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Nonprescription Orlistat GlaxoSmithKline Consumer Healthcare, Ltd New Drug Application (21-887)

Nonprescription Orlistat GlaxoSmithKline Consumer Healthcare, Ltd New Drug Application (21-887). Joint Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Meeting Bethesda, Maryland January 23, 2006 Julie Golden, M.D.

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Nonprescription Orlistat GlaxoSmithKline Consumer Healthcare, Ltd New Drug Application (21-887)

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  1. Nonprescription OrlistatGlaxoSmithKline Consumer Healthcare, LtdNew Drug Application (21-887) Joint Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Meeting Bethesda, Maryland January 23, 2006 Julie Golden, M.D. Division of Metabolic and Endocrine Products Center for Drug Evaluation and Research

  2. Outline • Background • Studies reviewed • Efficacy considerations • Safety considerations • Conclusions

  3. Background

  4. Definitions: Overweight and Obesity • Normal weight: BMI 18.5 – 24.9 kg/m² • Overweight: BMI 25 – 29.9 kg/m² • Obese: BMI > 30 kg/m² • Morbidly obese: BMI > 40 kg/m² • For this application: • Low overweight: BMI 25 – < 28 kg/m² • High overweight: BMI 28 – 29.9 kg/m²

  5. Orlistat LabelNonprescription vs. Prescription

  6. National Institutes of Health’s 2000 Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults • Weight loss through diet and exercise • Obese • Overweight + comorbidities • High-risk waist circumference + comorbidities • Pharmacotherapy • Only if lifestyle changes do not promote weight loss after 6 months • Obese (≥ 30 kg/m²) • BMI ≥ 27 kg/m² + comorbidities

  7. FDA’s Efficacy Criteria of Prescription Weight-Loss Drugs • Mean % weight loss (drug group) – mean % weight loss (placebo group) ≥ 5%, OR • The proportion of subjects who reach and maintain a loss ≥ 5% of baseline body weight is statistically greater in drug group vs. placebo group FDA 1996 Draft Guidance for the Clinical Evaluation of Weight-Control Drugs

  8. How Orlistat Works • Pharmacodynamic Effect • Orlistat 60 mg = ~25% fecal fat excretion • Orlistat 120 mg = ~30% fecal fat excretion • Behavioral Modification Effect • Claim: patients favorably modify their diet due to GI side effects • Patients may also decrease drug use because of side effects • The incidence of GI side effects is similar across different amounts of weight loss • Consume more fat: drug effect • Consume less fat: dietary/behavioral effect

  9. Efficacy

  10. 4 weeks 2 years 1 year 6 months Randomization Rx efficacy (weight loss) endpoint NonRx efficacy endpoint Rx efficacy (weight maintenance) endpoint 4 months Randomization NonRx efficacy endpoint Efficacy Studies BM14149, NM14161 (BMI 28-43 kg/m²) Placebo Orlistat 60 mg Orlistat 120 mg NM17247 (BMI 25-28 kg/m²) Placebo Orlistat 60 mg

  11. Efficacy Studies

  12. Completion Rates

  13. % of Subjects by BMI Group

  14. Categorical Weight Loss Results – LOCF * * * * *p < 0.05 vs. placebo

  15. Weight Change from Baseline – LOCF BM14149 Mth 6 BM14149 Mth 6 NM14161 Mth 6 NM14161 Mth 6 NM17247 Mth 4 NM17247 Mth 4 10 5 0 Wt change from baseline (kg) -5 -10 -15 -20 PLA 60 120 PLA 60 120 PLA 60

  16. Placebo-Subtracted Difference in Weight Change from Baseline (kg) and 95% CI – LOCF

  17. Placebo Placebo Placebo Orlistat Orlistat Weight Regain – 2 year data First year: hypocaloric diet; Second year: eucaloric diet • Pooled studies: BM14149 and NM14161 • Orlistat or placebo for 2 years • Additional study from Rx NDA, published in JAMA 1999 • Orlistat or placebo for 1 year • 2nd year:

  18. Pooled StudiesWeight Change Over 2 Years – Completers

  19. Weight Control and Risk Factor Reduction in Obese Subjects Treated for 2 Years With Orlistat: A Randomized Controlled Trial • Groups: • Placebo/placebo (n=133) • Orlistat 120/orlistat 120 (n=153) • Orlistat 120/orlistat 60 (n=152) • Orlistat 120/placebo (n=138) • Behavior modification program: Dietitians, food diaries, counseling Davidson MH, et al. JAMA 1999; 281:235-242

  20. Mean Body Weight Change During 2 Years of Double-Blind Treatment – Completers Adapted from: Davidson, MH, et al. JAMA 1999;281:235-242

  21. Randomized Trial of Lifestyle Modification and Pharmacotherapy for Obesity 224 obese adults, 1 year, sibutramine Wadden TA, et al. N Engl J Med 2005; 353:2111-20

