DIS News. Literature Highlight: Vismodegib in Patients with Basal-Cell Nevus Syndrome. Inside this issue: August 2012

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1 DIS News College of Health Professions and Biomedical Sciences Drug Informa tion Service Literature Highlight: Vismodegib in Patients with Basal-Cell Nevus Syndrome Basal-cell nevus syndrome, also known as Gorlin syndrome, is a rare, heritable disease that causes basal-cell carcinomas, odontogenic keratocysts, palmar and/or plantar pits, and ectopic calcifications of the cerebral dura mater. Basal-cell nevus syndrome is caused by a mutation in the patched 1 (PTCH1) gene, which is normally involved in inhibiting cell proliferation signaling. Vismodegib is a new drug that inhibits the cell proliferation signaling involved in basal-cell nevus syndrome. A randomized, double-blind, placebocontrolled trial evaluated the efficacy and safety of vismodegib in basal-cell nevus syndrome. The patients (n=42) had at least 10 surgically-eligible carcinomas at the start of the study or within the previous two years. Surgically-eligible carcinomas were 3 mm on the nose or periorbital skin, 5 mm on any other part of the face, and 9 mm on the rest of the body above the knee (below the knee was not monitored). Patients were randomly assigned to receive either an oral dose of 150 mg of vismodegib or placebo daily for an intended 18 months. The primary endpoint was the appearance rate of new basal-cell carcinomas eligible for surgical resection. Secondary endpoints included the reduction in size of existing carcinomas and differences in adverse events between groups. More than 2000 preexisting and 694 new carcinomas were followed throughout the study period. Vismodegib reduced the mean per-patient rate of new surgically-eligible carcinomas per year more than placebo (mean rate of 2 vs. 29; p<0.001). The mean size of existing carcinomas was reduced more in the vismodegib group than in the placebo group (mean size reduction of 65% vs. 11%; p<0.003). The average number of surgeries per patient for the duration of the study was significantly lower with vismodegib versus placebo (0.31 vs. 4.4; p<0.001). Adverse events were primarily mild to moderate; no severe events were reported. Taste disturbances, hair loss, weight loss, and muscle cramps were the most commonly reported side effects and were more frequent in the vismodegib group. Fifty-four percent of patients had discontinued vismodegib due to side effects at the conclusion of the study. More moderate adverse events were reported in patients receiving vismodegib than placebo. Side effects resolved within one to three months after discontinuation of vismodegib. The authors concluded that vismodegib was relatively safe and effective compared to placebo in preventing and treating basal-cell carcinomas in patients with basal-cell nevus syndrome. Patients were allowed to have carcinomas removed at the discretion of their personal dermatologist, and patients were not stratified by baseline rates of occurrence of carcinomas, both of which are confounding variables. The small number of patients and short duration of treatment limit this study. The process used to determine the occurrence of new carcinomas is a potential limitation of the study due to differences in investigator technique. The study is also limited because vismodegib was not compared to a currently accepted agent used in basal-cell nevus syndrome. CONCLUSION: Compared to placebo, vismodegib was safe and effective for the treatment of basal-cell carcinomas in patients with basalcell nevus syndrome. Active comparator trials are needed to establish the effectiveness of vismodegib relative to currently accepted treatments. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012;366: By Brandon Huss, August 2012 Volume 16, Issue 8 Inside this issue: Kalydeco (Ivacaftor) Cialis (Tadalafil) for BPH Literature Highlight Literature Highlight We welcome any comments and suggestions for future newsletter topics. Editors in Chief Sherrill Brown, DVM, Pharm.D., BCPS Tanner Higginbotham, Pharm.D

