TERIPARATIDE rhPTH 134

1
TERIPARATIDE (r-hPTH 1-34)

• Endocrinologic and Metabolic Drugs Advisory
  Committee
• Holiday Inn, Bethesda MD
• July 27, 2001
• Bruce S. Schneider, MD
• CDER FDA

Center for Drug Evaluation and Research
2
Teriparatide

• Need for an anabolic agent for treatment of many
  individuals with osteoporosis
• Consider whether benefit/risk profile of
  teriparatide merits approval

3
Teriparatide

• Clinical efficacy
• Osteosarcoma concerns

4
Principal outcomes

• PIVOTAL CONTROLLED CLINICAL TRIALS
• GHAC clearly established efficacy in reducing
  fracture risk (and in increasing BMD) in
  postmenopausal osteoporosis.
• GHAJ established efficacy in increasing spinal
  BMD in men with osteoporosis.
• For both men and women, beneficial effects at
  spine appeared to exceed those of any approved
  agent.
• Meet efficacy criteria for osteoporosis drugs.

5
PRECLINICAL DEVELOPMENT PROGRAM

• Mechanistic studies
• Anabolic action on bone
• Positive effects on bone quality ?
  
  
  

6
Clinical (Phase 1-2) Studies

• Rapid anabolic action in humans PD effects in
  15-40 ?g range (no-effect dose 6 ?g)
• Safety/tolerability profile ?
• Dose selection for pivotal clinical trials
• ? effects of less frequent dosing (e.g., 20 ?g
  every other day)

7
GHAC Effects of teriparatide in the Treatment of
Postmenopausal Women with Osteoporosis

• PRIMARY EFFICACY OBJECTIVE
• Reduction in the proportion of patients with new
  morphometric vertebral fractures.
• Eight secondary efficacy endpoints.
• PBO544 PTH 20 µg541 PTH 40 µg552

8
GHAC PRIMARY ENDPOINT RESULTSProportion of
patients with 1 or more new vertebral fractures

• PBO PTH20 PTH40
• of Pts. 14 5 4
• (64/448) (22/444)
  (19/434)
• Relative risk reduction 65 69
• Absolute risk reduction 9 10

9
Other Vertebral Fracture Results (not
pre-specified)

• Reduction in proportion of patients with multiple
  new vertebral fractures.
• Reduction in fracture severity.

10
Secondary endpoint New Non-vertebral Atraumatic
Fractures Combined

• PBO PTH20 PTH40
• 5.5 2.5 2.5
• (30/544) (14/541) (14/552)
• plt0.02 for each comparison vs. PBO without
  adjustment for multiple comparisons
• Relative risk reduction 53 54
• Absolute risk reduction 3 3

11
Study GHAC Non-vertebral Fractures by Site

• PBO PTH20 PTH40
• Wrist 1.3 0.4 0.5
• Ribs 0.9 0.6 0.4
• Ankle/foot 0.7 0.2 0.7
• Humerus 0.4 0.4 0.4
• Hip 0.7 0.2 0.5
• Pelvis 0.6 0 0
• Other 1.5 1.1 0.5

12
GHAC other secondary efficacy endpoints

• BMD of lumbar spine () and hip ()
• BMD of total body () forearm (no effect)
• Height (no effect on height loss)
• Histomorphometry ()
• Biochemical markers ()
• HRQOL indicators (no effect)

13
GHAJ Effects of teriparatide in the treatment of
men with primary osteoporosis and osteoporosis
associated with primary hypogonadism

• PRIMARY EFFICACY OBJECTIVE
• Increase in spinal BMD
• SECONDARY ENDPOINTS
• BMD at other sites, biochemical markers, height,
  HRQOL
• PBO147 PTH 20 µg151 PTH 40 µg139

14
GHAJ Treatment Exposure

• PBO PTH 20 PTH 40
• Randomized 147 151 139
• On study at end 88 82 74
• 6 months 94 87 81
• 12 months 37 26 26

15
GHAJ Results

• Primary endpoint lumbar spine BMD
• Highly significant increases compared to placebo
  for both doses (40 ?g gt 20 ?g).
• Secondary BMD endpoints (8 other sites)
• For PTH 20 ?g significant at femoral neck only.
• For PTH 40 ?g greater effects significant at
  total hip, femoral neck, intertrochanter, Wards
  triangle and whole body.
• Other secondary endpoints results similar to
  GHAC.

