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Teriparatide or LY333334 Eli Lilly & Company NDA 21-318 Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory Committee Advisory Committee Bethesda,

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Presentation on theme: "Teriparatide or LY333334 Eli Lilly & Company NDA 21-318 Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory Committee Advisory Committee Bethesda,"— Presentation transcript:

1 Teriparatide or LY333334 Eli Lilly & Company NDA 21-318 Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory Committee Advisory Committee Bethesda, Maryland Bethesda, Maryland 27 July 2001 27 July 2001 Bruce V. Stadel, MD, MPH Bruce V. Stadel, MD, MPH Medical Safety Reviewer Medical Safety Reviewer Division of Metabolic-Endocrine Drug Products Division of Metabolic-Endocrine Drug Products Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory Committee Advisory Committee Bethesda, Maryland Bethesda, Maryland 27 July 2001 27 July 2001 Bruce V. Stadel, MD, MPH Bruce V. Stadel, MD, MPH Medical Safety Reviewer Medical Safety Reviewer Division of Metabolic-Endocrine Drug Products Division of Metabolic-Endocrine Drug Products Center for Drug Evaluation and Research

2 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 2 P-VALUE CAVEAT In analyses of efficacy, hypotheses are ordinarily specified in advance of a study, and the use of p-values is focused on testing the pre-specified hypotheses. In analyses of safety, there usually are no pre-specified hypotheses, but there is still a need to assess the data to identify potential areas of concern. P-values as a descriptive tool are useful for this, with the understanding that a p-value associated with a new safety finding does not have the same meaning as a p-value associated with either the testing of a pre-specified efficacy hypothesis or a previously observed safety finding. New safety findings from one study should generally be tested in other studies, before a decision is made regarding validity.

3 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 3 Issues from Preclinical & Phase 1 Clinical Studies Phase I clinical studies Hypotension & tachycardia Decreased RR & QT intervals Increased serum & urine calcium Preclinical studies Renal histopathology & malfunction Osteosarcoma Phase I clinical studies Hypotension & tachycardia Decreased RR & QT intervals Increased serum & urine calcium Preclinical studies Renal histopathology & malfunction Osteosarcoma

4 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 4 Main Phase 3 Clinical Trials Main Phase 3 Clinical Trials GHAC: 1637 postmenopausal women >1 vertebral fracture Placebo, 20 mcg, 40 mcg* GHAJ: 437 men Low bone mineral density Placebo, 20 mcg, 40 mcg* * 20 mcg or 40 mcg = LY333334 20 mcg or 40 mcg per day, by subcutaneous injection GHAC: 1637 postmenopausal women >1 vertebral fracture Placebo, 20 mcg, 40 mcg* GHAJ: 437 men Low bone mineral density Placebo, 20 mcg, 40 mcg* * 20 mcg or 40 mcg = LY333334 20 mcg or 40 mcg per day, by subcutaneous injection

5 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 5 Patient Disposition Numbers of Patients Randomized in Clinical Trials

6 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 6 Duration of Treatment Numbers of Patients Treated in Clinical Trials GHAC: 1394 (85%) of the women were treated with LY333334 or placebo for 13-23 months GHAJ: 381 (87%) of the men were treated LY333334 or placebo for 6-14 months GHAC: 1394 (85%) of the women were treated with LY333334 or placebo for 13-23 months GHAJ: 381 (87%) of the men were treated LY333334 or placebo for 6-14 months

7 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 7 Duration of Treatment Numbers of Patients Treated in Clinical Trials Duration of Treatment Numbers of Patients Treated in Clinical Trials 1452 Patients were treated with LY33334 for >3 months This provides 95% confidence for detecting an event which occurs once in 484 or fewer treated patients 1452 Patients were treated with LY33334 for >3 months This provides 95% confidence for detecting an event which occurs once in 484 or fewer treated patients

8 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 8 Serious Adverse Events Fatal or life-threatening Hospitalization or prolongation of hospitalization Severe or permanent disability Cancer Congenital abnormality Drug overdose Other Fatal or life-threatening Hospitalization or prolongation of hospitalization Severe or permanent disability Cancer Congenital abnormality Drug overdose Other

9 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 9 Serious Adverse Events During Clinical Trials Number (%) of Patients

10 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 10 Adverse Events of Any Severity During Clinical Trials

11 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 11 Heart Rate and Blood Pressure No differences between treatment groups in routine measurements LY333334 40 mcg versus placebo 1 hour after dosing mean increase = 5 beats/minute range = 68-104 for LY333334 47-100 for placebo Phase 4 commitment for 20 mcg data on heart rate, blood pressure, and ECG No differences between treatment groups in routine measurements LY333334 40 mcg versus placebo 1 hour after dosing mean increase = 5 beats/minute range = 68-104 for LY333334 47-100 for placebo Phase 4 commitment for 20 mcg data on heart rate, blood pressure, and ECG

12 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 12 4-hour Postdose Serum Calcium During GHAC LY333334 20 mcg versus placebo

13 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 13 4-hour Postdose Serum Calcium During GHAC LY333334 20 mcg versus placebo Number (%) of Patients

14 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 14 24 Hour Urine Calcium During GHAC LY333334 20 mcg versus placebo

