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

Teriparatide or LY333334Teriparatide or LY333334Eli Lilly & CompanyEli Lilly & CompanyNDA 21-318NDA 21-318

Teriparatide or LY333334Teriparatide or LY333334Eli Lilly & CompanyEli Lilly & CompanyNDA 21-318NDA 21-318

Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory CommitteeAdvisory Committee Bethesda, Maryland Bethesda, Maryland 27 July 200127 July 2001

Bruce V. Stadel, MD, MPH Bruce V. Stadel, MD, MPH Medical Safety ReviewerMedical Safety Reviewer Division of Metabolic-Endocrine Drug ProductsDivision of Metabolic-Endocrine Drug Products

Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory CommitteeAdvisory Committee Bethesda, Maryland Bethesda, Maryland 27 July 200127 July 2001

Bruce V. Stadel, MD, MPH Bruce V. Stadel, MD, MPH Medical Safety ReviewerMedical Safety Reviewer Division of Metabolic-Endocrine Drug ProductsDivision of Metabolic-Endocrine Drug Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001

P-VALUE CAVEATP-VALUE CAVEATP-VALUE CAVEATP-VALUE CAVEATIn 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.


Issues from Preclinical & Phase 1 Clinical Studies

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


Main Phase 3 Clinical Trials Main Phase 3 Clinical Trials

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


Patient Disposition Patient Disposition Numbers of Patients Randomized in Numbers of Patients Randomized in

Clinical Trials Clinical Trials

Patient Disposition Patient Disposition Numbers of Patients Randomized in Numbers of Patients Randomized in

Clinical Trials Clinical Trials

LY333334Study Placebo 20 mcg 40 mcg

GHAC 544 541 552

GHAJ 147 151 139

Active ControlGHAF 125 122

GHAH 73 73


Duration of Treatment Duration of Treatment Numbers of Patients Numbers of Patients

Treated in Clinical Trials Treated in Clinical Trials


Treated in Clinical Trials 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



Treated in Clinical TrialsTreated in Clinical Trials


Treated in Clinical TrialsTreated 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


Serious Adverse EventsSerious Adverse EventsSerious Adverse EventsSerious 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


Serious Adverse Events Serious Adverse Events During Clinical Trials During Clinical Trials

Number (%) of PatientsNumber (%) of Patients

Serious Adverse Events Serious Adverse Events During Clinical Trials During Clinical Trials

Number (%) of PatientsNumber (%) of Patients LY333334Study Placebo 20 mcg 40 mcg P-value

GHAC 113 (21%) 93 (17%) 109 (20%) 0.31

GHAJ 16 (11%)

Active Control

15 (10%) 14 (10%) 0.96

GHAF 11 ( 9%) 13 (11%) 0.62

GHAH 9 (12%) 9 (12%) 1.00


Adverse Events of Any Severity Adverse Events of Any Severity During Clinical TrialsDuring Clinical Trials

Adverse Events of Any Severity Adverse Events of Any Severity During Clinical TrialsDuring Clinical Trials

LY333334Adverse Event 20 mcg 40 mcg

Back Pain

Nausea & Headache

Leg Cramps

Gout & Arthralgia

Urolithiasis

Dizziness, Syncope,& Vertigo * *

*Possible rare increase in severe dizziness


Heart Rate and Blood PressureHeart Rate and Blood PressureHeart Rate and Blood PressureHeart 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


4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo

4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo Median increased 0.08-0.12 mmol/L (p<0.01)

Frequency of hypercalcemia (>2.64 mmol/L) Number (%) of patients

LY333334 Placebo 20 mcg P-value

1 episode 7 (1%) 44 (8%)>2 episodes 1 (<1%) 16 (3%) <0.01

Hypercalcemia range = 2.65-2.89 mmol/L


4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placebo LY333334 20 mcg versus placebo


4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placebo LY333334 20 mcg versus placebo


Actiontaken

PlaceboLY33333420 mcg P-value

Calciumadjustment 3 (1%) 39 (7%) <0.01

Study drugadjustment 3 (1%) 15 (3%) <0.01

Studydiscontinued 1 (<1%) 1 (<1%) 1.00


24 Hour Urine Calcium 24 Hour Urine Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo

24 Hour Urine Calcium 24 Hour Urine Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo

Median increased 0.10-0.76 mmol (p<0.01)

