# Presentation: 136975

## 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. **
**Division of Metabolic and Endocrine Products**

**Center for Drug Evaluation and Research**** **

## Outline

**Background**
**Studies reviewed**
**Efficacy considerations**
**Safety considerations **
**Conclusions**

## Background

## Definitions:  Overweight and Obesity

**Normal weight: BMI 18.5 – 24.9 kg/m****2**
**Overweight: BMI 25 – 29.9 kg/m****2**** **
**Obese: BMI **_**>**_** 30 kg/m****2**
**Morbidly obese: ****BMI **_**>**_** 40 kg/m****2**
**For this application:**
**Low overweight: ****BMI 25 – < 28 kg/m****2**
**High overweight: ****BMI 28 – 29.9 kg/m****2**** **

## Orlistat LabelNonprescription vs. Prescription

|  | Nonprescription
GSK | Prescription
Roche |
| --- | --- | --- |
| Indication | Promotion of weight loss when used along with a reduced calorie and low fat diet | Obesity management including weight loss, weight maintenance, and prevention of weight regain when used in conjunction with a reduced-calorie diet |
| Population | “Overweight” (defined by the consumer)
≥ 18 yo | Obese (BMI ≥ 30 kg/m2) or
BMI ≥ 27 kg/m2 + other risk factors (e.g., HTN, DM, dyslipidemia)
≥ 18 yo; 12-16 yo |
| Duration of use | Up to 6 mos | Chronic (clinical data up to 4 yrs) |
| Dose | 60 mg; 1-2 capsules TID | 120 mg TID |

## 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/m****2)**
**BMI ****≥ 27**** kg/m****2**** + comorbidities**
**	**

## 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**FDA *****1996 Draft Guidance for the Clinical Evaluation of Weight-Control Drugs***

## 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**

## Efficacy

## Efficacy Studies

- BM14149, NM14161 (BMI 28-43 kg/m2)

- NM17247
- (BMI 25-28 kg/m2)

- Placebo
- Orlistat 60 mg
- Orlistat 120 mg

- Placebo
- Orlistat 60 mg

## Efficacy Studies

| Study | BM14149 | NM14161 | NM17247 |
| --- | --- | --- | --- |
| N (ITT) | PLA           236
60 mg        239
120 mg      241 | PLA           212
60 mg        213
120 mg      210 | PLA        184
60 mg     194 |
| BMI | 28-43 kg/m2 | 30-43 kg/m2 | 25-28 kg/m2 |
| Population | High overweight and obese | Obese | Low overweight |
| Diet | 30% fat

(BMR x 1.3) - 600 kcal
Minimum allowable: 1200 kcal/d | 30% fat

< 90 kg: 1200 kcal/d
 ≥ 90 kg: 1500 kcal/d | 30% fat

< 90 kg: 1200 kcal/d (F), 1400 kcal/d (M)
≥ 90 kg: 1400 kcal/d (F), 1600 kcal/d (M) |
| Educational Program | Regular counseling by dietician; food records returned monthly | No counseling; self-instructional; videos; food records returned every 2  mos | Self-instructional; dietary review; food records returned monthly |

## Completion Rates

|  | 6 months |  | 4 months |
| --- | --- | --- | --- |
|  | Study BM14149 | Study NM14161 | Study NM17247 |
| Placebo | 76% | 73% | 72% |
| Orlistat 60 | 82% | 79% | 78% |
| Orlistat 120 | 83% | 80% | NA |

## % of Subjects by BMI Group

|  | < 28 kg/m2 | 28 - < 30 kg/m2 | ≥ 30 kg/m2 |
| --- | --- | --- | --- |
| BM14149
N = 729 | 2.5% | 13.2% | 84.4% |
| NM14161
N = 642 | 0% | 7.2% | 92.8% |
| NM17247
N = 391 | 89.3% | 10.7% | 0% |

## Categorical Weight Loss Results – LOCF

- *

- *

- *

- *

******* ****p < 0.05 vs. placebo**

## Weight Change from Baseline – LOCF

**PLA**

**60**

**120**

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**Wt change from baseline (kg)**

