from 94% to 100% in the treatment groups.4 A similar trial (ION-2) compared use of the fixeddose combination of ledipasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks in 440 patients with previously treated HCV genotype infection; 20% of these patients had cirrhosis and 79% had genotype 1a infection An SVR was achieved in 94% of patients treated for 12 weeks and in 99% of those treated for 24 weeks with the combination alone The addition of ribavirin had little or no effect on SVR rates (96% with 12 weeks of treatment and 99% with 24 weeks) Among patients with cirrhosis, those treated for 12 weeks had SVR rates of 86% with the combination alone and 82% with addition of ribavirin; with 24 weeks of treatment, the SVR rate for patients with cirrhosis was 99% with or without ribavirin.5 In a randomized, open-label trial (ION-3) in 647 treatment-naive patients with chronic HCV infection without cirrhosis, SVR rates were 94% with weeks 111 The Medical Letter ® of treatment and 95% with 12 weeks of treatment with ledipasvir and sofosbuvir alone.6 ADVERSE EFFECTS — The most common adverse effects of ledipasvir and sofosbuvir have been headache, fatigue, nausea, diarrhea, and insomnia In all of the clinical trials, the percentages of patients who permanently discontinued treatment because of adverse effects were 0%,