Outline and New Treatments on the Horizon Steven R. Cummings, MD CPMC and UCSF San Francisco Coordinating Center Support from Lilly and Amgen New treatments, new mechanisms of action Cathepsin K inhibition Anti-sclerostin antibodies Muscle anabolics The //OPG system Part of TNF family is a membrane-bound bound and circulating protein : the receptor for OPG: circulating decoy receptor for Page 1
Rank-ligand binds to Rank (receptor) producing and activating osteoclasts Rank-ligand binds to Rank (receptor) producing and activating osteoclasts Adapted from Boyle et al. Nature. 23;423:337. Adapted from Boyle et al. Nature. 23;423:337. Rank-ligand binds to Rank (receptor) producing and activating osteoclasts Rank-ligand binds to Rank (receptor) producing and activating osteoclasts Differentiation & fusion Differentiation & fusion Active osteoclasts Adapted from Boyle et al. Nature. 23;423:337. Adapted from Boyle et al. Nature. 23;423:337. Page 2
OPG binds to RankL, inhibiting osteoclast development and activity OPG binds to RankL, inhibiting osteoclast development and activity OPG OPG Adapted from Boyle et al. Nature. 23;423:337. Adapted from Boyle et al. Nature. 23;423:337. OPG binds to RankL, inhibiting osteoclast development and activity OPG binds to RankL, inhibiting osteoclast development and activity OPG OPG Differentiation & fusion Differentiation & fusion s Adapted from Boyle et al. Nature. 23;423:337. Adapted from Boyle et al. Nature. 23;423:337. Page 3
(like OPG) binds -ligand, blocking its action (like OPG) binds -ligand, blocking its action Decreased differentiation & fusion Decreased osteoclasts Decreased differentiation & fusion Decreased osteoclasts Decreased resorption Decreased resorption Adapted from Boyle et al. Nature. 23;423:337. Adapted from Boyle et al. Nature. 23;423:337. (like OPG) binds -ligand, blocking its action Phase II Trial Decreased differentiation & fusion Decreased osteoclasts 412 postmenopausal women randomly assigned to 7 denosumab groups Q3 and Q mo intervals 4 different doses of Anti-RankL Antibody Alendronate 7 mg/d BMD and markers of bone turnover at 12 months Decreased resorption Adapted from Boyle et al. Nature. 23;423:337. McClung et al, NEJM 2; 354:821 Page 4
vs. Alendronate vs. vs. Alendronate vs. Alendronate Alendronate McClung et al, NEJM 2; 354:821 McClung et al, NEJM 2; 354:821 Stopping and restarting denosumab Effects of stopping and restarting denosumab Off On Off On P. Miller, et al, Bone 28;43:222-9 P. Miller, et al, Bone 28;43:222-9 Page 5
Study design: Subjects: The FREEDOM Trial Randomized trial Anti-RankL Ab mg or placebo SC every months for 3 months Plus 4-8 IU vitamin D and 1 g of calcium Postmenopausal women aged to 9 years Spine or hip T-score < -2.5 Cummings, et al. NEJM 29;31:75 Percent Change 8 4 2-2 -4 - -8-1 Substudy, N=1 Decrease in Serum CTX-I 8% relative reduction at month 1 Antibody 12 18 24 3 3 Study Month 72% P<.1 Cummings, et al. NEJM 29;31:75 Percent Change BMD Changes at Total Hip 4 2 Antibody -2 12 18 24 3 3 Study Month Substudy, N=1.% P<.1 Crude Incidence (%) 8 4 2 Decreased New Vertebral Fracture 8% 95% CI (59 to 74%) P<.1 7.2% 2.3% Antibody Clinical vertebral fractures were also reduced 9%; P<.1 Cummings, et al. NEJM 29;31:75 Cummings, et al. NEJM 29;31:75 Page
Cumulative Incidence (%) 1 8 4 2 Nonvertebral Fractures 8.%.5% 12 18 24 3 3 Study Month 2% P=.11 95% CI, (5 to 33%) Cummings, et al. NEJM 29;31:75 is more effective for nonvertebral fracture in women with FN T-scores -2.5 Subgroup Overall Age (yea rs) < 75 75 Body Mass I nde x (kg/m 2 ) < 25 25 to < 3 3 Femoralneck BMD T-score Š -2.5 > -2.5 Prevalen t vertebral fracture Yes No Prior nonverteb ral fracture Yes No N 531 341 19 251 22 74 24 259 11 3 224 37 SF McClung, Coordinating preparation Center HR (95% CI).8 (.7,.95).78 (.3,.9).84 (.3, 1.12).2 (.48,.8).98 (.75, 1.3) 1.13 (.71, 1.78).5 (.51,.83).97 (.7, 1.23) 1. (.78, 1.44).71 (.58,.88).84 (.5, 1.9).77 (.2,.97) Interaction P-value.4.1.2.4.1 35%.4.5 1. 1.5 2 Favors Cumulative Incidence (%) 2. 1.5 1..5. Hip Fracture Rates represent Kaplan-Meier estimates at 3 months 1.2%.7% 12 18 24 3 3 Study Month 4% P=.3 95% CI (3 to 3%) Cummings, et al. NEJM 29;31:75 No increases in risk of Safety Impaired fracture healing, CVD, infections, cancer No ONJ in the osteoporosis trial (cases have been seen with treatment in patients with breast cancer) Increased Cellulitis (requiring hospital care): 3/1, Atopic dermatitis: ~1% more than placebo Cummings, et al. NEJM 29;31:75 Page 7
