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Teriparatide Injection

(rDNA origin)FDA Advisory Committee Meeting

Bethesda, MarylandJuly 27, 2001

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FortoTeriparatide Injection

(rDNA origin)

Jennifer L. Stotka, MD

Executive Director, RegulatoryAffairs

Eli Lilly and Company

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Teriparatide Injection (rDNA origin)

First clinically useful bone formation agent activates osteoblasts and stimulates

formation of new bone unique mechanism of action compared to

antiresorptive agents

NDA submitted in November 2000 clinical trials enrolled over 2800 women and

men

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Regulatory History

Aug 1995 IND submission

Dec 1998 Finding of osteosarcoma in long-term rat study. All clinical trialsbrought to early closure

April 1999 Submitted recommendations of theOncology Advisory Board to the FDA

May 1999 Initiated observational study for patientspreviously enrolled in teriparatide trials

Dec 1996 Pivotal trial in women - Study GHAC

July 1997 Pivotal trial in men - Study GHAJ

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Regulatory History

FDA meeting: Lilly, FDA and externalconsultants

Sept 1999 FDA meeting: Agreement on data

package for NDA

July 2000 FDA meeting: Pre-NDA meeting

Nov 2000 NDA submission

March 2001 4-month safety update

July 1999

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Summary and Conclusions

Lilly Advisory Committee PresentationForto

Teriparatide Injection (rDNA origin)

Introduction

History, Mechanism ofAction, and Clinical Need

Nonclinical Overview

Clinical Efficacy

Clinical Safety

Jennifer L. Stotka, MD

John L. Vahle, DVM,PhD, DACVP

Robert Lindsay, MD, PhD

Bruce H. Mitlak, MD

Gregory A. Gaich, MD

Bruce H. Mitlak, MD

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External ConsultantsRichard Adamson, Ph.D.

Vice President for Scientific andTechnical Affairs

NSDA(Former Division Director, Cancer

Etiology, and Scientific Director,National Cancer Institute)

Bruce A. Chabner, M.D.Professor of Medicine, ChiefHematology/OncologyMassachusetts General Hospital

(Former Division Director,Division of Cancer Treatment,

National Cancer Institute)

Robert Lindsay, M.D., Ph.D.Professor of Clinical Medicine

Columbia University College ofPhysicians and Surgeons

Chief of Internal Medicine, HelenHayes Hospital

Robert Neer, M.D.Associate Professor of Medicine,

Harvard Medical SchoolDirector of MassachusettsGeneral Hospital OsteoporosisCenter

Director of Research

Massachusetts GeneralHospital

John T. Potts, M.D.

Andrew F. Stewart, M.D.Professor of MedicineChief, Division of Endocrinology

University of Pittsburgh MedicalCenter

Professor of Medicine andPharmacology

Chief, Division of EndocrinologyCollege of Physicians andSurgeons, Columbia University

John P. Bilezikian, M.D.

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History, Mechanism ofAction, and Clinical Need

Robert Lindsay, MD, PhDProfessor of MedicineColumbia University

Chief, Internal MedicineHelen Hayes Hospital

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Chronology of Advances inPTH Research

1880-1925 Glands discoveredFunction debated

Active gland extract purifiedCalcium regulation established

1925

1929 Bone mass increase in rats

1970s Hormone structure and synthesisBone anabolic effects animals confirmedHuman clinical trials in osteoporosis

Present Striking clinical benefit in osteoporosisestablished

1980 First clinical trial published(Reeve, Meunier, Parsons, et al.)

/ / / /

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%Changefrom

Invest/Yr N*CombinationTreatments

DurationBaseline

(Months) LS Hip

Lindsay, 1997 17 HRT 36 13** 3**

Hodsman, 1997 14 --- 24 10** 2

Roe, 1999 37 HRT 24 29** 9**

Lane, 1998 28 HRT/GC 12 11** 2

*N=number entering PTH treatment group **P 0.05.Total hip. Femoral neck. Cyclic, for 1 month every 3 months.

