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

Slides:

Advertisements

Similar presentations

OSTEOPOROSIS An overview of the condition and its treatment

Advertisements

The FRAX tool for Osteoporosis Should all GP’s be calculating the Frax score prior to treatment Dr Sanjeev Patel Consultant Physician & Senior Lecturer.

Teriparatide in Elderly Women with Osteoporosis Based on Poster SU0374 Fracture Incidence, Quality of Life and Back Pain in Elderly Women (age >75 years)

WHO Osteoporosis Definition (1996)

Modified Megestrol The Clinical Trials by : Carolina R. Akib

Aging of the Skeleton: Osteoporosis An Evolutionary and Biocultural Perspective.

Downloaded from 1 Alendronate vs. Risedronate Comparison Trial.

Slide 1 Update on Alendronate and Raloxifene in Osteoporosis EFficacy of FOSALAN ™ vs. Evista ® Comparison Trial (EFFECT) FOSALAN (alendronate) is a trademark.

Protelos Long-Term Antifracture Efficacy. Protelos Vertebral Antifracture Efficacy over 4 years in SOTI Favors Protelos  RR P

Interpreting Adverse Signals in Diabetes Drug Development Programs Featured Article: Clifford J. Bailey, Ph.D. Diabetes Care Volume 36: 1-9 July, 2013.

Oncology Pediatric Initiatives Richard Pazdur, MD Director, Division of Oncology Drug Products.

U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution Henry Bone, M.D. Michigan Bone & Mineral Clinic Detroit,

Treatment. Bisphosphonates Promotes bone formation and decreases bone resorption Mechanism of Action First line treatment for osteoporosis in both men.

Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

1 The Chemoprevention of Sporadic Colorectal Cancer Issues Surrounding a Benefit/Risk Analysis in Clinical Trials Mark Avigan MD CM Medical Officer Division.

Pharmacology of drugs used in calcium & vitamin D disorders

ECTS symposium 5 Anabolic treatment of osteoporosis.

Luveris ® New Drug Application ( ) Kate Meaker, M.S. Statistical Reviewer Division of Biometrics II Kate Meaker, M.S. Statistical Reviewer Division.

1 Ipriflavone in the Treatment of Postmenopausal Osteoporosis Randomized placebo-controlled, 4-year study conducted Europe 475 postmenopausal white women,

A Comparison of the Effectiveness of Estrogen-Progesterone and Estrogen-Testosterone Combination Therapies in the Prevention of Osteoporosis in Postmenopausal.

Bone Turnover Suppression Based on an ASBMR/ECTS Clincal Debate “Too Much Suppression of Turnover Is Bad for Bone” Co-Chairs: Socrates Papapoulos, Douglas.

Glucocorticoid-Induced Osteoporosis (GIO) Nguyen Thy Khue, MD, PhD Department of Endocrinology, HoChiMinh City University of Medicine and Pharmacy.

Vietnam Osteoporosis Workshop, HCM Cty 2006 OSTEOPOROSIS IN MEN Tuan Van Nguyen and Nguyen Dinh Nguyen Garvan Institute of Medical Research Sydney, Australia.

Pharmacology of drugs used in calcium & vitamin D disorders

Internal Medicine Weekly Conference 1392 Internal Medicine Weekly Conference 1392 Alimohammad Fatemi Assistant Professor of Rheumatology Alimohammad Fatemi.

Endpoint Comparison for Osteoporosis Assessment in Cancer Control Studies (N02C1 and N03CC) A. C. Dueck 1, P. J. Atherton 2, H. Liu 2, S. L. Hines 3, C.

Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002 ADVAIR and FLOVENT DISKUS Supplements for the COPD indication: SUMMARY and QUESTIONS.

Pulmonary-Allergy Drugs Advisory Committee January 17, FLOVENT ® DISKUS ® NDA , S004 GlaxoSmithKline Pulmonary-Allergy Drugs Advisory Committee.

CLAIMS STRUCTURE FOR SLE Jeffrey Siegel, M.D. Arthritis Advisory Committee September 29, 2003.

Extended Treatment Effects with Zoledronic Acid Based on Poster 1070 “The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a Randomized.

Estrogen plus Progestin, BMD and Fractures: Women’s Health Initiative Jane A. Cauley University of Pittsburgh JAMA 2003; 290 (13) :

FDA Presentation ODAC Meeting July NDA Applicant: Eli Lilly Evista ® (Raloxifene Hydrochloride)

1 ENTEREG ® (Alvimopan) Special Safety Section Marjorie Dannis, M.D. Division of Gastroenterology Products Office of Drug Evaluation III CDER, FDA The.

CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION OF OSTEOPOROSIS THERAPY Gideon A Rodan MD PhD Merck Research Laboratories Bone Biology and Osteoporosis.

FDA Case Studies Pediatric Oncology Subcommittee March 4, 2003.

1Bachelot T et al. Proc SABCS 2010;Abstract S1-6.

Osteoporosis Armed Forces Academy of Medical Sciences.

CR-1 Everolimus Benefit/Risk Assessment Howard J. Eisen, MD Thomas J. Vischer Professor of Medicine Chief, Division of Cardiology Drexel University College.

Food and Drug Administration Regulatory Implications of The WHI Study Eric Colman, MD Center for Drug Evaluation and Research Division of Metabolic and.

