Clinical utility of anti-sclerostin antibodies

Accepted Manuscript Clinical utility of anti-sclerostin antibodies

Michael R McClung PII: DOI: Reference:

S8756-3282(16)30374-X doi: 10.1016/j.bone.2016.12.012 BON 11213

To appear in:

Bone

Received date: Revised date: Accepted date:

29 August 2016 2 December 2016 16 December 2016

Please cite this article as: Michael R McClung , Clinical utility of anti-sclerostin antibodies. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Bon(2016), doi: 10.1016/j.bone.2016.12.012

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Clinical utility of anti-sclerostin antibodies

Michael R McClung

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Oregon Osteoporosis Center 2881 NW Cumberland Road Portland, OR 97210 (503) 929-9633 [email protected]

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The elucidation of sclerostin deficiency as the molecular pathogenesis of the high bone mass syndromes of sclerostiosis and van Buchem disease, and the pivotal role of sclerostin as a mediator of osteoblastic activity and bone formation, led to the concept that inhibiting sclerostin would be an attractive strategy to treat osteoporosis. (1) This idea became even more attractive when heterozygotes of the sclerostin deficiency syndromes were shown to have high bone mass and possible decreased fracture risk but were otherwise normal without evidence of deformities or neural compression due to bony overgrowth. (2,3) A robust preclinical program supported this concept. Studies in osteopenic rats and monkeys confirmed that inhibiting SCL with specific antibodies resulted in improved bone structure and normalized bone mass and strength. (4,5) This paper will review the current status of the evaluation of anti-sclerostin therapy in clinical trials.

Phase 1 studies

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The first clinical study involved 54 healthy men and postmenopausal women who received romosozumab (previously known as AMG 785), a humanized monoclonal antibody with high specificity for human sclerostin. (6) These patients were randomized to receive 0.1-10 mg/kg subcutaneously (SQ) or 1 or 5 mg/kg intravenously (IV). There were 6-9 patients per treatment arm. Following single doses, the marker of bone formation, serum procollagen type 1 N-terminal propeptide (P1NP), rapidly and substantially increased, reaching a peak of 184% above baseline at 29 days with the largest dose. The duration of the effect was related to the administered dose, and P1NP values gradually returned to baseline between 29 and 78 days after SQ dosing. Similar responses were observed with bone specific alkaline phosphatase (BSAP) and osteocalcin (OC). Unlike PTH analogs that stimulate bone resorption as well as formation, romosozumab reduced collagen type 1 C-telopeptide (β-CTX), a marker of bone resorption, by up to 49% percent, reaching a nadir on day 15 and gradually returning to baseline over the 85 day observation period. These divergent effects of romosozumab on bone formation and bone resorption resulted in a robust bone mineral density (BMD) response. BMD of the lumbar spine (LS) and total hip (TH), measured by DXA, increased by 5.2% and 1.1%, respectively, when measured 85 days after the single-dose.

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Encouraged by these results, an ascending multi-dose study with romosozumab was conducted to assess pharmacokinetics and pharmacodynamics of multiple dosing. (7) Romosozumab was administered by SQ injections of 1 or 2 mg/kg every two weeks (Q2W) or 2 or 3 mg/kg every four weeks (Q4W) for three months. The results were consistent with the single-dose study. The marker responses to sequential injections were maintained during the first two months of dosing but were somewhat blunted following the final dose compared to the initial dose. Pharmacokinetics in men and women were similar. The effects of romosozumab on trabecular and cortical structural parameters were assessed by high resolution computed tomography (HR-QCT) scans of the lumbar spine in 48 subjects (32 women, 16 men) with low bone mass in a placebo-controlled Phase 1b study. (8) Women received active treatment of 1 or 2 mg/kg Q2W or 2 or 3 mg/kg Q4W while men were given 1 mg/kg Q2W or 3 mg/kg Q2W for 3 months. Subjects were followed off therapy for an additional 3 months. All active treatment groups were combined for analyses. At 3 months, HR-QCT assessments of trabecular BMD and stiffness apparent density-weighted cortical thickness increased by 9.5% and 26.9%, respectively. The increase in trabecular thickness and decrease in trabecular separation were statistically significant from both baseline values and from the responses observed with placebo.

