Disclosures New Drugs for Osteoporosis and Bone Disorders · 1 New Drugs for Osteoporosis and Bone Disorders Edward Hsiao, MD, PhD University of California, San Francisco Division

1

New Drugs for Osteoporosisand Bone Disorders

Edward Hsiao, MD, PhD

University of California, San FranciscoDivision of Endocrinology and Metabolism

Metabolic Bone ClinicInstitute for Human Genetics

2015 UCSF Advances in Internal Medicine

Disclosures• Edward Hsiao receives research grant support

from Clementia Pharmaceuticals for unrelated clinical trials. He has no conflicts of interest.

• This presentation includes discussion of off-label, investigational use of a commercial product, or drugs that are not FDA approved.

• Care should be guided by expert opinion and literature. As always, we encourage the application of sound clinical judgment on a case-by-case basis

Objectives• Brief review of mechanism

• Osteoporosis drugs– New Anabolics

• Sclerostin antibodies• PTH analogs

– New Antiresorptive• Cathepsin K inhibitor

– Discontinued strategies

• Rare bone diseases– Hypophospatasia

Images adapted from the International Osteoporosis Foundation, Vertebral fracture teaching slide kit I (2010)

Normal

Osteoporotic

Effective treatments require understanding bone remodeling

Treatment goals: Bone formation Bone turnover

Osteoclasts

Osteocytes Calcified bone matrix

Bone lining cells

Osteoblasts

Resorbs bone Forms bone

2

Current Treatments for Osteoporosis

Decrease Bone Turnover• Hormone Therapy (HT)• SERM/Raloxifene (Evista)• Calcitonin (Miacalcin)• Bisphosphonates

– Alendronate (Fosamax)– Risedronate (Actonel)– Ibandronate (Boniva)– Zoledronate (Reclast/Aclasta)

• (Strontium ranelate)• RANKL inhibitors

– Denosumab (Prolia)

Increase Bone Formation• Parathyroid hormone

(rPTH, Teriparatide)

Recent Changes in Drugs for Osteoporosis

• Antiresorptives– Cathepsin K inhibitor

• Ondanacatib

– New considerations for denosumab

– Restrictions on strontium ranelate (in EU market)

– Vibration Therapy

• Anabolics– Anti-sclerostin

antibodies• Romosozumab• Blomosozunab

– PTHrP analog• Abaloparatide



• Ondanacatib







Sclerostin is a Key Mediator of Bone Formation

Frizzled

LRP5/6

WntSclerostin

β-Catenin

Activation of boneFormation pathways

XX

Brunkow et al. Am J Hum Gen 2001

Sclerosteosis

Normal

3

Anti-Sclerostin Antibody #1:Romosozumab

• Romosozumab (Amgen/UCB: AMG785, CDP7851)– Humanized monoclonal antibody

• Phase 1 study:– Single dose of AMG785, 72 men and women;– Peak serum concentration achieved after 1 week sq– Half life of 11-18 days– Dose ranging was done from 0.1-10 mg/kg– 10mg/kg (maximum dose tested)

• 120-184% increase in P1NP, BSAP, Osteocalcin• 54% decrease in CTX• Largest BMD effect at day 85• +5.3% lumbar spine BMD• + 2.8% in total hip BMD

Padhi, et al. JBMR 2011

Romosozumab: Phase I• Additional Phase I study

– Multiple doses– 32 postmenopausal women with low bone

mass• 6 doses, 1-2 mg/kg every 2 weeks, or• 3 doses of 2-34 mg/kg every 4 weeks, or

placebo– 16 healthy men with low bone mass.

• 1 mg/kg every 2 weeks, or• 3 mg/kg every 4 weeks, or placebo

Padhi, et al. J Clin Pharm 2014

Romosuozumab

• 12 weeks of drug, 12 weeks of followup• Appropriate changes in serum markers

observed.• No major effect on hip BMD• Persistence of effect after dosing stopped

Padhi, et al. J Clin Pharm 2014

Romosozumab: Phase II• 419 postmenopausal women

– T score between -2.0 and -3.5 in spine, total hip or femoral neck.

