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 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 2TeriparatideTeriparatide Need for an anabolic agent for treatment of many individuals with osteoporosis Consider whether benefit/risk profile of teriparatide merits approval Need for an anabolic agent for treatment of many individuals with osteoporosis Consider whether benefit/risk profile of teriparatide merits approval

3. Endocrinologic and Metabolic Advisory Committee July 27, 2001 3 TeriparatideTeriparatide Clinical efficacy Osteosarcoma concerns Clinical efficacy Osteosarcoma concerns

4. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 5 PRECLINICAL DEVELOPMENT PROGRAM –Mechanistic studies –Anabolic action on bone –Positive effects on bone quality  –Mechanistic studies –Anabolic action on bone –Positive effects on bone quality 

6. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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) 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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. PBO:544 PTH 20 µg:541 PTH 40 µg:552 PRIMARY EFFICACY OBJECTIVE: Reduction in the proportion of patients with new morphometric vertebral fractures. Eight secondary efficacy endpoints. PBO:544 PTH 20 µg:541 PTH 40 µg:552

8. Endocrinologic and Metabolic Advisory Committee July 27, 2001 8 GHAC PRIMARY ENDPOINT RESULTS Proportion of patients with 1 or more new vertebral fractures PBOPTH20PTH40 % of Pts. 14% 5% 4% (64/448) (22/444) (19/434) Relative risk reduction 65% 69% Absolute risk reduction 9% 10% PBOPTH20PTH40 % of Pts. 14% 5% 4% (64/448) (22/444) (19/434) Relative risk reduction 65% 69% Absolute risk reduction 9% 10%

9. Endocrinologic and Metabolic Advisory Committee July 27, 2001 9 Other Vertebral Fracture Results (not pre-specified) Reduction in proportion of patients with multiple new vertebral fractures. Reduction in fracture severity. Reduction in proportion of patients with multiple new vertebral fractures. Reduction in fracture severity.

10. Endocrinologic and Metabolic Advisory Committee July 27, 2001 10 Secondary endpoint: New Non-vertebral Atraumatic Fractures Combined PBOPTH20 PTH40 % 5.5% 2.5% 2.5% (30/544) (14/541) (14/552) p<0.02 for each comparison vs. PBO without adjustment for multiple comparisons Relative risk reduction 53% 54% Absolute risk reduction 3% 3% PBOPTH20 PTH40 % 5.5% 2.5% 2.5% (30/544) (14/541) (14/552) p<0.02 for each comparison vs. PBO without adjustment for multiple comparisons Relative risk reduction 53% 54% Absolute risk reduction 3% 3%

11. Endocrinologic and Metabolic Advisory Committee July 27, 2001 11 Study GHAC Non-vertebral Fractures by Site PBO PTH20 PTH40 Wrist1.3% 0.4% 0.5% Ribs0.9% 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% Pelvis0.6% 0% 0% Other1.5% 1.1% 0.5% PBO PTH20 PTH40 Wrist1.3% 0.4% 0.5% Ribs0.9% 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% Pelvis0.6% 0% 0% Other1.5% 1.1% 0.5%

12. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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) 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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 PBO:147 PTH 20 µg:151 PTH 40 µg:139 PRIMARY EFFICACY OBJECTIVE: Increase in spinal BMD SECONDARY ENDPOINTS: BMD at other sites, biochemical markers, height, HRQOL PBO:147 PTH 20 µg:151 PTH 40 µg:139

14. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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% 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 15 GHAJ Results Primary endpoint: lumbar spine BMD –Highly significant increases compared to placebo for both doses (40  g > 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, Ward’s triangle and whole body. Other secondary endpoints: results similar to GHAC. Primary endpoint: lumbar spine BMD –Highly significant increases compared to placebo for both doses (40  g > 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, Ward’s triangle and whole body. Other secondary endpoints: results similar to GHAC.

16. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 18 OSTEOSARCOMAOSTEOSARCOMA Robust, dose-dependent occurrence in rats. –No threshold dose demonstrated. Biologically plausible outcome. Involves hormonal stimulation of known target tissue. Robust, dose-dependent occurrence in rats. –No threshold dose demonstrated. Biologically plausible outcome. Involves hormonal stimulation of known target tissue.

19. Endocrinologic and Metabolic Advisory Committee July 27, 2001 19 OSTEOSARCOMAOSTEOSARCOMA 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 20 OsteosarcomaOsteosarcoma 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 21 OsteosarcomaOsteosarcoma High exposure in rat studies.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. High exposure in rat studies.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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 22 OsteosarcomaOsteosarcoma 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 23 OsteosarcomaOsteosarcoma 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? 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 24 OsteosarcomaOsteosarcoma 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 25 OsteosarcomaOsteosarcoma 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 26 OsteosarcomaOsteosarcoma 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. 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. Endocrinologic and Metabolic Advisory Committee July 27, 2001 27TeriparatideTeriparatide BENEFITS Known: Substantial BMD (M+F) and fracture efficacy (F), especially at lumbar spine. Unknown: Long-term benefits of architectural improvements from anabolic agent. RISKS Unknown: Risk of osteosarcoma. BENEFITS Known: Substantial BMD (M+F) and fracture efficacy (F), especially at lumbar spine. Unknown: Long-term benefits of architectural improvements from anabolic agent. RISKS Unknown: Risk of osteosarcoma.