ACCEPTED MANUSCRIPT These improvements in structural parameters were maintained during the 3 month off-treatment follow-up period.

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Skeletal responses to blosozumab, an IgG4 humanized monoclonal anti-SCL antibody, were also evaluated in single and multiple dose phase 1 studies. (9) In the single-dose study, 60 subjects were randomized to receive placebo or 7.5, 25, 75, 225 or 750 mg blosozumab by IV infusion or 150 mg by SQ injection. The responses of the serum bone turnover markers P1NP, BSAP, OC and β-CTX were dose-dependent and similar to those observed with romosozumab. Maximum increases in bone formation markers were observed between 2 and 4 weeks with the increase in P1NP reaching 300% at 4 weeks with the highest IV dose. Baseline levels of BTMs were lower and absolute changes were somewhat smaller in patients who had previously received bisphosphonates than in treatment-naïve subjects. Dose-dependent increases in BMD were observed with improvements, compared to baseline, of 3.4% in the lumbar spine and 2.4% in the total hip observed after the 750 mg IV dose at day 85. Lumbar spine BMD increased by 2.4% with that dose in patients who had previously received bisphosphonate therapy.

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In the multiple dose study, healthy subjects received SQ doses of 180 mg Q4W, 270 mg Q4W or 270 mg Q2W or IV doses of 540 mg Q4W or 750 mg Q2W. The last dose was administered at 8 weeks. BMD was measured on day 85, and BTMs were followed for 12 weeks after the final dose. Increases in bone formation markers were dose dependent, but the temporal patterns of responses of individual markers differed. Serum P1NP reached a peak of about 300% above baseline at 2 weeks in the 750 mg IV Q2W group, remained relatively stable while dosing continued and then fell to about 100% above baseline at 141 days. The largest SQ dose (270 mg Q2W) produced an increase in P1NP of almost 150% at 2 weeks, but then values returned to baseline even as dosing continued. Serum β-CTX was promptly reduced and remained below baseline until dosing was completed.

Phase 2 studies

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The phase 2 romosozumab dose-ranging study evaluated treatment responses in 419 postmenopausal women ages 55-85 with low bone mass. (10) They were randomly assigned to receive monthly SQ doses of romosozumab (70, 140 or 210 mg) or Q3M doses of 140 mg or 210 mg, or placebo injections. Two additional groups were randomly assigned to receive open label alendronate 70 mg weekly or teriparatide 20 µg SQ daily. As in the Phase 1 study, romosozumab therapy resulted in rapid and substantial increases in P1NP but a decrease in serum β-CTX (Figure). P1NP values returned to baseline between 3 and 6 months and were below baseline for the remained of the treatment interval. All doses of romosozumab increased BMD at the lumbar spine and proximal femur. At 12 months, increases in lumbar spine and total hip BMD were significantly greater with romosozumab 210 mg QM, the dose chosen for Phase 3 studies, compared to teriparatide and to alendronate. (Table) During the second year of the study, markers of bone formation and resorption remained below baseline in patients who continued romosozumab. (11) Consistent with these results, BMD increased progressively during the second year of romosozumab therapy, but those increases were smaller (3.8% in the lumbar spine) than had occurred in the first year. After two years, romosozumab therapy was discontinued, and patients were randomly assigned to receive denosumab 60 mg SQ Q6M or placebo for 12 months. BMD values in the spine and hip returned to or toward baseline values. In patients who were switched to denosumab, BMD increases in lumbar spine (3.7%) and total hip (1.1%) were similar to the increases during the second year of

ACCEPTED MANUSCRIPT romosozumab therapy. Formation markers returned to baseline values while serum β-CTX rose to values significantly greater than baseline before falling toward pre-treatment values In a subset of patients from the romosozumab Phase 2 study, volumetric BMD (vBMD) was assessed by quantitative computed tomography in patients who received placebo (n = 27), teriparatide 20 ug daily (n = 31) or romosozumab 210 mg QM (n = 24) for 12 months. (12) The increases in vBMD observed in both the lumbar spine and total hip were significantly greater with romosozumab compared to teriparatide. (Table)