Kurland, 2000 23 --- 18 13** 3**

Cosman, 2001 27 HRT 36 13** 4**

Effects of PTH(1-34) on Bone Mineral Densityin Postmenopausal Women and in Men

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n n n n n n n

B 6 12 18 24 30 36 -3

0

3

6

9

12

15

L u m

b a r

S p

i n e B

M D ( %

c h a n g e

)

Time (months)

PTH+HRT

n HRT

Cosman, et al JBMR 2001

Change in Lumbar Spine BMD

*

*

*

*

* *

P

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n

n n n n

n

n

B 6 12 18 24 30 36 -0.5 0.0

1.0

2.0

3.0

4.0

5.0

Time (months)

PTH+HRT

n HRT

Cosman, et al. JBMR 2001

Change in Total Hip BMD

*

*

*

P

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Effect of PTH + HRT vs. HRT Alone

on Vertebral Fractures at 3 Years

0

10

20

30

40

HRT PTH+HRT

P=0.020 Cosman, et al JBMR 2001

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Response to PTH(1-34)

Histomorphometry After 4 Weeks

Static variables:Control PTH

Osteoid surface 11.5 26.5

Osteoblast surface 14.9 22.7

Dynamic variable:

Bone formation rate 11.0 31.0

Hodsman, Bone 2000

*

*

P

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0 1 2 3 4 5 6 0

10

20

30

40

50

60

70

80

M e a n

% c h a n g e

i n t u r n o v e r m a r k e r

Time (months)

N-telopeptide

Osteocalcin

Lindsay et al, Lancet 1997

Early Changes in Biochemical Markersin Women with Osteoporosis on

PTH(1-34)

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Bone Structure: 3-D

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64 Year-Old Woman (M H)Before PTH(1-34)

After PTH(1-34) Ct.Th: 0.32 mmCD: 2.9/mm 3

Ct.Th: 0.42 mmCD: 4.6/mm 3

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Clinical Need for New

Osteoporosis Treatment

While current treatments reducefracture risk and allay bone loss,many patients remain at significantfracture risk

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Limitations of Current Therapies:Many Patients Remain at

Significant Risk Current antiresorptive therapies reduce

fracture risk

Current treatments are unable to restorebone matrix or architecture

Unmet medical need persists

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Conclusion

Teriparatide [rhPTH(1-34)]reduces fracture risk by aunique mechanism, thatpromises much for

patients with osteoporosis

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NonclinicalOverview

John Vahle, DVM, PhD, DACVPSenior Research PathologistLilly Research Laboratories

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Nonclinical Overview

Skeletal effects monkey

Nonclinical safety animal toxicity studies 2-year rat study

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Control Teriparatide

Teriparatide Increases Bone Mass andImproves Architecture in Ovariectomized

Monkeys

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Cortical Bone Quality is Normal in

Monkeys Treated with Teriparatide Cortical bone mass maintained Enhanced cortical remodeling

increased endocortical porosity increased cortical area and thickness

Increased resistance to fracture

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Nonclinical Safety

Monkey and rat chronic toxicity studies primary effects related to pharmacology

renal histological alterations in monkeys

Monkey pharmacology study

no renal histological alterations

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Comparison ofCynomolgus Monkey Models

Toxicology StudiesRenal Alterations

2.5 year old juveniles

Intact males & females Daily calcium intake

175 mg/kg/day Doses: 0.5 to 40 g/kg

3 to 12 monthstreatment Blood ionized calcium

Increased up to 50%

Pharmacology Study No Renal Alterations

9 to 11 year old adults

Ovariectomized females Daily calcium intake

75 mg/kg/day Doses: 1 or 5 g/kg

18 months treatment

Blood ionized calcium not measured

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Nonclinical Safety

Not genotoxic

2-year rat study exaggerated skeletal effects bone proliferative lesions no increase in soft tissue neoplasms

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Control 5 g/kg

30 g/kg 75 g/kg

Exaggerated Increases in Bone Mass2-year Rat Study

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Diaphysis

Systemic Exposure to Teriparatide (AUC, ng-hr/mL)

0.0 0.5 1.0 1.5 2.0 2.5

BMC(% AboveControl)

0

10

20

30

40

50Vertebra

0.0 0.5 1.0 1.5 2.0 2.5

0

10

20

30

40

50

OP Women

OP Women

RatsRats

Monkeys

Monkeys

Rat Skeleton Has An ExaggeratedResponse To Teriparatide Treatment

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Dose Group (g/kg/day)