NDA SE-011 Docetaxel FDA Review. FDA Review Team Biostatistics –Clara Chu, PhD. –Gang Chen, PhD. Biopharmaceutics –Safaa Ibrahim PhD –Atiq Rahman,

Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 FDA 2004: Revisiting the 1996 Obesity Drug Guidance David G. Orloff, M.D. Division.

Osteoporosis. Background ► The problem  Osteoporosis is common  Over 50% of women and 30-45% of men over age 50 have osteopenia/osteoporosis  White.

FDA’s Osteoporosis Guidance Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drugs Eric Colman, MD September 25, 2002.

Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis Elise Miller.

Teriparatide or LY Eli Lilly & Company NDA Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory Committee Advisory Committee Bethesda,

Preclinical Models of Drug Efficacy and Skeletal Toxicity René Rizzoli M.D. Division of Bone Diseases [WHO Collaborating Center for Osteoporosis and Bone.

Ten Years’ Experience with Alendronate for the Treatment of Osteoporosis in Postmenopausal Women Adapted from Bone HG, Hosking D, Devogelaer J-P, Tucci.

SNDA Letrozole (Femara®) Indication: First-line therapy in postmenopausal women with advanced breast cancer. Prior approval: Second-line therapy.

CR-1 Candesartan in HF Benefit/Risk James B. Young, MD Cleveland Clinic Foundation.

1 Risk Benefit and Conclusions George Sledge, MD Indiana University School of Medicine.

REGULATORY HISTORY of ZOMETA and AREDIA JAW OSTEONECROSIS (ONJ) Oncologic Drug Advisory Committee March 4, 2005 Nancy S. Scher, M.D.

CON - 1 Conclusions C David R. Parkinson Vice President, Global Head, Clinical Research and Development Novartis Pharmaceuticals Corporation.

Zometa for Prostate Cancer Bone Metastases Protocol 039 Amna Ibrahim, M.D. Oncology Drug Products FDA.

Weekly Alendronate Safe and Effective at Increasing Bone Mineral Density in HIV-Infected Persons on Antiretroviral Therapy Slideset on: McComsey GA, Kendall.

Chapter 47 Assessing Fracture Risk: Who Should Be Screened? © American Society for Bone and Mineral Research Contributed by John Schousboe, Brent Taylor,

Osteopenia and Osteoporosis Bradley K. Harrison, MD.

NICE, FRAX & NOGG VTS meeting Jonathan Day 7 th April 2010.

MA.17R: Reduced Risk of Recurrence With Extending Adjuvant Letrozole Beyond 5 Yrs in Postmenopausal Women With Early-Stage Breast Cancer CCO Independent.

Nymox Pivotal Phase 3 Fexapotide (NX-1207) BPH Extension Trial Successfully Meets Primary Endpoint

Βιβλιογραφική ενημέρωση / EULAR 2016 update

Post Menopausal Osteoporosis

Goal-directed Treatment for Osteoporosis

Fig. 1. Trial profile. From: Randomized Teriparatide [Human Parathyroid Hormone (PTH) 1–34] Once-Weekly Efficacy Research (TOWER) Trial for Examining the.

Osteoporosis Diagnosis 9/21/2018 OSTEOPOROSIS.

Primary Hyperparathyroidism and Bone

Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis

DEXA Techniques DEXA is a quick method that is:

Figure 1. Relative risks of vertebral, hip, and nonvertebral fractures (and 95% CIs) in response to the treatments for ... Figure 1. Relative risks of.

Gregory Levin, FDA/CDER/OTS/OB/DBIII

Late-Breaking Data on LDL-C Reduction

Presentation transcript:

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

Endocrinologic and Metabolic Advisory Committee July 27, TeriparatideTeriparatide 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

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

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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 

Endocrinologic and Metabolic Advisory Committee July 27, Clinical (Phase 1-2) Studies Rapid anabolic action in humans; PD effects in  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  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)

Endocrinologic and Metabolic Advisory Committee July 27, 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

Endocrinologic and Metabolic Advisory Committee July 27, 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%

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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%

Endocrinologic and Metabolic Advisory Committee July 27, 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%

Endocrinologic and Metabolic Advisory Committee July 27, 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)

Endocrinologic and Metabolic Advisory Committee July 27, 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

Endocrinologic and Metabolic Advisory Committee July 27, GHAJ Treatment Exposure PBO PTH 20 PTH 40 Randomized On study at end 88% 82% 74% 6 months 94% 87% 81% 12 months 37% 26% 26% PBO PTH 20 PTH 40 Randomized On study at end 88% 82% 74% 6 months 94% 87% 81% 12 months 37% 26% 26%

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, OsteosarcomaOsteosarcoma High exposure in rat studies: –Rats received about X proposed human dose, based on AUC and % of lifetime. – If background rate is 0.2% in rats, study dose range led to a X increase in tumors. –Risk projections depend on basal rates of tumor occurrence. High exposure in rat studies: –Rats received about X proposed human dose, based on AUC and % of lifetime. – If background rate is 0.2% in rats, study dose range led to a X increase in tumors. –Risk projections depend on basal rates of tumor occurrence.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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?

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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.

Endocrinologic and Metabolic Advisory Committee July 27, 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 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 patients treated for  3 months. Unlikely to detect increase in tumor occurrence, given low background rates.

Endocrinologic and Metabolic Advisory Committee July 27, TeriparatideTeriparatide 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.