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In the Phase 2 dose ranging study with blosozumab, 120 postmenopausal women with low BMD were randomly assigned to receive SQ doses of 180 mg Q4W, 180 mg Q2W, 270 mg Q2W or placebo. (13) Dose-dependent increases in BMD occurred progressively over the twelve-month treatment with average gains, compared to placebo, of 17.7% and 6.2% observed at the lumbar spine and total hip, respectively, in the 270 mg Q4W group. No statistically significant changes were noted in BMD at the one-third radius site. Total body bone mineral content increased by 1.7%, 4.2% and 7.3% in the 180 mg Q4 W, 180 mg Q2W and 270 mg Q4 W groups, respectively.

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The patterns of changes in bone turnover markers were similar to those observed with romosozumab. With the largest dose of blosozumab, P1NP increased to a peak of about 160% above baseline at 4 weeks. Formation markers remained above baseline at 6 months with the larger two doses but returned to or near baseline at 12 months despite ongoing therapy. Serum β-CTX decreased as much as 40% at week 2 of treatment, returning to baseline at week 12 and thereafter remained somewhat below both baseline values and those in the placebo group.

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Upon discontinuation of blosozumab in all patients after 12 months, 106 patients began a planned interval of observation off therapy, and 88 completed the 52 week follow up. (14) BMD in the LS and TH decreased in each patient group, although average values in the LS remained greater than placebo, after discontinuing treatment in all three groups and at the TH in the two highest of those groups. In the 270 mg Q2W group, LS BMD was 6.9% higher than baseline and 8.2% greater than the placebo group at the end of the observation period, while values of the TH were 3.9% higher than baseline and 5.2% greater than placebo.

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Safety

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Bone formation markers, which were near baseline when blosozumab was discontinued, remained stable during the year off therapy. Serum β-CTX returned to baseline within four weeks of stopping therapy but then, for the two smaller doses, was slightly higher than the value in the placebo group at month 12.

Except for mild injection site reactions observed with both romosozumab and blosozumab, these agents have been well tolerated. One patient in a Phase 1 romosozumab study developed symptomatic hepatitis one day after receiving a dose of 10 mg/kg. (6) Transaminase values rose to 300% above baseline, peaking at day 3 before gradually returning to normal. Generalized increases in transaminase values have not been observed with anti-sclerostin therapy. Mild, transient and asymptomatic decreases in serum calcium and reciprocal increases in PTH have been noted, especially with the highest doses of both drugs. This is an expected response to the large increase in bone formation of new bone matrix upon beginning treatment. Anti-drug antibodies were detected in small numbers of subjects. Anti-romosozumab antibodies were detected in 20% of patients during the first year of therapy. Although 3% of patients had

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antibodies with neutralizing activity in vitro, there was no evidence that these antibodies altered pharmacodynamics, pharmacokinetics or clinical response. Anti-drug antibodies were detected in 32 of 91patients who received blosozumab during the treatment phase of the phase 2 study and in an additional 12 patients during the follow-up year. Most patients had normal or declining levels by the end of the observation. One patient developed neutralizing antibodies at week 24 of treatment. Titers continued to rise during the treatment phase, reaching a high of greater than 1:160,000 at month 12. The BMD response in this patient appeared to be blunted. The presence or titer of antibodies did not correlate with injection site reactions or other adverse events.

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Phase 3 studies

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The Phase 3 romosozumab fracture endpoint study (FRAME) evaluated the effectiveness of romosozumab 210 mg monthly compared to placebo for 12 months followed, in both treatment groups, by additional 12 months of denosumab therapy in 7180 women with postmenopausal whose average age was 71 years. (15) During the first 12 months of therapy, vertebral fractures occurred in 59 of 3322 patients in the placebo group and in 16 of 3321 patients in the romosozumab group in whom spinal x-rays were available for analysis. Compared to placebo, romosozumab reduced the incidence of new vertebral fractures by 73% (0.5% vs 1.8% with placebo). Clinical fracture risk was also reduced by 36% at 12 months. Romosozumab therapy reduced non-vertebral fracture risk by 25% compared to placebo, but this was not statistically significant (adjusted p value = 0.06). This analysis was complicated by a significant interaction of non-vertebral fracture risk reduction with geography with no effect being observed in Lain American study sites where the risk of nonvertebral fracture was quite low. A significant 42% risk reduction was observed in study sites from the rest of the world.

