ROMOSOZUMAB MONOCLONAL ANTIBODY- SCLEROSTIN JOSEPH M. LANE, MD HOSPITAL FOR SPECIAL SURGERY Weill Cornell Medicine NEW YORK, NY Disclosure Joseph M. Lane, MD CollPlant, Inc: Stock Options Merck: Research Support On Foundation: Consultant/Board Member Radius Health, Inc: Consultant Terumo BCT Consultant NIH Study Section Research Grants OSTEOPOROSIS Fragility (Iow energy) Fractures Hip Fracture Mortality (1 year) Female ~ 24% Male ~ 30% 70% Lose One Level Function ANTIRESORPTION Bisphosphonates ↓R ↓F Denosumab ↓R SERMS ↓R Only spine ANABOLIC Teriparatide ↑F Late ↑R Abaloparatide ↑F Late ↑R ROM0S0ZUMAB ↑F ↓R ROMOSOZUMAB SCLEROSTIN MONOCLONAL ANTIBODY WHAT DO WE KNOW ABOUT SCLEROSTIN? Odd diseases Wnt Bone Pathway SCLEROSTIOSIS Inactivating Mutation SOST (codes for sclerostin) van Buchan Disease less severe ↑ Bone Mass ↓ Fractures SCLEROSTIN Secreted By Osteocyte (low mechanical load) Binds to LRP 5/6 Inactivates Wnt Pathway Ceases Osteoblastic Bone Formation Shah AD et al. Int J Womens Health, 2015. Pre-Clinical Data Romosozumab Genetic Deficiency Sclerostin Rodents ↑Bone Mass ↑ Bone Formation Trabecular Cortical Normal Bone Quality ↑Bone Strength Normal Mineralization Lack of Brittleness Sclerostin Monoclonal Antibody Animals ↑ Trabecular/Cortical Thickness ↓ Cortical Porosity Corrected Ovariectomy ↑ Bone Density LS, FN, Prox Tib, Distal Radius RANKL INHIBITOR AMPLIFIED GAIN Comparison of Changes in Areal And Volumetric BMD 12 Months Romo vs Teriparatide Romo Teriparatide 210mg qm 20ug/d Areal BMD (DXA) L-Spine 12.3%* 6.9%* Total Hip 3.9%* 0.8% Integral V-metric BMD (QCT) 17.7% * L-Spine 4.1% 12.9%* Total Hip 1.2% * p<.05 Genant JBMR 2017 Comparison of Changes in Estimated Bone Strength Finite Element Analyses Romo Teriparatide 210mg qm 20μg/d Estimated Bone Strength FEA by QCT 27.3%* 18.5% L-Spine 12.3%* 3.6%* 18.5% Total Hip -0.7% * p<.05 Keaveny JBMR 2017 Romosozumab vs. Teriparatide Postmenopausal Women Transitioning from Oral Bisphosphonates 12 month Total Hip Romosozumab 2.6% Teriparatide -0.6% p<.0001 Langdhal –Lancet 2017 Teripadatide vs. Abaloparatide vs. Romosuzmab – Heal/Fusion Teripadatide Abalo Romo Fx Healing ++ ? NS Spine Fusion + + ? NS Implant Fixation ++ ? NS Adverse Events Romo vs. Teriparatide Romo Teriparatide Nasopharyingitis 13% 10% Hypercalcemia <1% 10% Arthralgia 10% 6% Serious 8% 11% Discontinue 3% 6% Safety Information Potential risk of myocardial infarction, stroke and cardiovascular death Hypocalcemia Hypersensitivity Osteonecrosis of Jaw (Reported) Atypical femoral fracture (Reported) What is Cancer Risk with Romosozumb Scientific weight of evidence Low carcinogenic risk to humans No carcinogenic in a rat lifetime study Conclusion – Not pose a carcinogenic risk Chouinand – Rgulatory Toxicology 2016 ROMOSOZUMAB IN RADIATION Accelerates DNA Repair Structure and Strength in Radiated Bone No ↑ In Osteosarcoma HIGHLIGHTS Most effective bone formation. Coupled with Denosumab does not enhance fracture healing/spine fusion Rescues prior bisphosphonate treatment DOSAGE: Correct calcium/vitamin D 210mg (1/2 dose each upper arm) monthly x 12 Follow with Denosumab for 2 years.