2 Kalydeco (Ivacaftor): A New Treatment for Cystic Fibrosis Kalydeco (ivacaftor) is a new cystic fibrosis (CF) drug approved in January Ivacaftor is indicated for the treatment of CF in patients 6 years old who have a G551D mutation in the CF transmembrane receptor (CFTR) gene. 2,3 This mutation occurs in approximately 4% to 5% of people with CF and limits the CFTR s ability to regulate salt and water balance in tissues such as the lungs, sweat glands, pancreas, and gastrointestinal tract. 2 CF patients typically have worse lung function and a higher sweat chloride concentration than others of the same age, gender, and height. In patients with the G551D mutation, ivacaftor potentiates the CFTR protein and improves lung function, which is measured by the forced expiratory volume in one second (FEV1). 1,2,4-8 The following three studies have evaluated the effects of ivacaftor on FEV1 and sweat chloride concentration (an indicator of CFTR function) in CF patients with the G551D mutation. 2,4,8 A 2-part, double-blind, placebocontrolled, multicenter trial evaluated the effectiveness of ivacaftor in increasing FEV1 in CF patients 18 years old with the G551D mutation. 4 Part 1 was a modified crossover design in which patients were randomized to receive either placebo for two 14-day periods or two different doses of study drug (25, 75, or 150 mg) for 14 days at each dose; the 14-day treatments were separated by a washout period. Each group had four patients. Part 2 was a parallel design that randomized patients to receive ivacaftor 150 mg (n=8) or 250 mg (n=7) or placebo (n=4) orally every 12 hours for 28 days. Study endpoints for both parts included the percent predicted FEV1 and sweat chloride concentration changes from baseline. In part 1, there were significant improvements in FEV1 from baseline in the 75 mg and 150 mg groups (p=0.003 and p=0.006), and these improvements were significant compared to placebo (p=0.05 and p=0.04). In part 2, both treatment groups had a significant improvement in FEV1 from baseline (p=0.008 for the 150 mg group; p=0.03 for the 250 mg group). The mean change in sweat chloride concentration from baseline and compared to Page 2 placebo was significant for all treatment groups. No patients dropped out of the trial, and the adverse events profile was similar between groups. The authors concluded that ivacaftor was associated with improved lung function and had few severe side effects in CF patients with the G551D mutation. Effects of ivacaftor in patients under the age of 18 years old were not evaluated. Other limitations of the study were the small sample size and short duration. 4 A randomized, double-blind, placebocontrolled trial evaluated the effects of ivacaftor on FEV1 in patients 12 years old with CF and the G551D mutation. 2 Patients were randomized to receive either 150 mg ivacaftor orally every 12 hours (n=83) or placebo (n=78). The primary endpoint was the change in percent of predicted FEV1 between baseline and week 24. Secondary endpoints included the change in sweat chloride concentration from baseline. There was a significantly greater increase from baseline in percent predicted FEV1 in the ivacaftor group compared to placebo (mean between-group difference 10.6%, 95% CI 8.6% to 12.6%; p<0.0001) at week 24. There was a significant decrease in mean sweat chloride from baseline in the ivacaftor group. The incidence of adverse events was similar between groups. A greater proportion of patients in the ivacaftor group had elevated liver enzymes, but the significance of this difference was not discussed. Four out of the 10 patients in the placebo group and one out of six patients from the treatment group withdrew due to adverse events. The authors concluded that ivacaftor significantly improved FEV1 scores compared to placebo. The long-term outcomes associated with improved FEV1 scores were not evaluated in this trial. The study is also limited by its small sample size. 2 The effects of ivacaftor on FEV1 in younger patients was evaluated in a randomized, double-blind, placebocontrolled, multicenter study. 8 Patients 6 to 11 years old with CF and the G551D mutation were randomized to receive either 150 mg ivacaftor every 12 hours or placebo. Each group had 26 patients with similar baseline characteristics. Endpoints included the mean absolute change in percent predicted FEV1 and the mean change in sweat chloride from baseline. After 24 weeks, there was a 12.57% increase in FEV1 for the treatment group compared to a 0.04% increase in the placebo group (p<0.0001). The mean decrease in sweat chloride for the treatment group was significant. The frequency of adverse events was similar between groups, and no patients withdrew. The authors concluded that ivacaftor significantly improved FEV1 in patients 6 to 11 years old with CF and the G551D mutation. Long-term effects of the study drug on lung function were not evaluated, and the study was also limited by its short duration and small sample size. 8 The most commonly reported adverse events in clinical trials of ivacaftor were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, diarrhea, rash, and nausea. 1 Some study patients experienced elevated transaminases (AST or ALT), which should be monitored during treatment. Ivacaftor 150 mg is taken every 12 hours. 1 In conclusion, ivacaftor is indicated for the treatment of cystic fibrosis in patients 6 years old with a G551D mutation. Ivacaftor significantly improved FEV1 and sweat chloride concentration in CF patients with the G551D mutation in randomized clinical trials. However, the long-term clinical significance of the findings is still unknown. More studies are needed to determine the long-term efficacy of ivacaftor in improving disease progression, morbidity, and patient quality of life. By Sarah Stafford, (references on page 4) DIS News