– Monthly sq (70, 140, or 210 mg) or every 3 months (140 or 210 mg), for 12 months

– Open label comparison to • Alendronate 70 mg weekly• Teriparatide 20 ug/day

4

Romosozumab Gives Higher Increase in BMD

• Every 3 months – same as 70 mg/mo dose– Approx 5% increase in BMD at spine– Bone formation markers return to normal after 6-12 mo

Romosozumab: Phase III• Recent announcements indicate that it meets goals, but full

publications pending

• STRUCTURE trial* (Sept 2015 press release)– 436 postmenopausal women previously treated with

bisphosphonates– Romosozumab vs teriparatide– Met goals for total hip BMD

• FRAME trial** (Feb. 2016 press release)– 7180 patients, 210 mg sq/month– Reduced incidence of new vertebral fractures at 12 and 24 mo– Reduced incidence of clinical fractures at 12 mo– Unclear benefit for non-clinical fractures at 12 and 24 mo.

*STudy evaluating effect of RomosozUmab Compared with Teriparatide in postmenopaUsalwomen with osteoporosis at high risk for fracture pReviously treated with bisphosphonatE therapy** FRActure study in postmenopausal woMen with ostEoporosis

Romosozumab Side Effects(Reported in Phase I-III)

• Injection site reactions• No clear increase in serious adverse events

over alendronate, teriparatide• 20% develop binding antibodies, with 3%

showing in vitro blocking ability, but subjects still showed biologic response

• Awaiting results of Phase III for full profile

Anti-sclerostin Antibody #2: Blosozumab

• Humanized monoclonal antibody– Eli Lilly (LY2541546)

• Phase I trials– Single and multiple dose regimens tolerated up to

750 mg every 2 weeks for 8 wks– 3.4-7.7% increase in lumbar BMD at Day 85

McColm, et al. JBMR 2014

5

Blosozumab: Phase II

• 120 postmenopausal women, T score between -2.0 and -3.5

23996473

Recker, et al. JBMR 2015

Lumbar Spine Total Hip

Blosozumab: Phase IIDurability of treatment

• Followup study for 1 year post treatment– 88 of 120 women previously studied– Suggests antiresorptive will be needed

Recknor, et al. JBMR 2015



• Ondanacatib







Osteoblast Activation by PTHrP: Parathyroid Hormone Related Protein


Calcified bone matrix

Bone lining cells

Osteoblasts

PTHPTHrP

PTH/PTHrP Receptor

Gs GPCR boneanabolic response

6

Abaloparatide: A PTHrP analog• Synthetic peptide analog of human

PTHrP• Phase II:

– 24 weeks of daily sq injections• Postmenopausal women• 20, 40, or 80 ug vs 20 ug of teriparatide

– Lumbar spine BMD increased 2.8-6.7%, vs 5.5% in teriparatide and 0.8% in placebo

– Femoral neck increased 1.4-2.6%, vs. 0.5% in teriparatide and 0.4% in placebo

Leder, et al. JCEM 2015

Abaloparatide: Phase III• ACTIVE fracture prevention trial

– 2463 postmenopausal women– 18 mo daily 80 ug abaloparatide vs placebo vs 20 ug

teriparatide.– 89% decrease in new fracture rate vs. placebo– Teriparatide showed an 80% decrease

• No significant differences in wrist fractures• Increased BMD in spine and hip at 6, 12, and 18 months

– Major complications: hypercalcemia, and injection site reactions.