**PLA**

**60**

**120**

**PLA**

**60**

**BM14149 Mth 6**

**BM14149 Mth 6**

**NM14161 Mth 6**

**NM14161 Mth 6**

**NM17247 Mth 4**

**NM17247 Mth 4**

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

|  | BM14149
High overweight/obese 
Month 6 | NM14161
Obese
Month 6 | NM17247
Low overweight 
Month 4 |
| --- | --- | --- | --- |
| Pla vs 60 | -1.8 (-2.6, -1.0)  | -2.4 (-3.2, -1.6)  | -1.1 (-1.7, -0.5)  |
| Pla vs 120 | -2.1 (-2.9, -1.3) | -3.3 (-4.1, -2.5) |  |

## 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**
**2****nd**** year:**

## Pooled StudiesWeight Change Over 2 Years – Completers

## 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**

## Mean Body Weight Change During 2 Years of Double-Blind Treatment – Completers

**Adapted from:  Davidson, MH,  et al.  JAMA 1999;281:235-242**

## Randomized Trial of Lifestyle Modification and Pharmacotherapy for Obesity

**224 obese adults, 1 year, sibutramine**

|  | Type of Visit | No. of visits/duration | Diet/activity record review |
| --- | --- | --- | --- |
| Drug + Intensive Therapy | Primary care provider + 
weekly group meetings w/trained psychologist | 30 visits/90 min +
8 visits/10-15 min | yes |
| Drug + Brief Therapy | Primary care provider | 8 visits/10-15 min | yes |
| Intensive Therapy | Weekly group meetings w/trained psychologist | 30 visits/90 min | yes |
| Drug Alone | Primary care provider | 8 visits/10-15 min | no |

**Wadden TA, et al.  N Engl J Med 2005; 353:2111-20**

## 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**

## Safety

## 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**

## Pooled Safety Studies

| Study | BM14149 | NM14161 | NM14302 |
| --- | --- | --- | --- |
| N (ITT) | PLA           237
60 mg        239
120 mg      242 | PLA           212
60 mg        213
120 mg      210 | PLA        185
30 mg     186
60 mg     171
120 mg   180 |
| Design | 4-week lead-in; 1-year weight loss; 1-year weight maintenance | 4-week lead-in; 1-year weight loss; 1-year weight maintenance | 6-month lead-in (dietary weight loss); 1-year weight maintenance |
| Multivitamin | No | No | Yes |

## Safety Issues for Discussion

**Fat-soluble vitamins**
**Drug interactions**
**Pancreatitis**

## Study BM14149 (No MVI)Mean Change in Vitamin Concentrations Over Time

- *

- *

- *

- *

- *

- *

- * p < 0.001 vs. placebo

## Study NM14161 (No MVI)Mean Change in Vitamin Concentrations Over Time

- *

- *

- *

- *

- †

- * p < 0.05 vs. placebo; † p < 0.10 vs. placebo

## Study NM14302 (+ MVI)Mean Change in Vitamin Concentrations Over Time

- *

- *

- *

- *

- †

- * p < 0.05 vs. placebo; † p < 0.10 vs. placebo

- *

## Frequency of 2 Consecutive Plasma Vitamin Concentrations Below the Limit of the Reference Range after 1 Year of Treatment

|  | Placebo | Orlistat 60 | Orlistat 120 |
| --- | --- | --- | --- |
| Vitamin A | 0.5% | 1.0% | 1.8% |
| Vitamin D | 3.6% | 3.8% | 7.7% |
| Vitamin E | 0.5% | 4.1% | 3.9% |
| Beta-carotene | 0.5% | 1.9% | 5.4% |

- Rx NDA, 7 Phase 3 studies

## Drug InteractionWarfarin

**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 **

## Drug InteractionCyclosporine

**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**

## 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**

## Conclusions

## Efficacy ConclusionsDose 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**

## 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)**

## Efficacy Conclusions Duration and Lifestyle

**Weight regain after discontinuation of orlistat (JAMA paper)**
**Weight-loss drug more effective with lifestyle intervention (NEJM paper)**

## 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**

## Safety ConclusionsImportant 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**

## Safety ConclusionsPancreatitis: 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**

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

## 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**