3 Cialis (Tadalafil) for Benign Prostatic Hyperplasia (BPH) Cialis (tadalafil) was approved in October 2011 for the treatment of symptoms related to benign prostatic hyperplasia (BPH). 1 The most common symptoms of BPH include urinary frequency, urgency, intermittency, nocturia, decreased force of stream, hesitancy, and straining. Alpha-1 adrenergic blockers or 5-alpha reductase inhibitors are effective for men with moderate to severe BPH but have side effects, such as sexual dysfunction. 2,3 Several published studies have shown phosphodiesterase-5 (PDE5) inhibitors (e.g., tadalafil) to be effective in treating symptoms of BPH. 2 Although, PDE5 inhibitors have previously demonstrated little to no change in maximum urinary flow rate (Qmax), recent studies have demonstrated that tadalafil has a greater impact on Qmax than previously reported. 3 In an international, randomized, doubleblind, placebo-controlled trial, tadalafil 5 mg once daily significantly improved the International Prostate Symptom Score (IPSS) compared to placebo. 3 The 325 patients ( 45 years of age) had BPHlower urinary tract symptoms (BPH- LUTS) for >6 months. Patients were randomized to receive either tadalafil 5 mg or placebo once daily. The primary endpoint was the change in IPSS, and the secondary endpoint was the change in the BPH Impact Index (BII) scores. After 12 weeks, the IPSS change was significantly greater in the tadalafil group compared to the placebo group (-5.6 vs. -3.6; p=0.004). At the end of treatment, BII scores were not significantly different between the tadalafil and placebo groups (-1.8 vs. -1.3; p=0.057). Qmax was not reported individually, but the authors stated that it increased in the tadalafil group, although the increase was not considered clinically significant. The authors concluded that tadalafil 5 mg once daily significantly improved BPH-LUTS as demonstrated by the change in the IPSS. Limitations of this trial include potential bias because the manufacturer of tadalafil helped design, conduct, and financially support the study. Also, data collection and all statistical analyses were performed and retained by the manufacturer. 3 A 12-week study assessed the efficacy of both 2.5 mg and 5 mg of tadalafil taken orally once daily in men ( 45 years old) with BPH-LUTS for >6 months. 4 Six hundred and six men were randomized to receive either tadalafil 2.5 mg or 5 mg or placebo once daily. The primary outcome was the change in the IPSS. The key secondary endpoint was the change in BII. The change in IPSS was not significantly greater in the tadalafil 2.5 mg group compared to the placebo group (-4.6 vs. -3.8; p=0.18). However, the change in IPSS for tadalafil 5 mg was significantly greater compared to placebo (-6.1 vs ; p<0.001). The difference in the change in BII scores was not significant between the placebo and tadalafil 2.5 mg groups (-1.6 vs. -1.2; p=0.16). However, tadalafil 5 mg had a significantly greater change in the BII score compared to placebo (-2.1 vs. -1.2; p<0.001). Three patients from placebo group, three from the 2.5 mg group, and six from the 5 mg group discontinued treatment due to adverse events. The authors concluded that tadalafil 5 mg significantly improved BPH- LUTS. The short duration and the lack of an active comparator limit this study. 4 A double-blind, placebo-controlled, paralleldesign trial compared the effectiveness of tadalafil to placebo in treating BPH-LUTS and used tamsulosin as an active control. 