Osteoporosis: the final frontier 9 January 2015 Adrian Moore

2 The science creative quarterly The skeleton

Bone cells 3 Osteoclasts: multinucleated giant cells that break down bone Osteoblasts: cells that lay down bone Osteocytes: cells within the bone matrix 5-10% of our bone structure is replaced each year. This is a normal process that allows repair of tiny cracks and structural weaknesses Osteoclast Osteoblasts Osteocytes

4 Bone quantity is the net effect of bone formation and bone resorption Normal Osteoporosis Animation courtesy of Dr Susan Ott, University of Washington

5 Osteoporosis is a serious and growing problem Human cost: One year after hip fracture, of the patients that survive: 40% of patients are unable to walk independently, 60% have difficulty with at least one essential activity of daily living, and 80% are restricted in activities, such as driving and grocery shopping C. Cooper The crippling consequences of fractures and their impact on quality of life Am J Med Healthcare cost: In the US the estimated direct expenditure in hospitals and nursing homes for osteoporosis-associated fractures was $18 billion in National Osteoporosis Foundation Future projection: The World Health Organisation estimates that the number of fractures worldwide due to osteoporosis will rise from 1.7 million in 1990 to 6.3 million in 2050

Medications for osteoporosis 6 Most available osteoporosis drugs are anti-resorptives

Sclerosteosis – An inherited high bone mass disorder 7 Bone deposited in a normal manner and is very strong No reported traumatic fractures in sclerosteosis patients Brunkow et al 2001* reported a point mutation leading to loss of function Gene termed SOST and its protein product sclerostin The genetics of sclerosteosis suggests that targeting the protein sclerostin could result in bone growth Normal Sclerosteosis *Brunkow, M.E. et al., Am. J. Hum. Genet. 2001

What is sclerostin? Sclerostin is a 190 amino acid glycoprotein It contains a cystine knot motif from which 3 loops emanate The protein was cloned (and patented) by scientists at Celltech R&D An antibody project, targeting sclerostin, was instigated with the main indication being post menopausal osteoporosis An agreement was signed between Amgen and the former Celltech organisation in 2002 to cover the development and commercialisation of sclerostin antibodies Veverka et al JBC 2009 NMR structure of sclerostin

Where is it found? 9 Sclerostin is produced by the osteocyte and negatively regulates bone formation by limiting the anabolic output of the osteoblast lineage

What does it do? 10 Modified from No bone formation Bone formation

Wild typeTransgenic More in formation on SOST transgenics: Winkler et al Embo J. 2003;22:6267–6276 Phenotype of sclerostin KO and transgenic mice Sclerostin KO Wild type Li et al JBMR 2008 KO: dense strong bones Transgenic: weak brittle bones

Sclerostin antibody reverses bone loss in a rat model of post menopausal osteoporosis OVX + Scl-Ab Sham OVX L4-L5 Vertebra SHAM OVX *p<0.05 Scl-Ab * * Maximum Load [N] Ominsky et al JBMR 2006; 21(1): S44. Tibia-Femur

P1NP sCTx Adapted from Padhi D, et al. J Bone Miner Res. 2010; DOI /jbmr Time (Day) Mean Percent Change From Baseline Time (Day) mg/kg 3 mg/kg Placebo SC (n = 14) 0.1 mg/kg SC (n = 6) 0.3 mg/kg SC (n = 6) 1 mg/kg SC (n = 9) 3 mg/kg SC (n = 6) 5 mg/kg SC (n = 9) 10 mg/kg SC (n = 6) 5 mg/kg Romosozumab increased a marker of bone formation and decreased a marker of bone resorption

Bone mineral density – Year Month Percent Change from Baseline Month Lumbar SpineTotal Hip Romosozumab 210 mg QMALN TPTD Placebo McClung et al. NEJM 2014;370:5. Data are means and 95% CIs 11.3% 4.1%

Space, the final frontier 15 July 20, 1969, Neil Armstrong became the first man on the moon …and in 45 years we’ve gone no further afield… Images courtesy of NASA History Office and the NASA JSC Media Services Center.

Challenges of spaceflight are more biological than engineering 16 Increased radiation levels Redistribution of fluid to the upper body Increased intracranial pressure and disrupted vision Back and abdominal pain Disturbed circadian rhythm, sleep loss and fatigue Raw and painfully sensitive skin Loss of muscle mass Loss of bone mass Percent change in BMD per month of spaceflight LeBlanc JMNI % -1.06% -0.04% …and if that leaves you wanting to cry - don’t!

Effects of sclerostin antibody on bone loss in space Experimental design Female, C57Bl/6N mice 9 weeks old at launch 4 groups: Ground + vehicle (n=15) Ground + sclerostin antibody (n=15) Flight + vehicle (n=15) Flight + sclerostin antibody (n=15) Mission Flight: on STS-135 for 13 days Bouxsein et al, ASBMR Annual Meeting 2012.

Trabecular bone microarchitecture improved by Scl-Ab BV/TV (%) TbTh (µm) TbN (mm -1 ) # p <0.05 Gr-Veh vs FL-Veh GroundFlight Veh # # SclAb FL-Veh GR-SclAb FL-SclAb GR-Veh Bouxsein et al, ASBMR Annual Meeting 2012.

Stiffness (N/mm) Ground Flight Veh SclAb # Maximum Load (N) Ground Flight Veh SclAb # Energy to Failure (mJ) Ground Flight Veh SclAb # Femoral biomechanical properties by 3 point bending Bouxsein et al, ASBMR Annual Meeting 2012.

Acknowledgments 20 Martyn Robinson, UCB Romosozumab project teams at UCB and Amgen STS-135 Musculoskeletal Research Team

Thanks!