• Extension trial in progress

2015 Endocrine Society poster: LB-OR01-3



• Ondanacatib







Cathepsin K: Functions in Osteoclast Resorption Pits


Osteoclasts

Osteocytes

Resorbs bone

Cathepsin K- secreted by osteoclasts- cleaves helical collagen- induces bone resorption

7

Ondanacatib: Anti-Cathepsin K• Related to two other Cathepsin K inhibitors

– Relacatib: nonselective inhibitor of K, L, V, and S• No clinical information• Kumar, et al. Bone 2007 (monkey model)

– Balicatib: showed BMD increases, but had cutaneous adverse events.• Adami, et al. JBMR 2006

– Ondanacatib: selective for Cathepsin K and orally bioavailable.

• Bone, et al. JBMR 2009

Ondanacatib: Phase II

• 399 postmenopausal women– Generally well tolerated– No significant major side effects reported



• Ondanacatib







Denosumab• Human monoclonal antibody that inhibits RANKL (required for

osteoclast function and survival)

• Given 60 mg sq every 6 months over 3 years reduces fracture risk (FREEDOM) and Freedom extension

Vertebral Non-vertebral

Hip N (Ref #)

Alendronate (10 mg qd)

0.55 (0.43-0.69)

0.84(0.74-0.94)

0.60(0.40-0.92)

12,068(2)

Zoledronate(5 mg/yr iv)

0.30(0.24-0.38)

0.75(0.64-0.87)

0.59(0.42-0.83)

7,765(1)

Denosumab(60 mg/6 mo sq)

0.32*(0.26-0.41)

0.80*(0.67-0.95)

0.60(0.37-0.97)

7868(3)

Relative risk of drug vs. placebo* Hazard ratios (secondary endpoints of study)

1. Black, et al. NEJM 2007 (HORIZON)2. Wells, et al. Cochrane DB or Syst. Rev. 2008 (CD001155 Alendronate)3. Cummings, et al. NEJM 2009 (FREEDOM)

8

Long-term Denosumab Use• FREEDOM extension (total of 5 years) just reported, with

persistent gains in BMD and fracture risk (1)

• Transition from alendronate to 1 year of denosumab appears safe and may have a slightly improved BMD (no fracture data) (2)

• Likely cost effective, particularly for patients with low compliance to bisphosphonates (3,4)

• Main complications:– skin infection, urinary tract infection; dermatitis /eczema/rash– ONJ reported in cancer patients receiv ing high doses (120 mg every 4 weeks)

of denosumab (5, 6) and was seen in 2 patients in the FREEDOM extension (1)– Likely occurs at same rate as bisphosphonates, during c linical trials

1. Papapoulos, et al. JBMR 20112. Kendler, et al. JBMR 20103. Jonsson, et al. Ost. Int 2011 (Sweden)4. Hiligsmann, et al. Pharmacoeconomics 2011 (Belgium)5. Smith, et al., Lancet 2012 (Prostate cancer)6. Stopeck, et al. J Clin Oncol 2010 (Breast cancer)

Antiresorptives May Have Direct Anti-Tumor Effects

• Denosumab– Increased disease free survival in breast cancer (no

overall survival data; vs. placebo) (1)– Prolongs survival in lung cancer vs. zoledronate (2)– Delay metastasis in prostate cancer (3) probably

better than zoledronate (4)• Zoledronic Acid

– Does not work as an adjuvant for early breast cancer, but does reduce bone metastases (5)

1: Gnant, et al. Lancet 20152: DeCastro, et al. Clinical Lung Cancer 20153: Smith et al., Lancet 2012

4: Fizazi, et al Lancet 20115: Coleman, et al. Lancet 2014; Coleman NEJM 2011

Meet Thy Neighbor… Recent Changes in Drugs for Osteoporosis


• Ondanacatib







9

Strontium RanelateRestrictions in EU Market

• Was never FDA approved in the US– Previously approved by the EMA in Europe

• Often confused with other forms, such as strontium citrate (available in health food stores)– Other forms not studied for bone, so unknown efficacy or

toxicity

Strontium RanelateCurrent Recommendations

• Reportedly increased incidence of cardiovascular events in multiple randomized control trials

• Unclear if this is also seen in real life, as trials may have had higher proportion of subjects with cardiovascular diase

• Recommendation to restrict to severe osteoporosis patients only, and only in patients with low baseline cardiovascular risk (though specifics are still vague)

Vibration Therapy for Osteoporosis?