Finding Sex 0 5 30 75

Osteosarcoma Male 0 3 21 31 Female 0 4 12 23

Osteoma Male 0 0 2 1 Female 0 0 0 1

Osteoblastoma Male 0 0 2 7 Female 0 1 1 3

Focal OsteoblastHyperplasia

Male 0 1 2 4 Female 0 2 1 3

Metastases Male 0 0 10 17 Female 0 1 2 4

2-Year Rat StudyIncidence of Bone Proliferative Lesions (n=60/sex/group)

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Profound increases in bone mass Bone proliferative lesions No increases in soft tissue neoplasms

Important Findings2-Year Rat Study

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Rat Findings are Unlikely to be Predictive of anIncreased Risk of Osteosarcoma in Humans Treated

with Teriparatide for Osteoporosis

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Exaggerated skeletal response in rat near-lifetime duration of exposure differences in skeletal biology compared to humans

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Teriparatide is not genotoxic Chronic hormonal stimulation can induce tumors

in rats that are not relevant to human safety

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No bone tumors in the 18-month pharmacologystudy in monkeys

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No bone tumors in the 18-month pharmacologystudy in monkeys

In humans, hyperparathyroidism is not associatedwith an increased risk of bone neoplasia

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Nonclinical Conclusions Teriparatide stimulated bone formation

increased bone mass improved microarchitecture increased resistance to fracture maintenance of cortical bone quality

Important effects in toxicity studies primarilyrelated to known pharmacologic effects of

teriparatide Bone proliferative lesions in rats are unlikely

to be predictive of an increased risk in

humans

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Clinical Efficacy

Bruce H. Mitlak, MD

Medical DirectorLilly Research Laboratories

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GHAC Effects of Teriparatide in the Treatment ofPostmenopausal Women with Osteoporosis

GHAJ Effects of Teriparatide in the Treatment of Menwith Osteoporosis

GHAF Effects of Teriparatide in PostmenopausalWomen on Estrogen and Progestin Therapy

GHAH Teriparatide Compared with Alendronate inPostmenopausal Women with Osteoporosis

GHBJ Observational Follow-up of Patients in

Teriparatide Trials

Teriparatide Clinical Trials

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GHAC - 1637 women21 months

GHAJ - 437 men12 months

Treatment endpoint

GHBJ

Teriparatide Treatment Trialsand Follow-up

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Pivotal Trial in Women

Study GHAC

Prospective, randomized, double-blind trialperformed at 99 sites in 17 countries

1637 postmenopausal women with a prevalentvertebral fracture

Primary endpoint: Proportion of women withone or more new vertebral fractures

Teriparatide 20 g, 40 g, or placebo by oncedaily self-injection

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Baseline Characteristics - GHAC

Age (years SD)

Years postmenopausal (SD)

Previous OP therapy

Spine sBMD (mg/cm 2) (SD)

Spine T-score

Vertebral fractures1

2

PlaceboN = 544

69 7

21 9

15%

821 172

-2.6

28%

62%

PTH20N = 541

70 7

21 9

16%

820 167

-2.6

31%

60%

PTH40N = 552

70 7

22 8

13%

821 172

-2.6

32%

58%

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100

150

200

250

N u m

b e r o f

w o m e n

Months completed

Placebo PTH20 PTH40

0

50

0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27

Duration of Study GHAC(From randomization to last radiograph)

l f

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Semiquantitative Evaluation ofVertebral Fractures

Grade0

1

2

3

Normal

Anterior Posterior

Anterior

Anterior

Posterior

PosteriorSevere

Anterior

Middle

Posterior

Genant et al. JBMR, 1993

Moderate

Mild

i id d h i k

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0

2

4 6

8

10

12

14

16

Placebo

PTH20

PTH40

% o

f w o m e n w

i t h

1 f r a c

t u r e

*P

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Teriparatide Reduced the Risk of Moderateand Severe Vertebral Fractures - GHAC

RR 0.10 (0.04, 0.27) *

RR 0.22 (0.11, 0.45) *

2

0

4

6

8

10

12

14

16

Placebo PTH20 PTH40 *P

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Teriparatide Reduced the Risk ofMultiple Vertebral Fractures - GHAC