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The salutary effect on vertebral fracture risk was maintained during the year of denosumab therapy. Compared to the group of 3327 women that received placebo followed by denosumab (in whom 25 new vertebral fractures occurred during year 2), the risk of new vertebral fracture was decreased by 80% in the group of 3325 women (5 patients with fractures) who had received romosozumab before receiving denosumab.

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Follow-up of these patients in on-going. These results formed the basis of the recent filing with regulatory agencies for registration of romosozumab as a treatment for postmenopausal osteoporosis. A second Phase 3 fracture endpoint study will compare the effects of SQ romosozumab 210 mg monthly with oral alendronate 70 mg weekly for 12 months, followed by another year in which both treatment groups will receive alendronate. These large studies will also provide important information about the safety of romosozumab therapy. The Phase 3 fracture trial with blosozumab has been postponed indefinitely. No trials are currently being conducted with that agent.

Role of anti-sclerostin therapy in osteoporosis The information in hand, including the well characterized genetic defects, the robust pre-clinical program and the early clinical experience, provides optimism that anti-sclerostin therapy, with its unique ability to substantially increase new bone formation while inhibiting resorption, will be a welcome and important addition to our menu of treatment options. Whether warnings or precautions

ACCEPTED MANUSCRIPT will accompany registration is not yet known. From a clinical perspective, therapy should be avoided in patients with untreated hypocalcemia and in patients with osteomalacia or severe vitamin D deficiency because of the known effects of anti-sclerostin therapy on reducing serum calcium at the beginning of treatment. Treatment should also be avoided in patients with known skeletal metastases, other than myeloma, and with neurological compression syndromes until more is known about the safety of this therapy.

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We still have much to learn about how this new therapy will be incorporated into daily clinical practice. It is my opinion that romosozumab will be an appropriate initial therapy for patients with severe osteoporosis and very low BMD who are in need of skeletal restoration and reconstruction. It is apparent from the Phase 2 study that the anabolic effect of romosozumab therapy in humans lasts only a few months. While the mechanism of that transient effect is unclear, this fact did influence the design of the Phase 3 studies in which romosozumab treatment for 12 months is followed by an anti-remodeling agent. On the basis of the FRAME study design and results, romosozumab will likely be approved for the treatment of patients at high risk of fracture for an interval of 12 months to be followed by an anti-remodeling agent. Because some patients may then be candidates for another course of romosozumab, it will be important to assess the re-treatment responses in patients previously treated with bisphosphonates and/or denosumab. The design of the Phase 3 studies, was based on the transient anabolic effect noted in the Phase 2 trial and will likely determine the doing strategy approved by regulatory agencies.

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Possible use in other populations and diseases

Osteoporosis in men:

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With its potent anabolic effect, romosozumab has interesting potential as a treatment of osteoporosis in other populations and in some other diseases. Preclinical evidence for some of these possibilities has been reviewed elsewhere in this journal. Clinical studies in other groups of patients have been begun or completed but the results are not yet available.

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A phase 3 registration study evaluating the safety and effectiveness of romosozumab in men with osteoporosis has recently been completed (NCT02186171). The study will assess changes in BMD, bone turnover markers and adverse events during 12 months of treatment. Based on the similar pharmacokinetic and BMD responses observed in men and women in Phase 1 studies, the Phase 3 study is expected to show BMD responses similar to those observed in women. Those Phase 3 data should be sufficient for registration of the drug to treat osteoporosis in men.