5 Subjects were 45 years old, with BPH- LUTS for >6 months, and had an IPSS 13 and a Qmax between 4 and 15 ml/s. All subjects (n=511) underwent a four-week, single-blind, placebo lead-in period, then were randomized to receive either tadalafil 5 mg, tamsulosin 0.4 mg, or placebo once daily. The primary endpoint was the change in IPSS. The secondary endpoint was the change in the BII score. Both tadalafil and tamsulosin produced significantly greater changes in the IPSS compared to placebo (tadalafil: -6.3 vs. -4.2; p=0.001 and tamsulosin: -5.7 vs. -4.2; p=0.023). The BII scores significantly improved in both active treatment groups compared to placebo (tadalafil: -0.8; p=0.003 and tamsulosin: -0.6; p=0.026). Two subjects in the placebo group (1.2%), two in the tadalafil group (1.2%), and one in the tamsulosin group (0.6%) discontinued treatment due to adverse events. The authors concluded that tadalafil 5 mg or tamsulosin 0.4 mg taken once daily provided similar improvements versus placebo in BPH-LUTS symptoms. Additionally, they stated that tadalafil and tamsulosin yielded similar improvements in Qmax. This study was not powered to find a difference between tadalafil and tamsulosin, which limits knowledge about the comparative effectiveness of tadalafil. Also, the short duration and the differences in the severity of BPH between patients are limitations of this study. 5 Tadalafil 5 mg by mouth once daily is used to treat BPH. 3-5 Side effects of tadalafil most commonly reported in clinical trials were headache and back pain. 3-5 Tadalafil was approved in 2011 for the treatment of symptoms related to BPH and has demonstrated usefulness in the management of the disease. Tadalafil has produced similar changes to the IPSS as tamsulosin. One problem associated with PDE5 inhibitors has been the lack of Qmax improvement. However, two of the three studies presented here showed an improvement in Qmax with the use of tadalafil, although the clinical significance of their findings was uncertain. More studies with direct comparisons to standard treatments for BPH are still needed. By Brandon Huss, REFERENCES: 1. Cialis [package insert]. Indianapolis, IN: Lilly USA, LLC;2011 October 2. Lee M. Benign prostatic hyperplasia. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York (NY): McGraw Hill;2011: Porst H, Kim ED, Casabe AR, et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 2011;60: (references continued on page 4) Volume 16, Issue 8 Page 3

4 Literature Highlight: A Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes The occurrence of type 2 diabetes in adolescence is increasing. Directing the treatment of type 2 diabetes in youth can be difficult because evidence and guidelines are limited. This multicenter, randomized trial compared the efficacy of metformin monotherapy to metformin and rosiglitazone and to metformin and an intensive lifestyle intervention program in youth with type 2 diabetes. Patients were years of age, had type 2 diabetes for less than two years before randomization, and had a BMI greater than the 85th percentile. Patients were assigned to receive either metformin 1000 mg twice daily (n=232), metformin 1000 mg twice daily with rosiglitazone 4 mg twice daily (n=233), or metformin 1000 mg twice daily with an intensive lifestyle intervention program. Patients were monitored for an average of 3.86 years. The primary outcome was treatment failure, defined by either the occurrence of HbA1c values greater than 8% for more than six months or failing to end insulin therapy within three months of an acute metabolic decompensation. Overall, 319 patients failed their selected treatment program. The median time to treatment failure was 11.5 months. The metformin only group had a failure rate of 51.7% (95% CI 45.3 to 58.2%; 120 of 232 patients). The metformin plus rosiglitazone group had a failure rate of 38.6% (95% CI 32.4 to 44.9%; 90 of 233 patients). The metformin plus lifestyle intervention group had a treatment failure rate of 46.6% (95% CI 40.2 to 53.0%; 109 of 234 patients). There was a 25.3% decrease in treatment failure with metformin plus rosiglitazone compared to metformin alone (p=0.006). However, there was not a significant difference in the failure rate between the metformin plus lifestyle intervention group and the metformin monotherapy or metformin plus rosiglitazone groups. The authors concluded that metformin plus lifestyle intervention was no more effective in maintaining glycemic control than metformin alone in youth with type 2 diabetes. They also concluded that metformin plus rosiglitazone was more effective than metformin alone in maintaining glycemic control. The true effect of the lifestyle intervention could not be properly evaluated because the lifestyle intervention group was largely noncompliant. CONCLUSION: Youth with type 2 diabetes had a difficult time maintaining glycemic control while on metformin monotherapy, which suggests combination medication therapy or insulin therapy may be required within a few years of diagnosis. Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366(24): By Amber Walks Over Ice, REFERENCES: 1. Kalydeco [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated;2012 January. 2. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D Mutation. N Engl J Med 2011;365(18): Wright CC, Vera YY. Cystic fibrosis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. 