Frequency of hypercalciuria (>7.5 mmol/24 hrs) Number (%) of patients


1 episode 101 (19%) 96 (18%)>2 episodes 14 ( 3%) 26 ( 5%) 0.46

Hypercalciuria range = 7.6-20.2 mmol/24 hrs


Serum Total Alkaline PhosphataseSerum Total Alkaline Phosphatase During GHAC During GHAC

LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo

Serum Total Alkaline PhosphataseSerum Total Alkaline Phosphatase During GHAC During GHAC

LY333334 20 mcg versus placeboLY333334 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)


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)


5 (1%) 8 (2%) 0.40


Post-Treatment Follow-up Post-Treatment Follow-up Study GHBJStudy GHBJ

Numbers of Patients Enrolled From Numbers of Patients Enrolled From Clinical Trials Clinical Trials

Post-Treatment Follow-up Post-Treatment Follow-up Study GHBJStudy GHBJ

Numbers of Patients Enrolled From Numbers of Patients Enrolled From Clinical Trials Clinical Trials

LY333334Study Placebo 20 mcg 40 mcg

GHAC 414 436 412

GHAJ 127 121 107

Active ControlGHAF 97 94

GHAH 53 52


Serious Adverse EventsSerious Adverse Events in Post-treatment Follow-up in Post-treatment Follow-up


Serious Adverse EventsSerious Adverse Events in Post-treatment Follow-up in Post-treatment Follow-up

Number (%) of PatientsNumber (%) of Patients LY333334Study Placebo 20 mcg 40 mcg P-value

GHAC 49 (12%) 73 (17%) 54 (13%) 0.10

GHAJ 11 (9%)

Active Control

19 (16%) 16 (15%) 0.20

GHAF 7 (7%) 1 (1%) 0.03

GHAH 4 (8%) 1 (2%) 0.18



Adverse Events of Any Severity Adverse Events of Any Severity in Post-treatment Follow-up in Post-treatment Follow-up

GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJNumber (%) of PatientsNumber (%) of Patients

Cardiovascular Disorder* Cardiovascular Disorder*

Adverse Events of Any Severity Adverse Events of Any Severity in Post-treatment Follow-up in Post-treatment Follow-up

GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJNumber (%) of PatientsNumber (%) of Patients

Cardiovascular Disorder* Cardiovascular Disorder* Placebo 20 mcg 40 mcg P-value

During trial 4 (1%) 9 (2%) 11 (3%)

In follow-up 7 (2%) 15 (3%) 20 (5%) Total 8 (2%) 17 (4%) 22 (5%) 0.03

*55% heart murmurs and valve disorders


Laboratory Safety Variables Laboratory Safety Variables in Post-treatment Follow-upin Post-treatment Follow-up

GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJLY333334 20 mcg versus PlaceboLY333334 20 mcg versus Placebo

Laboratory Safety Variables Laboratory Safety Variables in Post-treatment Follow-upin Post-treatment Follow-up

GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJLY333334 20 mcg versus PlaceboLY333334 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% ) 0.06Range: (104-115) (104-137)


OsteosarcomaOsteosarcomain U.S. Populationin U.S. Population OsteosarcomaOsteosarcomain U.S. Populationin 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


Osteosarcoma Osteosarcoma in Paget’s Diseasein Paget’s DiseaseOsteosarcoma Osteosarcoma in Paget’s Diseasein 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


Paget’s Disease Paget’s Disease in U.S. Populationin U.S. Population

Paget’s Disease Paget’s Disease in U.S. Populationin 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


Paget’s Disease Paget’s Disease in Clinical Trial Population in Clinical Trial Population

Paget’s Disease Paget’s Disease in Clinical Trial Population 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


Osteosarcoma Surveillance Osteosarcoma Surveillance Osteosarcoma Surveillance 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


Osteosarcoma SurveillanceOsteosarcoma SurveillanceOsteosarcoma SurveillanceOsteosarcoma 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


AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

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

Documents

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