Glucocorticoid-induced osteoporosis: Impaired bone formation is a major factor in the pathogenesis of glucocorticoid-induced osteoporosis (GIO). Anti-sclerostin therapy is effective in pre-clinical models of GIO and could be an important strategy for treating patients on long-term glucocorticoid therapy. (16)

Severe renal dysfunction

ACCEPTED MANUSCRIPT Renal osteodystrophy, especially adynamic bone disease, is a serious skeletal disorder without effective therapy. A trial evaluating the effect of romosozumab in patients with stages 4 and 5 renal impairment has been completed. (NCT01833754)

Multiple myeloma

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This disorder is characterized by marked inhibition of bone formation and very high bone resorption resulting in common skeletal complications. Anti-sclerostin therapy increases bone formation in animal models of myeloma with no apparent stimulation of tumor growth. (17) Such treatment, especially if combined with a potent inhibitor of bone resorption, might be very useful to manage the skeletal aspects of this disease.

Osteogenesis imperfecta

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Bone formation is impaired in patients with osteogenesis imperfecta (OI) and related disorders of collagen synthesis. Serum sclerostin levels are normal in patients with OI, but those patients may still benefit from the anabolic effect of anti-sclerostin therapy. (18) For those patients who make abnormal collagen, it would be important to evaluate the effect of anti-sclerostin therapy on fracture risk. Appreciating the difficulty in conducting such a study and the low probability of having that information, the effects of anti-sclerostin therapy on bone strength and structure will need to be assessed very carefully in these patients.

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Other disorders of impaired bone formation

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Markedly impaired bone formation is a component of chronic immobilization and serious eating disorders. Serum sclerostin levels are elevated in both disorders, suggesting that sclerostin inhibition might be an effective therapy. (19, 20)

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Patients previously treated with bisphosphonates

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Many patients who may be candidates for anti-sclerostin therapy will have received therapy with bisphosphonates. In rats, prior or current bisphosphonate therapy did not impair the anabolic response the anti-sclerostin therapy. (21) In contrast, the BMD response to blosozumab was reduced in bisphosphonate-exposed patients. (13) A study evaluating the effect of romosozumab on BMD and bone turnover in patients previously treated with alendronate has been completed. (NCT01588509)

Fracture healing Beneficial effects on fracture healing have been shown in animals receiving anti-sclerostin therapy. (22) Clinical trials to evaluate the effect of romosozumab on healing of wrist fractures and of tibial diaphyseal fractures after intramedullary nailing have been completed. (NCT01081678 and NCT00907296) However, the fracture repair development program was abandoned because of the

ACCEPTED MANUSCRIPT difficult logistics in conducting the study and the high hurdles that exist to achieve regulatory approval for that indication.

Conclusions

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The novel skeletal effects of anti-sclerostin antibody therapy, especially its unprecedented acute anabolic action, offer great promise for the treatment of many forms of osteoporosis and disorders of impaired bone formation. The Phase 3 studies will provide important information about safety, and romosozumab will become an important part of our treatment of osteoporosis. Exploring the effects of this therapy in other conditions will be exciting.

ACCEPTED MANUSCRIPT References 1. Sharifi M, Ereifej L, Lewiecki EM. Sclerostin and skeletal health. (2015) Rev Endocr Metab Disord. 2015;16:149-56. 2. van Lierop AH, Hamdy NA, van Egmond ME, et al. Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res. 2013;28:848-54.

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3. van Lierop AH, Hamdy NA, Hamersma H, et al. Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. J Bone Miner Res. 2011;26:2804-11.

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4. Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res. 2010;25:948-59.

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5. Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. 2009;24:578-88.

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6. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26:19-26.

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7. Padhi D, Allison M, Kivitz AJ, et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol.2014;54:168-78.

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8. Graeff C, Campbell GM, Peña J, et al. Administration of romosozumab improves vertebral trabecular and cortical bone as assessed with quantitative computed tomography and finite element analysis. Bone. 2015;81:364-9.

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9. McColm J, Hu L, Womack T, Tang CC, Chiang AY. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res. 2014;29:935-43. 10. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370:412-20.

