TERIPARATIDE (r-hPTH 1-34) Endocrinologic and Metabolic Drugs Advisory Committee Holiday Inn, Bethesda MD July 27, 2001 Bruce S. Schneider, MD CDER FDA

TERIPARATIDE (r-hPTH 1-34)TERIPARATIDE (r-hPTH 1-34) TERIPARATIDE (r-hPTH 1-34)TERIPARATIDE (r-hPTH 1-34)

Endocrinologic and Metabolic Drugs Advisory Endocrinologic and Metabolic Drugs Advisory CommitteeCommittee

Holiday Inn, Bethesda MDHoliday Inn, Bethesda MDJuly 27, 2001July 27, 2001

Bruce S. Schneider, MDCDER FDA

Endocrinologic and Metabolic Drugs Advisory Endocrinologic and Metabolic Drugs Advisory CommitteeCommittee

Holiday Inn, Bethesda MDHoliday Inn, Bethesda MDJuly 27, 2001July 27, 2001

Bruce S. Schneider, MDCDER FDA

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Endocrinologic and Metabolic Advisory Committee Endocrinologic and Metabolic Advisory Committee July 27, 2001July 27, 2001

TeriparatideTeriparatideTeriparatideTeriparatide

• 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



• Clinical efficacy

• Osteosarcoma concerns

• Clinical efficacy

• Osteosarcoma concerns


Principal outcomesPrincipal outcomesPrincipal outcomesPrincipal outcomesPIVOTAL 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.


PRECLINICAL DEVELOPMENT PRECLINICAL DEVELOPMENT PROGRAMPROGRAM

PRECLINICAL DEVELOPMENT PRECLINICAL DEVELOPMENT PROGRAMPROGRAM

– Mechanistic studies– Anabolic action on bone– Positive effects on bone quality

– Mechanistic studies– Anabolic action on bone– Positive effects on bone quality


Clinical (Phase 1-2) StudiesClinical (Phase 1-2) StudiesClinical (Phase 1-2) StudiesClinical (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)


GHAC:GHAC: Effects of teriparatide in the Treatment of Effects of teriparatide in the Treatment of Postmenopausal Women with OsteoporosisPostmenopausal Women with Osteoporosis

GHAC:GHAC: Effects of teriparatide in the Treatment of Effects of teriparatide in the Treatment of Postmenopausal Women with OsteoporosisPostmenopausal 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


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

GHAC PRIMARY ENDPOINT RESULTSGHAC PRIMARY ENDPOINT RESULTSProportion of patients with 1 or more new vertebral fracturesProportion 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%

PBO PTH20 PTH40% of Pts. 14% 5% 4%

(64/448) (22/444) (19/434)



Other Vertebral Fracture ResultsOther Vertebral Fracture Results (not pre-specified)(not pre-specified)

Other Vertebral Fracture ResultsOther Vertebral Fracture Results (not pre-specified)(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.


Secondary endpoint: New Non-vertebral Secondary endpoint: New Non-vertebral Atraumatic Fractures CombinedAtraumatic Fractures Combined

Secondary endpoint: New Non-vertebral Secondary endpoint: New Non-vertebral Atraumatic Fractures CombinedAtraumatic Fractures Combined

PBO PTH20 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


PBO PTH20 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



Study GHAC Study GHAC Non-vertebral Fractures by SiteNon-vertebral Fractures by Site

Study GHAC Study GHAC Non-vertebral Fractures by SiteNon-vertebral Fractures by Site

PBO PTH20 PTH40Wrist 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%

PBO PTH20 PTH40Wrist 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%


GHAC: other secondary efficacy GHAC: other secondary efficacy endpointsendpoints

GHAC: other secondary efficacy GHAC: other secondary efficacy endpointsendpoints

• 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)


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

primary hypogonadismprimary hypogonadism

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

primary hypogonadismprimary 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


GHAJ Treatment ExposureGHAJ Treatment ExposureGHAJ Treatment ExposureGHAJ Treatment Exposure

PBO PTH 20 PTH 40Randomized 147 151 139On study at end 88% 82% 74%

6 months 94% 87% 81%12 months 37% 26% 26%

PBO PTH 20 PTH 40Randomized 147 151 139On study at end 88% 82% 74%

6 months 94% 87% 81%12 months 37% 26% 26%


GHAJ ResultsGHAJ ResultsGHAJ ResultsGHAJ 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.


Teriparatide: Clinical Efficacy SummaryTeriparatide: Clinical Efficacy SummaryTeriparatide: Clinical Efficacy SummaryTeriparatide: Clinical Efficacy SummaryIn 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.


Teriparatide: Clinical Efficacy SummaryTeriparatide: Clinical Efficacy SummaryTeriparatide: Clinical Efficacy SummaryTeriparatide: Clinical Efficacy SummaryIn 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.


OSTEOSARCOMAOSTEOSARCOMAOSTEOSARCOMAOSTEOSARCOMA

• 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.


OSTEOSARCOMAOSTEOSARCOMAOSTEOSARCOMAOSTEOSARCOMA

• 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.


OsteosarcomaOsteosarcomaOsteosarcomaOsteosarcoma

• 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.



• 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.



• 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.


OsteosarcomaOsteosarcomaOsteosarcomaOsteosarcoma• 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?



• 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.


OsteosarcomaOsteosarcomaOsteosarcomaOsteosarcoma• 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.



• 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.



BENEFITSKnown: 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.

BENEFITSKnown: 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.

Documents

TERIPARATIDE (r-hPTH 1-34) Endocrinologic and Metabolic Drugs Advisory Committee Holiday Inn, Bethesda MD July 27, 2001 Bruce S. Schneider, MD CDER FDA