# Presentation: 006021

## TERIPARATIDELilly Research Laboratories

**Endocrinologic and Metabolic Drugs Advisory Committee Meeting **
**Holiday Inn, Bethesda, Maryland**
**July 27, 2001**

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

## TERIPARATIDELilly Research Laboratories

**Preclinical Safety Evaluation**
**Gemma Kuijpers, Ph.D., Pharmacology Reviewer**
**Division of Metabolic and Endocrine Drug Products**

## Main Preclinical Issue

**Teriparatide causes bone neoplasms in the rat**

## Carcinogenicity Studies

**In vivo bioassay**
**Species: rat, mouse**
**Two year duration**
**Multiple dose groups**
**Histological tissue examination**
**Statistical analysis**
**Risk assessment**

## Carcinogenicity Study with Teriparatide

**Species: F344 rat**
**Duration: 2 Years**
**Doses: 0, 5, 30, 75 ********g/kg/day (****LD, MD, HD****)**
**60 animals/group**
**Bone sites examined**
**femur, tibia, sternum**
**vertebra**
**gross lesions**

## Teriparatide Causes Bone Neoplasms in the Rat Percent of animals with tumors

## Systemic Exposure to Teriparatide

## Incidence of Osteosarcomaby Multiple of Human AUC

**males**

**females**

**Incidence of Osteosarcoma****by Multiple of Human AUC**

**x**

**x**

**x**

## Sites of OsteosarcomaOrder of frequency

**Males**
**Tibia**
**Femur**
**Vertebra**
**Sternum**
**Rib**
**Skull**
**Humerus**
**Pelvis**

**Females**
**Vertebra**
**Femur**
**Rib**
**Tibia**
**Sternum**
**Pelvis**
**Skull**

##  Male Rats with Osteosarcoma Time of Death

## Female Rats with Osteosarcoma Time of Death

**Female Rats with Osteosarcoma ****Time of Death**

## Control Incidence of Osteosarcoma in F344 Rats

## Relative Risk of Osteosarcoma in Teriparatide-Treated Rats

## Effect of Teriparatide on Bone Mass (Female Rat)

**control**

**LD**

**Effect of Teriparatide on Bone Mass (Female Rat)**

**MD**

**HD**

## ConclusionsResults of 2-year rat study

**Teriparatide causes osteoblast neoplasms**
**Tumor induction is dependent on dose and treatment duration**
**No-effect-dose was not established**
**Teriparatide increases bone mass**

## Risk AssessmentHormonal Carcinogenesis

**Hormones are non-genotoxic tumor promotors**
**Mechanism of action is stimulation  of cell proliferation**

## Teriparatide-Induced Rat Bone Tumors

**Plausible mechanism:**
**Stimulation of osteoblast proliferation**
**Increased chance of neoplastic transformation**

## Clinical Relevance of Rat Bone Tumor Finding

**Mechanism of action operative in humans?**
**Clinical relevance of rodent bone tumors unclear**

## Further Considerations on Clinical Relevance of Tumor Finding

**Validity of rat model**
**Monkey pharmacology study**
**Hyperparathyroidism**

## Validity of Rat Model

**Different from humans**
**Age of animals at start of treatment**
**Prolonged treatment duration**
**Extent of skeletal response**

## Validity of Rat Model

**Similar to humans**
**Increased bone formation and bone mass**
**Osteoblast response to intermittent PTH receptor occupation**

## Follow-up Animal Studies

**Rat Study **
**Variables**
**animal age at start of treatment (2-6 mo) **
**duration of treatment (6-24 mo)**
**Monkey Study**
**18-month treatment**
**3 year follow-up**

## Conclusions

**The clinical relevance of the rat bone neoplasms induced by teriparatide is unclear**
**There is a potential increase in the risk for bone neoplasms in humans treated with teriparatide**