• Originally developed for space flight– Vibrations for 25-30 Hz at 0.3 x g can

prevent bone loss • deZeptnek, et al. J Rehab Res Dev 2009

– Vibration studies in sheep forelimbs (20 min/day 5 days/week) can increase bone formation in limbs • Rubin, et al. Nature 2001

– Seemed potentially useful for osteoporosis

Vibration Therapy is Falling out of Favor

• Human trials have been quite variable, with some suggesting gain but others not

• Best trial is of 202 postmenopausal women• 30 vib/min, 20 min per day, 0.3 x g (low energy)• 90 vib/min, 20 min per day, 0.3 x g

• After 1 year – no difference in BMD• Main adverse events: dizziness, fainting due

to passive standing x 20 min.• Slatkovska, et al. Ann Int Med 2011• Wysocki, et al. Ann Int Med 2011

10

Vibration Therapy is not FDA Approved

• Often sold on the internet, and many devices have higher energies (> 1 x g)

• Currently, no FDA oversight for devices

• Being investigated for other situations, such as spinal cord injury

• Vibration exposure is regulated in the workplace as a hazard

• http://www.cdc.gov/nios h/docs/89-106/89- 106.pdf

Objectives• Brief review of mechanism

• Osteoporosis drugs– New Anabolics

• Sclerostin antibodies• PTHrP analog

– New Antiresorptive• Cathepsin K inhibitor

– Discontinued strategies

• Rare bone diseases– Hypophospatasia

Images adapted from the International Osteoporosis Foundation, Vertebral fracture teaching slide kit I (2010)

Normal

Osteoporotic

Hypophosphatasia: treatment by enzyme replacement

• Deficiency of tissue non-specific alkaline phosphatase (ALPL/TNSALP)– Partial or complete loss of function– Hypomineralization, respiratoy compromise– Mild forms may show progressive osteomalacia;

poor dentition– Multiple mutations have been identified– Increase pyridoxal 5’ phosphate (PLP),

phosphoethanolamine (PLP), and PPi

Whyte, et al. JCEM 2016Whyte, et al. NEJM 2012

Major Forms of Hypophosphatasia

• Perinatal – usually autosomal recessive– Respiratory distress, renal failure, soft bones

• Adult form – usually partial mutations, heterozygous– Skeletal manifestations, early dental loss– Low age adjusted alkaline phosphatase

• Traditional treatments:– Optimization of calcium and vitamin D– Treatment for craniosynostosis– Experimental treatments with teriparatide to favor

mineralization

11

Asfotase alfa – a new drug forHypophosphatasia

• Recombinant TNSAP (ENB-0040) with a peptide tag to target specifically to bone– Improved respiratory outcome

for invantile form (76% vs 5% from historical controls)

– Improved skeletal findings; increased PTH levels, requiring calcium supplements

Whyte, et al. JCEM 2016Whyte, et al. NEJM 2012

Asfotase Alfa Approval

• FDA approved for perinatal, infantile, and juvenile onset hypophosphatasia

• Also approved in the EU

• Injections 3-6 times/week

• Currently being studied for adult HPP

Conclusions• Several new medications for osteoporosis and other

bone diseases coming to market soon

• New anabolic drugs– Anti Sclerostin Antibodies: Romosozumab and Blosozumab– PTHrP Analog: abaloparatide

• New anti-resorptive– Cathepsin K blocker: Ondanacib

• Novel breakthrough medication for HPP: Asfotase Alfa

• Continued research on indications and complications

“I hear and I forget. I see and I remember. I do and I understand.”

