Upcoming Agents for Osteoporosis May 5, 2017 Michael R. McClung, MD, FACP Director, Oregon Osteoporosis Center Portland, Oregon, USA Professorial Fellow, Institute of Health and Ageing Australian Catholic University, Melbourne, Australia
Disclosures I am disclosing financial relationships as follows: Global Advisory Boards: Amgen, Radius Honorarium for speaking: Amgen, Radius Michael McClung, MD 2017
Osteoporosis: Definition and Pathogenesis Definition A disorder due to bone loss that damages skeletal architecture, weakens the skeleton and predisposes a patient to fracture - a combination of low bone mass and damaged microarchitecture Pathogenesis Imbalance in bone remodeling such that rate of resorption exceeds that of formation Images Courtesy of Drs. David Dempster, Roger Zebazi and Sergio Ragi
Osteoporosis Drugs FDA Approved Indications 2017 ANTI-REMODELING AGENTS Bisphosphonates Alendronate Risedronate Ibandronate Zoledronic acid Raloxifene Denosumab BONE STIMULATING AGENT Teriparatide
Osteoporosis Treatment: Benefits Many of our current drugs are very effective for treating osteoporosis vertebral fracture by 60-70% hip fracture by 40-60% non-vertebral fracture by 20-35% Fracture protection occurs early after treatment starts and persists as long as treatment is taken In general are well tolerated In clinical trials, have been very safe
Osteoporosis Treatment: Limitations Real or perceived intolerance Concerns about safety, especially the long-term safety of bisphosphonates Inconvenient or awkward dosing regimens Poor adherence to therapy No agent restores skeletal structure or strength to normal levels i.e., no cure for osteoporosis Expense M McClung. Personal opinion
New and Emerging Treatments Anti-remodeling agents Cathepsin K inhibitors Anabolic agents New analogs of PTH Biological activators of bone formation Anti-sclerostin antibody DKK inhibitors
Cathepsin K Inhibition
Odanacatib Cathepsin K, the major proteolytic enzyme of osteoclasts Odanacatib very specific inhibitor of cathepsin K inhibits bone resorption without decreasing osteoclast number and function thus preserving bone formation in pre-clinical studies, increased endocortical and periosteal bone formation; increased cortical thickness and strength Convenient once weekly oral dosing in clinical studies
Cortical Thickness mm Cortical Thickness mm Odanacatib Increases Cortical Thickness and Strength in Femur of OVX Monkeys 4.0 3.6 3.2 0 1.6 Proximal Femur # p<0.05 vs VEH Veh p = 0.08 vs VEH # 6 30 ODN, mg/kg Femoral Neck Central Femur *** Increased cortical volumetric BMD (31% vs controls) Increased cortical thickness in the radius (30%) and femur Increased bending strength 1.4 1.2 0 Veh 6 30 ODN, mg/kg Cusick T et al. J Bone Miner Res. 2012;27:524 37.
Percent Change vs Placebo Un - Coupling With Odanacatib 100 50 0-50 Odanacatib - CTX Odanacatib P1NP Sustained inhibition of bone resorption markers Transient decrease in bone formation markers Fully reversible -100 0 3 6 12 24 Months Adapted from Eisman JA, McClung MR et al. J Bone Miner Res. 2011;26:242 51
% Change from Baseline (Mean ± SE) % Change from Baseline (Mean ± SE) Odanacatib: Bone Mineral Density: 5 Years Placebo ODN 50 mg/ Q week Marked and progressive increase in BMD 14 12 10 8 6 4 2 0-2 Lumbar Spine 0 1 3 6 12 18 24 30 36 42 48 54 60 Month 12 11.9% Femoral Neck 10 8 6 4 2 0-2 03 12 24 36 48 60 1 6 18 30 42 54 Month 9.8% Full-Analysis-Set Population / LOCF Langdahl et al. J Bone Miner Res 2012 ;27:2251-8.
