# Presentation: 660823

## Teriparatide or LY333334Eli Lilly & CompanyNDA 21-318 

**  ****Metabolic-Endocrine Drugs **
**  ****Advisory Committee**** **
**   ****Bethesda, Maryland  **
**   ****27 July 2001**
**  ****Bruce V. Stadel, MD, MPH **
**  ****Medical Safety Reviewer**
**   ****Division of Metabolic-Endocrine Drug Products**

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

**Notes:**
GENERAL AGREEMENT WITH SPONSOR ABOUT  SAFETY FINDINGS IN CLINCAL TRIALS

TWO PURPOSES:

       BRIEFLY REVIEW TRIALS

       DISCUSS THE POTENTIAL FOR OSTEOSARCOMA 
       SURVEILLANCE

## 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.**

## 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**

**Notes:**
PHASE 1  CLINCAL STUDIES
       175 HEALTHY AND 31 CHRONIC RENAL PATIENTS,
               659 DOSES, 5-100 MCG
       ADDED 49 HEALTHY  AND 13 CHF PATIENTS,  20 MCG

       TOTAL ECGs AT  20 MCG = 91 HEALTHY AND 13 CHF
              PATIENTS, AFTER 1 DOSE
       NO ECGs AFTER REPEAT DOSING OR IN PHASE 2/3
              CLINICAL TRIALS

PRECLINICAL STUDIES
       RENAL HISTOPATHOLOGY IN  MONKEYS
       2-40 MCG/KG FOR 3 MONTHS
       0.5-10 MG/KG FOR 1 YEAR

OSTEOSARCOMA IN RATS
       5-75 MCG/KG FOR 2 YEARS

##  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**

## Patient Disposition Numbers of Patients Randomized in Clinical Trials 

## 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**

## 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 **

## Serious Adverse Events

**Fatal or life-threatening**
**Hospitalization or prolongation of hospitalization**
**Severe or permanent disability**
**Cancer **
**Congenital abnormality**
**Drug overdose**
**Other**

## Serious Adverse Events                    During Clinical Trials                    Number (%) of Patients

## Adverse Events of Any Severity  During Clinical Trials

## 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**

**Notes:**
GHAM: POSTMENOPAUSAL WOMEN RANDOMIZED TO 

HRT+LY 40 MCG                       6
HRT+INJ PLBO                           7
RALOX+LY 40 MCG                 4
RALOX+INJ PLBO                     7
ORAL PLBO+LY 40 MCG          7
ORAL PLBO+ INJ PLBO             5

TOTAL                                      36

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

## 4-hour Postdose Serum Calcium  During GHAC                                       LY333334 20 mcg versus placebo Number (%) of Patients

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

## 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**

**Notes:**
LY333334 TREATEMENT MAY NOT PRECLUDE THE USE
OF SERUM TOTAL ALKALINE PHOSPHATASE IN 
MONITORING FOR PAGET’S DISEASE OR OTHER 
BONE DISORDERS WHICH LEAD TO INCREASES

## Post-Treatment Follow-up Study GHBJ Numbers  of Patients Enrolled From Clinical Trials 

## Serious Adverse Events in Post-treatment Follow-up Number (%) of Patients

## Slide 18

**Notes:**
AGE CONFOUNDING

## Adverse Events of Any Severity in Post-treatment Follow-up GHAC Patients Enrolled in GHBJNumber (%) of Patients Cardiovascular Disorder*

##   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)         **

**Notes:**

                       PLACEBO    20 MCG    20 MCG 
          GHAC        7                17              16
          GHAJ         3                  6                6
                           10                23              22  =  55

4 DEATHS: 1 IN 20 MCG, 3 IN 40 MCG -- INCLUDED
                  IN DEATH ANALYSES 

18 FOLLOW-UP CREATININES: 

       7 DECREASED:    PLACEBO=1, 20 MCG=3, 40 MCG=3
       4 UNCHANGED: PLACEBO=1, 20 MCG=1, 40 MCG=2       
       7 INCREASED:     PLACEBO=3, 20 MCG=4, 40 MCG=0

## 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          **
**          **
**           **

**Notes:**
STUDIES TERMINATED IN 1998

## 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**

## 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**

**Notes:**
PREVALENCE MAY HAVE DECREASED SINCE NHANES I

## 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**

## 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**

**Notes:**
    WOULD TAKE SEVERAL YEARS

## 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**

## Acknowledgements

**              ****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**