Placebo

PTH20

PTH40

% w

o m e n w

i t h

2 f r a c

t u r e s

0

2

4

6

8

10

12

14

16

RR 0.23 (0.09, 0.60) *

RR 0.14 (0.04, 0.47) *

22 5 3

*P

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Placebo

PTH20 PTH40

*

*P 0.015

All Radius/Wrist

Ribs Humerus Hip Pelvis Other0

6

5

4

3

2

1

* RR 0.46 (0.25, 0.86)RR 0.47 (0.25, 0.88)

Teriparatide Reduced NonvertebralFragility Fractures - GHAC

Foot/Ankle

Time to First Nonvertebral

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LOG-RANK p-value = 0.014 WILCOXON p-value =LOG-RANK p-value = 0.014 WILCOXON p-value =LOG-RANK p-value = 0.014 WILCOXON p-value =LOG-RANK p-value = WILCOXON p-value =LOG-RANK p-value = WILCOXON p-value = 0.032

Months since randomization

PlaceboPTH20PTH40

0 3 15 18 21 9 12 6

*P

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Months

% c

h a n g e

S E

02

4

6

8

10

12

1416

0 6 12 243

**

*

* *

**

*P

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Months*

P

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Placebo PTH20

PTH40

2

Months

- 4

- 3

- 2

- 1

0

1

2

0 6 12 18 24

Ultradistal Radial Shaft

- 4

- 3

- 2

- 1

0

1

0 6 12 18 24

* *

*P

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Placebo PTH20 PTH40

%

c h a n g e

S E

*P

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Histologically Normal Bone

Study GHAC

Baseline Endpoint

Patient 113120 g/day

Patient 1234

40 g/dayTBV 12% TBV 18%

TBV 20% TBV 22%

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Pivotal Trial in Women

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Pivotal Trial in WomenGHAC Summary

Treatment with teriparatide 20 g and 40 g: Reduced the risk of vertebral fractures by 65% and 69%

Reduced the risk of nonvertebral fragility fractures

by 53% and 54% Fracture risk reduction was similar for each dose

Increased BMD at the spine and hip, but not the forearm

Increased total body bone mineral

Improved bone microarchitecture

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Pivotal Trial in MenStudy GHAJ

Prospective randomized trial performed at 34sites in 11 countries

437 men with idiopathic or hypogonadalosteoporosis (spine or hip T-score < -2 SD)

Primary endpoint: Change in spine BMD Teriparatide 20 g/day, 40 g/day, or placebo by

once-daily self-injection

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Baseline Characteristics - GHAJ

PlaceboN = 147

PTH20 N = 151

PTH40 N = 139

Age ( years SD) 59 13 59 13 58 13

Lumbar spine

Prior osteoporosistreatment

12% 15% 18%

-2.4 -2.0 -2.2

Femoral Neck

Total Hip

-2.7 -2.6 -2.7

-1.9 -1.8 -1.9

T-score

Duration of Study GHAJ

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Duration of Study GHAJ (From randomization to last BMD)

Months Completed

0

10

20

30

40

50

60

70

0-2 3-5 6-8 9-11 12-14 15-17

N u m

b e r o

f p a

t i e n

t s

Placebo PTH 20 PTH 40

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Months

% c

h a n g

e S E

10

12

*

0

2

4

6

8

0 3 6

*

**

* *

Endpoint

9

Placebo PTH20

PTH40

*P

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%

c h a n g e

S E

Placebo PTH20 PTH40 0

1

2

3

*

*

0

1

2

3

Total Hip Femoral Neck4 4

Placebo PTH20 PTH40

*P

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Placebo PTH20 PTH40

% c h

a n g e

i n B M

C S E

0

-1

1

2

3

* *

*P

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Change in Spine BMD for Women

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Time (Months)

0 3 6 9 12 15 18

0.0

0.02

0.04

0.06

0.08

0.10

0.12

C h a n g e

i n S p

i n e

B M D ( g / c m

) Women Men

g p Wand Men - GHAC and GHAJ

Teriparatide 20 g

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Efficacy Summary

Treatment with teriparatide 20 g and 40 g :

Significantly reduced the risk of vertebral

and nonvertebral fractures in postmenopausalwomen. The reduction was similar for each dose.

Rapidly and significantly increased bone densityin postmenopausal women and in men.

Improves bone microarchitecture.