15 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 15 Serum Total Alkaline Phosphatase During GHAC LY333334 20 mcg versus placebo Median increased 3.00-10.00 U/L (p<0.01) Frequency above upper limit of normal (131-174 U/L depending on age, race) LY333334 Placebo 20 mcg P-value 5 (1%) 8 (2%) 0.40 Median increased 3.00-10.00 U/L (p<0.01) Frequency above upper limit of normal (131-174 U/L depending on age, race) LY333334 Placebo 20 mcg P-value 5 (1%) 8 (2%) 0.40

16 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 16 Post-Treatment Follow-up Study GHBJ Numbers of Patients Enrolled From Clinical Trials

17 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 17 Serious Adverse Events in Post-treatment Follow-up Number (%) of Patients

18 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 18

19 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 19 Adverse Events of Any Severity in Post-treatment Follow-up GHAC Patients Enrolled in GHBJ Number (%) of Patients Cardiovascular Disorder*

20 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 20 Laboratory Safety Variables in Post-treatment Follow-up GHAC Patients Enrolled in GHBJ LY333334 20 mcg versus Placebo Laboratory Safety Variables in Post-treatment Follow-up GHAC Patients Enrolled in GHBJ LY333334 20 mcg versus Placebo Serum Creatinine Median increased 1.0 mcmol/L Frequency above upper limit of normal (101 mcmol/L) LY333334 Placebo 20 mcg P-value 7 (2%) 17 (4% ) 0.06 Range: (104-115) (104-137) Serum Creatinine Median increased 1.0 mcmol/L Frequency above upper limit of normal (101 mcmol/L) LY333334 Placebo 20 mcg P-value 7 (2%) 17 (4% ) 0.06 Range: (104-115) (104-137)

21 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 21 Osteosarcoma in U.S. Population Average annual incidence in Women and men >50 years of age is 4 cases per million per year, increasing at the older ages Total in U.S. = about 300 per year Occurrence similar by gender and race Average annual incidence in Women and men >50 years of age is 4 cases per million per year, increasing at the older ages Total in U.S. = about 300 per year Occurrence similar by gender and race

22 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 22 Osteosarcoma in Paget’s Disease Cumulative incidence in clinical series of patients with Paget’s Disease 1-5% Occurrence in Paget’s Disease patients is generally at >50 years of age Cumulative incidence in clinical series of patients with Paget’s Disease 1-5% Occurrence in Paget’s Disease patients is generally at >50 years of age

23 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 23 Paget’s Disease in U.S. Population NHANES* I (1971-75) 3936 anteroposterior x-rays of pelvic region Prevalence of Paget’s Disease about 1% in women and men >50 years of age, increasing with age Prevalence generally similar by gender and age *National Health and Nutrition Examination Survey NHANES* I (1971-75) 3936 anteroposterior x-rays of pelvic region Prevalence of Paget’s Disease about 1% in women and men >50 years of age, increasing with age Prevalence generally similar by gender and age *National Health and Nutrition Examination Survey

24 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 24 Paget’s Disease in Clinical Trial Population A 64 year old man was found to have Paget’s Disease of the pelvis 2 months after completing 13 months of treatment with LY333334 40 mcg in clinical trial GHAJ The diagnosis was by pelvic x-ray and bone scan. A bone scan shortly before enrollment in GHAJ did not show the disease although a very mild form cannot be ruled out The investigator called this possibly drug related; Lilly called it probably coincidental A 64 year old man was found to have Paget’s Disease of the pelvis 2 months after completing 13 months of treatment with LY333334 40 mcg in clinical trial GHAJ The diagnosis was by pelvic x-ray and bone scan. A bone scan shortly before enrollment in GHAJ did not show the disease although a very mild form cannot be ruled out The investigator called this possibly drug related; Lilly called it probably coincidental

25 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 25 Osteosarcoma Surveillance Post-treatment follow-up study GHBJ Drug use data and spontaneous adverse event reports Case-control study based on cases from referral centers and controls from residential areas of the cases Population-based case-control study using the SEER* system or other registry * Surveillance, Epidemiology, and End Results Post-treatment follow-up study GHBJ Drug use data and spontaneous adverse event reports Case-control study based on cases from referral centers and controls from residential areas of the cases Population-based case-control study using the SEER* system or other registry * Surveillance, Epidemiology, and End Results

26 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 26 Osteosarcoma Surveillance Attributable risk If incidence = 4/million/year, and relative risk = 3, then attributable risk =12-4 = 8/million If 250,000 people use drug, there would be 2 attributable cases per year Attributable risk If incidence = 4/million/year, and relative risk = 3, then attributable risk =12-4 = 8/million If 250,000 people use drug, there would be 2 attributable cases per year

27 Metabolic-Endocrine Drugs Advisory Committee 27 July 2001 27 AcknowledgementsAcknowledgements CDER Review Team Medical: Bruce S. Schneider, MD Bruce V. Stadel, MD, MPH Pharm/Tox: Gemma Kuijpers, PhD Statistics: Joy Mele, MS Biopharmaceutics: Jim Wei, PhD Sang Chung, PhD Chemistry: Yvonne Yang, PhD Project Management: Randy Hedin, RPh CDER Review Team Medical: Bruce S. Schneider, MD Bruce V. Stadel, MD, MPH Pharm/Tox: Gemma Kuijpers, PhD Statistics: Joy Mele, MS Biopharmaceutics: Jim Wei, PhD Sang Chung, PhD Chemistry: Yvonne Yang, PhD Project Management: Randy Hedin, RPh

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