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11. McClung MR, Chines A Brown JP, et al. Effects of 2 years of treatment with romosozumab followed by 1 year of denosumab or placebo in postmenopausal women with low bone mineral density. ASBMR 2014 abstract 1152. 12. Genant HK, Engelke K, Bolognese MA, et al. Effects of romosozumab compared with teriparatide on bone density and mass at the spine and hip in postmenopausal women with low bone mass. J Bone Miner Res. 2016;Aug 3. doi: 10.1002/jbmr.2932. [Epub ahead of print] 13. Recker RR, Benson CT, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Miner Res. 2015;30:216-24.

ACCEPTED MANUSCRIPT 14. Recknor CP, Recker RR, Benson CT, et al. The effect of discontinuing treatment with blosozumab: follow-up results of a phase 2 randomized clinical trial in postmenopausal women with low bone mineral density. J Bone Miner Res. 2015;30:1717-25. 15. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis N Engl J Med. 2016;375:1532-43. 16. Yao W, Dai W, Jiang L et al. Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int. 2016;27:283-94.

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17. Delgado-Calle J, Anderson J, Cregor MD et al. Genetic Sost deletion or pharmacological inhibition of sclerostin prevents bone loss and decreases osteolytic lesions in immunodeficient and immunocompetent preclinical models of multiple myeloma. J Bone Miner Res. 2016, Annual Meeting Abstract #1091, pS30. 18. Palomo T, Glorieux FH, Rauch F. Circulating sclerostin in children and young adults with heritable bone disorders. J Clin Endocrinol Metab. 2014;99:E920-5.

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19. Gaudio A, Pennisi P, Bratengeier C, et al. Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab. 2010;95:2248-53.

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20. Maïmoun L, Guillaume S, Lefebvre P, et al. Role of sclerostin and dickkopf-1 in the dramatic alteration in bone mass acquisition in adolescents and young women with recent anorexia nervosa. J Clin Endocrinol Metab. 2014;99:E582-90.

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21. Li X, Ominsky MS, Warmington KS, Niu QT, et al. Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats. Endocrinology. 2011;152:3312-22.

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22. Liu Y, Rui Y, Cheng TYet al. Effects of sclerostin antibody on the healing of femoral fractures in ovariectomised rats. Calcif Tissue Int. 2016;98:263-74.

ACCEPTED MANUSCRIPT Legend to Figure

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Percentage Change from Baseline in Bone-Turnover Markers. Shown are median changes in the bone-formation marker serum procollagen type I N-terminal propeptide (PINP; upper panel) and the bone-resorption marker serum β-isomer of the C-terminal telopeptide of type I collagen (β-CTX; lower panel) for 210-mg monthly dose of romosozumab ◊ and placebo ●. Bars indicate interquartile ranges. The asterisk indicates P<0.04 for the comparison of the 210-mg monthly dose of romosozumab with placebo.

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Figure

ACCEPTED MANUSCRIPT Table. Areal and volumetric BMD changes in the romosozumab Phase 2 study. (percentage changes from baseline)a From references and .

Endpoint

Placebo

Romosozumab Teriparatide 210 QM SQ 20 ug/day SQ

Alendronate 70 mg QW

47

49

46

49

Lumbar spine

-0.1

11.3 a

7.1

4.1

Total hip

-0.7

4.1 a

1.3

1.9

1/3 radius

-0.9

-1.3

-1.7

-0.3

Volumetric BMD by QCT (N)

27

24

31

Not assessed

Lumbar spine integral

-0.8

17.7

Lumbar spine trabecular

NR

Lumbar spine cortical

NR

Total hip integral

0.3

Total hip trabecular

NR

Total hip cortical

NR

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20.1

13.7a

5.7

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12.9

18.8

4.1a

1.2

10.8 a

4.2

1.1

-0.9

Statistically significant compared to teriparatide. NR: not reported

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Areal BMD by DXA (N)

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MCCLUNG – Highlights

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Based on a strong platform of preclinical data, anti-sclerostin therapy has been evaluated in the clinical setting. Unique effects on bone remodeling are observed, characterized by a marked but transient increase in bone formation and a decrease in bone resorption. Rapid increases in bone mineral density are observed, and a recent Phase 3 study demonstrated significant reductions in vertebral and clinical fractures in postmenopausal women with osteoporosis. There are potential uses of anti-sclerostin therapy in other bone disorders, especially those characterized by low bone formation.