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Clinical Safety

Gregory A. Gaich, MDSenior Clinical Research Physician

Lilly Research Laboratories

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Overview

Overall safety experience Clinical and laboratory evaluations in

postmenopausal women Follow-up observational study Clinical and laboratory evaluations in men Drug interaction studies and special

populations

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Total Experience and Exposure

25 clinical trials Over 2800 women and men enrolled 1943 participants received teriparatide Doses

5 to 100 g in short-term trials 20 and 40 g in long-term trials

Total exposure 1967 patient-years

Overall Clinical Safety

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Overall Clinical SafetyPivotal Trials in Women and in Men

Studies GHAC and GHAJPlaceboN = 691

n (%)

PTH20 N = 692

n (%)

PTH40N = 691

n (%)

1 Adverseevent

1 Seriousadverse event

585 (85) 568 (82) 588 (85)

129 (19) 108 (16) 123 (18)

Deaths 4 (0.6) 8 (1.2) 6 (0.9)

Cancer 19 (2.7) 10 (1.4) 6 (0.9) *

*P

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Clinical Safety Evaluations

Study GHAC

T R l d Eff

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Treatment-Related EffectsGHAC

PlaceboN = 544

n (%)

PTH20 N = 541

n (%)

PTH40N = 552

n (%)

Leg cramps 6 (1.1) 17 (3.1) * 13 (2.4)

Headache 45 (8.3) 44 (8.1) 72 (13) *

Nausea 41 (7.5) 51 (9.4) 98 (18)

Back pain 123 (23) 91 (17) * 87 (16)

*P< 0.05 P< 0.01

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Pharmacokinetic and Safety

Laboratory EvaluationsStudy GHAC

Teriparatide 20 g Pharmacokinetics

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p gGHAC

T e r i p a r a

t i d e c o n c e n

t r a

t i o n

( p m

o l / L )

Upper Limit of NormalEndogenous PTH(1-84)

0 24 3 9 18 21 15 12 0

10

20

30

40

50 60

70

Time (Hours) 6

Pharmacologic Effect: Transient Increase

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in Serum Calcium - GHAC

Time Since Last Dose (Hours)

0 4 8 12 16 20 24

0

50

100

150

200

250

T e r i p a r t

i d e

C o n c e n

t r a

t i o n

( p g

/ m L ) Teriparatide (20 g)

Concentrations

Serum Calcium Concentrations

2.0

2.2

2.4

2.6

2.8

S e r u m

C a

l c i u m

C o n c e n

t r a

t i o n

( m m o

l / L )

ULN SCa 10.5 mg/dL

Postdose Effects on Serum Calcium

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are Small and Transient - GHAC

20 g/day teriparatide median postdose serum calcium 0.3 to 0.5 mg/dL

higher than placebo 97% never exceeded 11 mg/dL at any visit 8% had a single high serum calcium ( 10.5 mg/dL) 3% had high 4-6 hour postdose serum calcium

on 2 consecutive visits 40 g/day teriparatide

median postdose serum calcium 0.5 to 0.7 mg/dLhigher than placebo

Not associated with clinical adverse events

Pharmacologic Effect:

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gPredose Serum Calcium - GHAC

LLN

ULN

Months0 3 6 9 12 15 18

2.0

2.1

2.2

2.32.4

2.5

2.62.7

*

* P

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Serum and Urinary Calcium

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ySummary - GHAC

Transient increase in serum calcium magnitude of transient increase in serum calcium

is small - 0.3 to 0.5 mg/dL duration is brief - serum calcium returns to

baseline prior to next dose Small increase in 24-hour urinary calcium

excretion median 30 mg/day

No clinical adverse events associated withincreases in serum or urine calcium

Monitoring serum or urine calcium is not

necessary

Pharmacologic Effect:

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* P

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Incidence of Gout or ArthralgiaWas Not Increased - GHAC

PlaceboN = 544

n (%)

PTH20N = 541

n (%)

PTH40N = 552

n (%)

Gout

Arthralgia

1 Elevatedserum uric acid

3 (0.6)

56 (10) 49 (8.9)

4 (0.7) 15 (2.8) * 27 (5.0)

1 (0.2) 2 (0.4)

49 (9.0)

*P

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Cardiovascular disease

Hypertension Peptic ulcer disease Renal insufficiency Urolithiasis

No Significant Increase in ConditionsAssociated with Hyperparathyroidism

Study GHAC

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No Adverse Effects on the KidneyStudy GHAC

No significant effects on:

urolithiasis or related terms serum creatinine measured creatinine clearance routine urinalysis