16
Teriparatide Clinical Efficacy Summary

• In postmenopausal osteoporotic women
• Teriparatide 20 ?g is highly effective in
  increasing lumbar spine BMD (and BMD at other
  sites) and in reducing risk of morphometric
  vertebral fractures.
• The drug is effective in preventing non-vertebral
  fractures combined, but the data are not as
  robust as in the spine.
• The 20 ?g dose is as effective as 40 ?g in
  reducing the risk of fractures.
• The drug did not prevent height loss.

17
Teriparatide Clinical Efficacy Summary

• In men with primary osteoporosis (with or without
  primary hypogonadism)
• Teriparatide 20 ?g is highly effective in
  increasing lumbar spine BMD, but is either
  ineffective, or only marginally effective, in
  increasing BMD at other skeletal sites.
• The 40 ?g dose was substantially more effective
  than 20 ?g at nearly all skeletal sites.
• The drug did not prevent height loss.
• There are no fracture efficacy data from GHAJ or
  from any other randomized controlled clinical
  trials in men.

18
OSTEOSARCOMA

• Robust, dose-dependent occurrence in rats.
• No threshold dose demonstrated.
• Biologically plausible outcome. Involves hormonal
  stimulation of known target tissue.

19
OSTEOSARCOMA

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age.
• Negative monkey study.
• Rat bone differs from human.
• No increase in other malignancies in treated
  rats.
• Hyperparathyroidism in humans.
• Observations post-treatment with PTH.

20
Osteosarcoma

• High exposure in rat studies
• Rats received about 25-1000X proposed human dose,
  based on AUC and of lifetime.
• If background rate is 0.2 in rats, study dose
  range led to a 30-200X increase in tumors.
• Risk projections depend on basal rates of tumor
  occurrence.

21
Osteosarcoma

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age. Are
  young animals particularly or exclusively
  susceptible?
• Further experiments are in progress to determine
  whether effect is age-dependent in rats.

22
Osteosarcoma

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age.
• Monkey study. Number of animals too small to
  detect even a large increase in tumor occurrence
  if background rate is low.

23
Osteosarcoma

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age.
• Monkey study.
• Rat bone differs from human. Architecture,
  growth and remodeling patterns differ.
  Do the two
  species differ in ability of osteoblast precursor
  pools to replicate and expand clonally in
  response to intermittent hormonal stimulation?

24
Osteosarcoma

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age.
• Monkey study.
• Rat bone differs from human.
• No increase in other malignancies in treated
  rats. PTH is not a carcinogen. Concern is with
  promotional effects of hormone in specific target
  tissue.

25
Osteosarcoma

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age.
• Monkey study.
• Rat bone differs from human.
• No increase in other malignancies in treated
  rats.
• Hyperparathyroidism in humans. Many patients have
  chronic, mild PTH elevations. Osteosarcoma is
  not increased in this group. However, there may
  be different cellular responses to intermittent
  vs. sustained elevations in PTH, as with overall
  bone PD.

26
Osteosarcoma

• High exposure in rat studies.
• Treatment of rats began at 6-7 weeks of age.
• Monkey study.
• Rat bone differs from human.
• No increase in other malignancies in treated
  rats.
• Hyperparathyroidism in humans.
• Observations post-treatment with PTH. 1452
  patients treated for ? 3 months. Unlikely to
  detect increase in tumor occurrence, given low
  background rates.

27
Teriparatide

• BENEFITS
• Known Substantial BMD (MF) and fracture
• efficacy (F), especially at lumbar
  spine.
• Unknown Long-term benefits of
• architectural improvements from anabolic
  agent.
• RISKS
• Unknown Risk of osteosarcoma.