4. Egerdie RB, Auerbach S, Roehrborn CG, et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperpla- Kalydeco (Ivacaftor) for Cystic Fibrosis (from page 3) New York (NY): McGraw Hill;2011: Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D- CFTR mutation. N Engl J Med 2010;363(21): Ivacaftor. Drug Facts and Comparisons. Facts & Comparisons eanswers [online] Available from Wolters Kluwer Health, Inc. Access July 5, Ivacaftor. In: DRUGDEX System [Internet database]. Greenwood Cialis (Tadalafil) for BPH (from page 4) sia: results of a randomized, placebo-controlled, double-blind study. J Sex Med 2012;9: Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin simi- Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. 7. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi- Comp s Drug Information Handbook. 20th ed. Hudson (OH):Lexi-Comp; Aherns R, Rodriguez S, Yen K, et al. VX-770 in subjects 6 to 11 years with cystic fibrosis and the G551D-CFTR mutation (abstract). Pediatr Pulmonol 2011;(suppl 34):283. larly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomized, parallel, placebo-controlled clinical trial. Eur Urol 2012;61: Page 4 DIS News

5 Literature Highlight: Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new drug class that may effectively lower blood sugar in patients with uncontrolled hyperglycemia. Dapagliflozin is a competitive inhibitor of SGLT2, which is responsible for approximately 90% of glucose reabsorption. Increased excretion of glucose may help control hyperglycemia in patients with type 2 diabetes independent of insulin use. This 24-week, multicenter, double-blind, randomized trial was conducted to evaluate the safety and efficacy of dapagliflozin in patients with inadequately controlled type 2 diabetes taking insulin with or without oral antidiabetic drugs [OADs]. Patients were men and women, 18 to 80 years old, with type 2 diabetes, a body mass index of 45 kg/m 2, and poor glycemic control (HbA1C 7.5% and 10.5%). Patients were randomized to receive one of the following: placebo (n=193) or dapagliflozin 2.5 mg (n=202), 5 mg (n=211), or 10 mg (n=194) once daily. Patients continued their open-label insulin therapy along with previously prescribed OADs. No dosing adjustments were allowed for OADs during the study except if necessitated by cases of hypoglycemia. The primary endpoint was the change in HbA1C from baseline to week 24. Change from baseline in total body weight and mean daily insulin dose were secondary endpoints. Out of the 808 patients randomized, 800 were analyzed. Those excluded from the analysis were missing baseline or postbaseline efficacy values. All groups had similar baseline and demographic characteristics. Dapagliflozin (all doses) lowered HbA1C more than placebo from baseline to week 24 (mean between-group differences of -0.40% [95% CI -0.54% to -0.25%] for the 2.5 mg group, -0.49% [95% CI % to -0.34%] for the 5 mg group, and -0.57% [95% CI -0.72% to -0.42%] for the 10 mg group). All dapagliflozin treatment groups lost weight, and the placebo group gained weight from baseline to week 24 (mean between-group differences of kg [CI kg to kg] for the 2.5 mg group, kg [CI kg to kg] for the 5 mg group, and kg [CI kg to kg] for the 10 mg group). The mean daily insulin dose decreased in the dapagliflozin groups but increased in the placebo group (mean between-group differences of U [CI U to U] for the 2.5 mg group, U [CI U to U] for the 5 mg group, and U [CI U to U] for the 10 mg group). The dapagliflozin groups had a higher incidence of hypoglycemic events and urinary tract or genital infections. The authors concluded that dapagliflozin improved glycemic control in patients with type 2 diabetes and uncontrolled hyperglycemia. The lack of clinical outcome information on morbidity and mortality is a limitation of the study. Other limitations include its short duration and lack of participant s daily blood sugar control information. CONCLUSION: The use of dapagliflozin resulted in a significantly reduced mean HbA1C from baseline compared to placebo in patients with type 2 diabetes and uncontrolled hyperglycemia (HbA1C 7.5% and 10.5%) taking insulin with or without additional OADs. Active treatment was associated with higher incidences of hypoglycemic events and urinary tract or genital infections. Wilding JP, Woo V, Soler NG, et al. Longterm efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin. Ann Intern Med 2012;156: By Sarah Stafford, College of Health Professions and Biomedical Sciences Drug Information Service The University of Montana Skaggs School of Pharmacy 32 Campus Drive Missoula, MT Phone: Fax: druginfo@umontana.edu