Hemodynamic Evaluations

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Hemodynamic EvaluationsTeriparatide 20 g

Clinical pharmacology studies small increase (3-5 bpm) in postdose heart rate no QTc prolongation

no significant effect on supine or standing bloodpressure one subject (out of 104) had documented and

symptomatic postural hypotension

Phase 3 studies no difference in postural hypotension no difference in sitting blood pressure or pulse rate

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Clinical and Laboratory EffectsAfter Discontinuation of

TreatmentStudy GHAC-GHBJ

Ongoing Follow-up Study

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GHAC

GHAJ 30 months

39 months1262 women

355 men

Cumulativeobservation

GHBJ

Ongoing Follow-up StudyGHBJ

Clinical and Laboratory Effects

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Clinical and Laboratory EffectsAfter Discontinuation of Treatment

Study GHAC-GHBJ By Visit 1 (~6 months after GHAC last visit)

clinical and laboratory effects resolved serum uric acid remained slightly (

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Clinical and Laboratory EffectsAfter Discontinuation of Treatment

Study GHAC-GHBJ By Visit 2 (through 18 months after GHAC

last visit) no new clinically significant safety findings no increase in:

cancer

urolithiasis gout or arthralgia

lower incidence of new or worsened backpain

No Increase in Nonvertebral Fracturesf f

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Months since randomization

After Discontinuation of Treatment (GHAC-GHBJ)

0 24 27 30 33 36 39181512963 210

12

10

8

6

4

2

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Treatment of Osteoporosis

in Men

Study GHAJ

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Clinical and Laboratory SafetyEvaluations - GHAJ

PlaceboN = 147

n (%)

PTH20N = 151

n (%)

PTH40N = 139

n (%)

1 High serum Ca 0 9 (6.0) 22 (16) High serum Ca on 2

consecutive tests0 2 (1.3) 8 (5.8)

Nausea 5 (3.4) 8 (5.3) 26 (19)

Headache 6 (4.1) 8 (5.3) 15 (11) * Leg cramps 3 (2.0) 1 (0.7) 1 (0.7)

Discontinued due to AE 7 (4.8) 14 (9.3) 18 (13) *

*P

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in Women and in Men

Studies GHAC and GHAJ Time to peak concentration and half-life

similar in men and women

Serum concentrations of teriparatide20-30% lower in men than in women Same effects on spine and hip BMD Same effects on serum and urinary

calcium and other laboratory endpoints Same effects on clinical adverse events

Vertebral Fracture Incidence in Men

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During Treatment and Follow-Up (GHAJ-GHBJ)

0

2

4

6

8

10

12

14

% o

f m e n w

i t h v e r t e b r a

l f r a c

t u r e Placebo

PTH20PTH40

12 5 5 7 1 1Fractures Moderate/Severe Fractures

No Clinically Significant

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No Clinically SignificantPharmacokinetic or Safety Issues

in Special Populations Studied

Geriatric patients Subjects with renal insufficiency Subjects with mild to moderate heart

failure Subjects with hypertension

N Cli i ll Si ifi

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No Clinically SignificantDrug Interactions

Hydrochlorothiazide Furosemide Calcium channel blockers Atenolol Digoxin

Hormone replacement therapy Raloxifene

S f S

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Safety SummaryPivotal Phase 3 Trials

Clinical effects leg cramps and nausea in 20 g group 40 g more likely to cause headache, nausea,

and discontinuation due to adverse event no increase in symptomatic postural

hypotension in either 20 or 40 g groups lower incidence of new or worsened back pain

in both 20 and 40 g groups

S f S

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Safety SummaryPivotal Phase 3 Trials

Laboratory effects expected transient effect on serum calcium expected pharmacologic effects on urinary

calcium and serum uric acid not associated with adverse clinical effects

40 g was more likely to cause increasedserum calcium and uric acid

Safety Summaryll d

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Post-treatment Follow-up StudyGHBJ

By 6 months nausea, headache, and leg cramps resolved laboratory effects resolved, except for small

increase in uric acid Through 18 months

no new clinically significant adverse effects no increase in the incidence of cancer,

urolithiasis, gout and arthralgia no increase in the rate of nonvertebral fracture significant reduction in back pain maintained