  22. Results of Lifestyle Modification Study – LOCF Weight % Subjects Change w/ 5% loss Drug + Intensive Therapy -12.1 kg 73% Drug + Brief Therapy -7.5 kg 56% Intensive Therapy -6.7 kg 53% Drug -5.0 kg 42% Wadden TA, et al. N Engl J Med 2005; 353:2111-20

  23. Safety

  24. Safety Database • Studies from original Rx NDA (pooled): BM14149, NM14161, NM14302 • New study: NM17247 • Supportive studies: BM14150, Actual Use Trial, Consumer Use Study • Post-marketing data: FDA Adverse Event Reporting System (AERS) • Published literature • Review of original Rx orlistat NDA

  25. Pooled Safety Studies

  26. Safety Issues for Discussion • Fat-soluble vitamins • Drug interactions • Pancreatitis

  27. Study BM14149 (No MVI)Mean Change in Vitamin Concentrations Over Time * * * * * * * p < 0.001 vs. placebo

  28. Study NM14161 (No MVI)Mean Change in Vitamin Concentrations Over Time * † * * * * p < 0.05 vs. placebo; † p < 0.10 vs. placebo

  29. Study NM14302 (+ MVI)Mean Change in Vitamin Concentrations Over Time * † * * * * * p < 0.05 vs. placebo; † p < 0.10 vs. placebo

  30. Frequency of 2 Consecutive Plasma Vitamin Concentrations Below the Limit of the Reference Range after 1 Year of Treatment Rx NDA, 7 Phase 3 studies

  31. Drug InteractionWarfarin • No significant alteration of pharmacokinetics of warfarin • Post-marketing, literature reports of prolonged prothrombin time • Post-marketing reports of bleeding • 7 of 14 patients on warfarin initially failed to identify that orlistat was inappropriate for their use

  32. Drug InteractionCyclosporine • Weight gain is common after organ transplantation • Orlistat-cyclosporine interaction study demonstrated decreased cyclosporine concentrations • Post-marketing reports of decreased cyclosporine concentrations • 2 cases of acute organ rejection: 1 mild, 1 moderate • 1 of 2 patients on cyclosporine initially failed to identify that orlistat was inappropriate for use

  33. Pancreatitis • FDA AERS Data • 99 raw reports of “pancreatitis” for orlistat (30 US reports) • 8 raw reports of “pancreatitis” for sibutramine (1 US report) • No increase in incidence of pancreatitis in placebo-controlled trials of orlistat in patients treated for up to 4 years • Review of issue is ongoing

  34. Conclusions

  35. Efficacy ConclusionsDose and Population • Low overweight population at 4 months, orlistat 60 mg TID (Study NM17247) • Mean weight loss 1.1 kg • Primary Rx weight loss drug efficacy criterion (categorical weight loss) was not met

  36. Efficacy Conclusions Duration and Lifestyle • Pooled studies, obese and high overweight population (Study NM14161 and Study BM14149) • Greater overall weight loss was seen with intensive lifestyle intervention (BM14149) • Smaller drug treatment and dose effect was seen with intensive lifestyle intervention (BM14149) • More weight regained over 2 years with less intensive lifestyle intervention (NM14161)

  37. Efficacy Conclusions Duration and Lifestyle • Weight regain after discontinuation of orlistat (JAMA paper) • Weight-loss drug more effective with lifestyle intervention (NEJM paper)

  38. Safety Conclusions Fat-Soluble Vitamin Malabsorption • A higher percentage of orlistat-treated subjects had 2 consecutive plasma fat-soluble vitamin concentrations below the lower limit after 1 year of treatment than placebo-treated subjects • Prolonged orlistat use without appropriate supplementation may lead to clinically significant fat-soluble vitamin malabsorption • Bone • Warfarin

  39. Safety ConclusionsImportant Drug Interactions • Warfarin • Reports of prolonged PT and bleeding likely reflect vitamin K malabsorption and vitamin K insufficiency • Cyclosporine • Reports of subtherapeutic cyclosporine concentrations, organ rejection (2), reflect decreased cyclosporine absorption when taken with orlistat • Actual use trial indicates that labeled warnings may not be adequately communicated

  40. Safety ConclusionsPancreatitis: Unclear Association with Orlistat • No evidence from clinical studies that orlistat increases the risk for pancreatitis • Increased number of AERS reports of pancreatitis in users of orlistat • Investigation ongoing

  41. Do you believe that the potential benefits of nonprescription orlistat outweigh the risks?

  42. Acknowledgements • DMEP Clinical Review Team • Eric Colman, M.D. • Mary Parks, M.D. • Statistical Review Team • Joy Mele, M.S. • Todd Sahlroot, Ph.D. • Office of Drug Safety • Joslyn Swann, Pharm.D. • Lanh Green, Pharm.D., M.P.H. • Cynthia Kornegay, Ph.D. • Project Management • Patricia Madara

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