FDA approved indication for Women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fractures or patients who have failed or are intolerant to other available therapy in Men With Non-Metastatic Prostate Cancer Receiving ADT 148 men Undergoing bilateral orchiectomy or starting GnRH agonists Randomized to Anti-RankL Antibody mg or placebo SC every months for 3 months Smith et al. NEJM 29;31:745 Decreased risk of new vertebral fracture 4 2 Month 12 (N=73) RR.15 P=.4 Month 24 RR.31 P=.4 Antibody (N=79) Month 3 RR.38 P=. is critical to survival and evolution of the species causes breasts to develop and lactate during pregnancy causes resorption of bone to supply calcium for the milk No - pups die of starvation Percentage 1.9%.3% of Subjects 3.3% (%) 1.% 13 2 22 7 3.9% 1.5% 2 1 Smith et al. NEJM 29;31:745 Page 8
Cathepsin K Inhibitor Odanacatib Cathepsin K produced by osteoclasts, is released during bone resorption and degrades collagen Blocking Cathepsin K produces shallower resorption pits ODN is an antiresorptive Does it permit formation? (Uncoupling) Blocks the resorption of proteins which limits bone resorption to shallow pits. Theoretically, this would decrease resorption a little, but would allow full bone formation. Does it promote more formation than resorption? Geometric Mean Percent Change from Baseline 5 4 3 2 1-1 -2-3 s-bsap 1 3 12 18 1 3 12 18 Month Month ODN 3 mg 7 5 4 3 2 1-1 -2-3 -4-5 ODN 1 mg ODN 25 mg s-p1np ODN 5 mg SE = Standard error Page 9
Change in BMD over 3 months Transient rebound increase in bone resorption when treatment is stopped Lumbar Spine BMD (vs. baseline, %) Femoral Neck BMD (vs. baseline, %) Serum CTx (vs. baseline, %) Urine NTx (vs. baseline, %) Mean Percent Change From Baseline 9 8 7 5 4 3 2 1-1 -2 3 1 / 5 mg/ 5 mg/5 mg 12 18 Month 24 3 3 Mean Percent Change From Baseline 5 4 3 2 1-1 -2 3 1 / 5 mg/ 5 mg/5 mg 12 18 Month 24 3 3 Geometric Mean Percent Change from Baseline 15 125 1 75 5 25-25 -5-75 -1 1 W1 3 / 5 mg/ 5 mg/5 mg 12 18 Month 25 3 3 24 27 33 Geometric Mean Percent Change from Baseline 75 5 25-25 -5 1 W1 3 / 5 mg/ 5 mg/5 mg 12 18 Month 25 24 27 3 33 3 Eisman et al, ASBMR 29 Eisman et al, ASBMR 29 The Osteocyte Network The largest organ in the body Anti-sclerostin antibodies J Feng and LF Bonewald, UMKC (Seeman, E, NEJM, 2) Page 1
Strain Osteocytes receive signals (e.g. strain) then send signals d to osteoclasts and osteoblasts on the surface of bone Produced by mature osteocytes Not found in any other cell Produced in response to decreased loading Inhibits the formation of osteoblasts Sclerostin From Lynda Bonewald Sclerosteosis: lack of sclerostin Sclerosteosis Very high bone mass Narrowing of neural foramina Can increase intracranial pressure causing death Due to mutations in the SOST gene, decreasing the production of biologically active sclerostin Page 11
% Change from Baseline (Mean ± SEM) 2 15 1 5-5 -1 Single doses of 5 & 1 mg/kg Scl mab increased P1NP (formation) and decreased sctx (resorption) 5 mg/kg (N=) 25 PINP CTX 7 14 21 28 35 42 49 5 3 7 77 84 Time (day) 48 healthy postmenopausal women % Change from Baseline (Mean ± SEM) 25 2 15 1 5-5 -1 1 mg/kg (N=) 7 14 21 28 35 42 49 5 3 7 77 84 Time (day) Mean % Change from Baseline 7 5 4 3 2 1-1 -2-3 In healthy postmenopausal women, scl mab increased spine BMD 5-% and hip BMD 3-4% in < 3 months Pbo Spine 28 5 84 Time (day) 84 days (N=7) 1 mg/kg (N=) 3 mg/kg (N=) 5 mg/kg (N=) 1 mg/kg (N=) Scl Ab 48 healthy postmenopausal women Total Hip 28 5 84 Time (day) Pbo 84 days Scl Ab Forms new bone on quiescent surfaces Anti-sclerostin antibodies In general, osteoblasts form bone where it has been reabsorbed But anti-sclerostin antibodies induce formation of bone on quiet surfaces, such as the periosteum This increases the diameter - and bending strength - of long bones The most potent bone forming agent yet discovered Has the potential to rapidly restore bone mass and architecture to normal Highly specific to bone Human trials are in phase II Page 12
Myostatin Increasing muscle and bone mass Myostatin inhibits development and differentiation of muscle cells Animals with myostatin mutations (or knock-outs) outs) have much more muscle! Blocking myostatin increases callus formation and fracture healing The potential of Myostatin antibodies Mice Wild-type (WT) Myostatin KO Fractured fibula MSTN KO mice had more bone in callus at 2 and 4 weeks r Ideal for recovery after fracture May have added benefits of improved insulin sensitivity and cardiac function Anti-myostatin antibodies in early human trials An example new interventions that act on fundamental pathways, (such as mitochondrial function), to preserve muscle, slow aging, and increase bone mass Kellum, Bone 29;44:17-2323 Page 13
New treatments The new generation is based on fundamental mechanisms : the most potent antiresorptive yet Will odanacatib reduce nonvertebral fractures more than current treatments? Will anti-sclerostin antibodies cure osteoporosis? Will muscle building agents also build bone, prevent falls and dramatically decrease frailty fractures? Will we be able to afford new treatments? Page 14