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Safety Conclusions

Teriparatide 20 and 40 g/day were safeand well-tolerated in postmenopausalwomen and in men with osteoporosis

Routine laboratory monitoring is notnecessary Restrictions or monitoring in special

populations studied are not necessary Significant drug interactions not observed Teriparatide 20 g/day was associated

with fewer adverse effects

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TeriparatideSummary and Conclusions

Bruce H. Mitlak, MDMedical Director

Lilly Research Laboratories

PTH Oncology Board

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Dr. Bruce Chabner Chief, Hematology/Oncology, Mass. General Hospital(Chair) Former Division Director, Cancer Therapeutics, NCI

Dr. Richard Adamson Vice President for Scientific and Technical Affairs, NSDAFormer Division Director, Cancer Etiology, and ScientificDirector, National Cancer Institute

Dr. Karen Antman Chief, Medical Oncology, Columbia University

Dr. Brian Henderson Prof. of Preventive Medicine, University Southern Calif.

Dr. Christopher Fletcher Director Surgical Pathology, Brigham & Womens Hospital

Dr. A. Kevin Raymond Associate Professor of Pathology, MD Anderson Hospital

Dr. Henry Kronenberg Chief, Endocrine Unit, Massachusetts General Hospital

Dr. Samuel Doppelt Chief, Department of Orthopedics, Cambridge Hospital

PTH Oncology Board Summary

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"Based on current information, the findings in the rat study

were unlikely to predict for the development of bonetumors in patients who had received teriparatide in clinicaltrials." This conclusion was reached with consideration ofthe following:

The lifetime duration of treatment in the rats compared with therelatively brief exposure in humans

The fact that treatment was initiated during the rapid growthphase of the animals

The difference in rat and human bone biology and response toPTH

The lack of clinical association between hyperparathyroidismand osteosarcoma in humans

gy y

Additional Considerations RegardingR t O t Fi di g

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Rat Osteosarcoma Findings

No skeletal lesions were observed in an 18-monthstudy in monkeys that had approximately4 - 8 times the exposure as in the Phase 3 trials

The lack of clinical association betweenhyperparathyroidism and osteosarcoma Survey of national cancer registry in Sweden

Experience with our study patients and otherpatients treated with teriparatide

It is unlikely that the findings in the long-term rodent studypredict a risk in women or in men receiving teriparatide

for the treatment of osteoporosis

Risk Communication

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Risk Communication

Description of findings in the rodentstudy

Exclusion of groups at increased riskfor osteosarcoma

Duration of treatment

Post-Approval Safety SurveillanceP

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Program

Spontaneous adverse event reporting

Long-term monitoring of women and

men in observational study GHBJ Active surveillance program

population-based database sentinel sites tracking prescription use

External Safety Review Board

Teriparatide Improves

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Skeletal Architecture

Baseline Follow-up

Dose Selection

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Vertebral and nonvertebral fracture risk reduction issimilar for 20 g and 40 g teriparatide groups in women

Each dose increased bone mineral density in womenand men

The 40 g dose was more likely to cause adverse events,transient elevations in serum calcium, and resultedin a higher rate of discontinuations from the trials inwomen and in men

Teriparatide 20 g is an appropriate dose fortreatment of osteoporosis in postmenopausal

women and in men

Clinical Efficacy

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Teriparatide 20 g

In women (Study GHAC): Reduced the risk of vertebral fracture by 65%

Reduced the risk of nonvertebral fracture by 53%

Increased bone mineral density spine and hip without significant effect at the

forearm

Increased total body bone mineral No increase in fracture risk for at least 18 months after

cessation of treatment

Clinical Efficacy

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Clinical EfficacyTeriparatide 20 g

In men (Study GHAJ):

Increased bone mineral density spine, femoral neck without significant

effect at the total hip

Increased total body bone mineral

Clinical SafetyT i tid 20

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Teriparatide 20 g

Adverse Events nausea, leg cramps postural hypotension

Laboratories mild transient increases in serum calcium increases in serum uric acid

No increase in risk of cancer - no primarybone tumor in any patient

No effect on mortality

Conclusions

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Teriparatide improves bone microarchitecture,increases bone mass, and prevents bothvertebral and nonvertebral fractures.

Clinical trials support that teriparatide 20 gper day is an effective and safe treatment forosteoporosis in postmenopausal women andin men and fulfills an important unmet medicalneed.

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