Cathepsin K Inhibitor: Odanacatib Phase 3: Fracture Risk Reduction In LOFT study of 16,371 patients, odanacatib 50 mg po once weekly significantly reduced fracture risk in women with osteoporosis Relative risk reduction (%), 95% (confidence interval) spine 54% (2.3% vs 7.2%) hip Discontinue therapy47% (0.7% vs 1.2%) non-vertebral * 23% (6.5% vs 8.0%) Discontinue therapy * Time-dependent decrease in non-vertebral fracture risk Increase in BMD in patients previously treated with alendronate Because of unexpected risk of stroke, development was halted in 2016. McClung M et al. ASBMR 2014, 2016
Abaloparatide
Abaloparatide: Synthetic Analogue of Human PTHrP 1-34 hpth 1-34 hpthrp 1-34 Abaloparatide 22 30 34 100% hpthrp 38% hpthrp Functional optimization of BA058 based on amino acids 22-34 More selectively binds to R*G PTH receptor than does PTHrP Hattersley R et al. Endocrine Society. OR31-5, 2014
Abaloparatide Abaloparatide Phase 3 study (ACTIVE) Compared to teriparatide less activation of bone remodeling than teriparatide somewhat greater increases in BMD Miller PD et al. JAMA 2016;316:722-33
Abaloparatide Phase 3 Extension Study (ACTIVE) Total hip BMD Lumbar spine BMD Miller PD et al. JAMA 2016;316:722-33
Abaloparatide Phase 3 Extension Study (ACTIVE) Miller PD et al. JAMA 2016;316:722-33
Abaloparatide Phase 3 Extension Study (ACTIVExtend) Fracture protection sustained during 6 months of alendronate therapy Cosman F et al. Mayo Clin Proc 2017;92:200-10
Abaloparatide Phase 3 Extension Study (ACTIVExtend) Cosman F et al. Mayo Clin Proc 2017;92:200-10
Abaloparatide Phase 3 Study (ACTIVE) Adverse events balanced among treatment groups Adverse events of interest Placebo N = 820 (%) Abaloparatide N = 822 (%) Teriparatide N = 818 (%) Back pain 10.0% 8.5% 7.2% Hypercalciuria 9.0% 11.3% 12.5% Hypercalcemia (uncorrected serum calcium) 0.4% 3.4% 6.4% Miller PD et al. JAMA 2016;316:722-33
Abaloparatide - Approval April 28: Abaloparatide approved by FDA for treatment of postmenopausal women with osteoporosis and high risk of fracture warning about risk of osteosarcoma (like teriparatide) cumulative use of teriparatide and abaloparatide limited to 2 years in a patient s lifetime www.tymlos.com
Sclerostin Inhibition
LRP5/Wnt Signaling in Osteoblasts BMP PTH Mechanical Load Sclerostin LRP5/Wnt β-catenin Dkk1 Altered transcription of several genes Enhanced bone formation
Sclerostin Deficiency Sclerosteosis / van Buchem s Increased bone mass throughout skeleton Very low fracture risk Normal due to absence of sclerostin (SOST) - a bone formation inhibitor Heterozygotes have normal phenotype except high bone mass Photo: Janssens and Van Hul. Hum Mol Genet. 2002;11:2385-93.
Sclerostin Antibody Therapy in Rats Rats ovariectomized at age 6 months. Treatment for 5 weeks beginning at 13 months of age 3D µct images of distal femur at end of study Li et al. J Bone Miner Res. 2009;24.578-88
Sclerostin Antibody Increases Cancellous Bone Volume and Bone Formation Cynomolgus monkeys treated for 10 weeks with sclerostin antibody L2 VERTEBRA PROXIMAL TIBIA VEHICLE Scl-AbIV (30 mg/kg) VEHICLE Scl-AbIV (30 mg/kg) E F G H Marked increase in modeling-based bone formation Ominsky MS et al, J Bone Miner Res 2010;25:948-59
Romosozumab Humanized IgG2 monoclonal antibody with high specificity for binding sclerostin Administered subcutaneously at dose of 210 mg Q 4 weeks Inhibits sclerostin action Marked but transient increase in bone formation Decreased bone resorption McClung MR et al. N Engl J Med. 2014;370:412-20 Cosman F et al. N Engl J Med. 2016;375:1532-43
Percentage Change From Baseline Romosozumab Phase 2 Study: Bone Mineral Density Placebo ALN TPTD Romosozumab 210 mg QM 12 10 8 6 4 *P < 0.0001 vs placebo P < 0.0001 vs ALN ʌ P 0.0025 vs TPTD * ʌ Lumbar Spine 11.3% * ʌ * ʌ 5 4 3 2 1 * Total Hip *P < 0.0001 vs placebo P < 0.0001 vs ALN ʌ P < 0.0001 vs TPTD * ʌ * ʌ 4.1% 2 0 0 1 2 2 0 3 6 9 12 Month Data are LS means and 95% CIs. 0 3 6 9 12 Month McClung et al. NEJM 2014;370:412-20
Percent Change from Baseline Romosozumab Phase 2 Study: Year 3 - BMD Romosozumab Discontinuation: Transition to Denosumab Romosozumab 210 mg QM* Placebo* Placebo Q6M Lumbar Spine Total Hip 24 15 16 15.7% 10 6.0% 8 5 0 0-8 -5 BL 3 6 12 18 24 30 36 BL 3 6 12 18 24 30 36 Month McClung MR et al. ASBMR 2014.
Percent Change from Baseline Romosozumab Phase 2 Study: Year 3 - BMD Romosozumab Discontinuation: Transition to Denosumab Romosozumab 210 mg QM* Placebo* Denosumab 60 mg Q6M Placebo Q6M Lumbar Spine Total Hip 24 19.4% 15 16 15.7% 10 6.0% 7.1% 8 5 0 0-8 -5 BL 3 6 12 18 24 30 36 BL 3 6 12 18 24 30 36 Month McClung MR et al. ASBMR 2014.
Romosozumab: Phase 3 Studies Phase III studies are underway - evaluation of safety will be important FRAME Year 1 Year 2 Year 3 extension ClinicalTrials.gov Identifier: NCT01575834 Romosozumab Denosumab Denosumab Placebo Denosumab Denosumab ARCH ClinicalTrials.gov Identifier: NCT01631214 Romosozumab Alendronate Alendronate Alendronate
Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Vertebral Fracture Risk Reduction Year 1 ClinicalTrials.gov Identifier: NCT01575834 Romosozumab Placebo 7180 postmenopausal women with osteoporosis Average age 71 years T-scores: L spine -2.7 Total hip -2.5 Prior vertebral fracture 18% Prior non-vert fracture 21% FRAX 10 year MOF risk 13.4% Placebo Romosozumab Cosman F et al. N Engl J Med 2016;375:1532-43
Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Vertebral Fracture Risk Reduction Year 1 Year 2 ClinicalTrials.gov Identifier: NCT01575834 Romosozumab All patients on Placebo denosumab 60 mg Q6M Fracture protection sustained during 12 months of denosumab therapy Year 2: N=25 Year 2: N=5 Placebo Romosozumab Placebo Romosozumab Cosman F et al. N Engl J Med 2016;375:1532-43
Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Non-vertebral Fracture Risk Denosumab Geographic disparity in non-vertebral fracture risk and response to treatment. Placebo Romosozumab Cosman F et al. N Engl J Med 2016;375:1532-43
Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Clinical Fracture Risk Denosumab Placebo Romosozumab Cosman F et al. N Engl J Med 2016;375:1532-43
Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: BMD Cosman F et al. N Engl J Med 2016;375:1532-43
Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Adverse Events, Year 1 Placebo N = 3576 N (%) Romosozumab N = 3581 N (%) Adverse events 2850 (79.7) 2806 (78.4) Death 23 (0.6) 29 (0.8) Hypocalcemia 0 1 (<0.1) Hypersensitivity 245 (6.9) 242 (6.8) Injection site reactions 104 (2.9) 187 (5.2) ONJ 0 1 (<0.1) Femoral fracture with atypical features 0 1 (<0.1) Hyperostosis 27 (0.8) 19 (0.5) Cosman F et al. N Engl J Med 2016;375:1532-43
Romosozumab Carcinogenic Potential and Rat Toxicity Study Romosozumab is an anabolic bone forming agent and an activator of canonical Wnt signaling, raising questions about potential carcinogenic risk. Evidence from genetic models of sclerostin deficiency in humans and animals and from chronic toxicity studies in rats and monkeys suggested that romosozumab could pose a low carcinogenic risk to humans. In a rat lifetime study, no romosozumab-related effects on tumor incidence were observed. The findings of the lifetime study and the weight of evidence factors collectively indicate that romosozumab administration would not pose a carcinogenic risk to humans. Chouinard L et al. Regul Toxicol Pharmacol 2016 81:212-22
New Anabolic Therapies: Phase 3 Study Designs Beginning anabolic therapy followed by an anti-remodeling agent will become standard practice ACTIVE - abaloparatide Abaloparatide Alendronate 18 36 Months Cosman F et al. Mayo Clin Proc 2017;92:200-10 FRAME - romosozumab Romosozumab Denosumab 12 24 Months Cosman F et al. N Engl J Med 2016;375:1532-43
Where Will New Drugs Fit into Treatment Menu? Abaloparatide Likely occupy the same niche as teriparatide high risk of vertebral fracture failure of anti-remodeling therapy not yet studied in men or patients on glucocorticoids Romosozumab patients at high risk for fracture in need of skeletal reconstruction patients at imminent risk for vertebral fracture, especially those with recent vertebral fracture patients with very low hip BMD in whom anti-remodeling therapy will never achieve a BMD target
New Drugs for Osteoporosis: The Future There are no other drugs in late stage (Phase 2 or 3) clinical development Hopefully, the FNIH project and other studies can provide an appropriate surrogate for fractures so that studies with future drugs can be more efficient and less costly Clinical research efforts must turn from developing new drugs and tools to learning how to implement the strategies we have into clinical practice and meaningful clinical outcomes Photo courtesy of Betsy Love McClung, RN, MN
Thank you Michael R. McClung, MD, FACP Founding Director Oregon Osteoporosis Center Portland, Oregon, USA mmcclung@orost.com