– Confucius

12

Metabolic Bone Clinic / Institute for Human GeneticsDivision of Endocrinology and MetabolismUniversity of California, San FranciscoP: (415)353-2350 F: (415)353-2337

[email protected] / http://www.tiny.ucsf.edu/hsiaolab

Thank you! Additional ResourcesAnti SclerostinAntibodies

McClung, Michael R, Andreas Grauer, Steven Boonen, Michael A Bolognese, Jacques P Brown, Adolfo Diez-Perez, and others, ‘Romosozumab in Postmenopausal Women with Low Bone Mineral Density.’, The New England Journal of Medicine, 370 (2014), 412–20 <http://dx.doi.org/10.1056/NEJMoa1305224>

Mccolm, Juliet, Leijun Hu, Theresa Womack, Cheng Cai Tang, and Alan Y. Chiang, ‘Single- and Multiple-Dose Randomized Studies of Blosozumab, a Monoclonal Antibody against Sclerostin, in Healthy Postmenopausal Women’, Journal of Bone and Mineral Research, 29 (2014), 935–43 <http://dx.doi.org/10.1002/jbmr.2092>

Padhi, Desmond, Mark Allison, Alan J. Kivitz, Maria J. Gutierrez, Brian Stouch, Christine Wang, and others, ‘Multiple Doses of Sclerostin Antibody Romosozumab in Healthy Men and Postmenopausal Women with Low Bone Mass: A Randomized, Double-Blind, Placebo-Controlled Study’, Journal of Clinical Pharmacology, 54 (2014), 168–78 <http://dx.doi.org/10.1002/jcph.239>

Recker, Robert R., Charles T. Benson, Toshio Matsumoto, Michael A. Bolognese, Deborah A. Robins, Jahangir Alam, and others, ‘A Randomized, Double-Blind Phase 2 Clinical Trial of Blosozumab, a Sclerostin Antibody, in Postmenopausal Women with Low Bone Mineral Density’, Journal of Bone and Mineral Research, 30 (2015), 216–24 <http://dx.doi.org/10.1002/jbmr.2351>

Recknor, Christopher P., Robert R. Recker, Charles T. Benson, Deborah A. Robins, Alan Y. Chiang, Jahangir Alam, and others, ‘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’, Journal of Bone and Mineral Research, 30 (2015), 1717–25 <http://dx.doi.org/10.1002/jbmr.2489>

Sugiyama, Toshihiro, Tetsuya Torio, Tsuyoshi Miyajima, Yoon Taek Kim, and Hiromi Oda, ‘Romosozumab and Blosozumab: Alternative Drugs of Mechanical Strain-Related Stimulus Toward a Cure for Osteoporosis’, Frontiers in Endocrinology, 6 (2015), 10–13 <http://dx.doi.org/10.3389/fendo.2015.00054>

Additional ResourcesAbaloparatide

Day, Browse By, and Endocrine Society Home, ‘Effects of Abaloparatide on Vertebral and Non-Vertebral Fracture Incidence in Postmenopausal Women with Osteoporosis - Results of the Phase 3 Active Trial’, 36 (2015), 11–14

Leder, Benjamin Z, Louis St L O’Dea, José R Zanchetta, Prasana Kumar, Kathleen Banks, Kathleen McKay, and others, ‘Effects of Abaloparatide, a Human Parathyroid Hormone-Related Peptide Analog, on Bone Mineral Density in Postmenopausal Women with Osteoporosis.’, The Journal of Clinical Endocrinology and Metabolism, 100 (2015), 697–706 <http://dx.doi.org/10.1210/jc.2014-3718>

Asfotase Alfa

Whyte, Michael P., Cheryl R. Greenberg, Nada J. Salman, Michael B. Bober, William H. McAlister, Deborah Wenkert, and others, ‘Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia’, New England Journal of Medicine, 366 (2012), 904–13 <http://dx.doi.org/10.1056/NEJMoa1106173>

Additional ResourcesCathepsin K inhibitors

Bone, Henry G, Michael R McClung, Christian Roux, Robert R Recker, John A Eisman, Nadia Verbruggen, and others, ‘Odanacatib, a Cathepsin-K Inhibitor for Osteoporosis: A Two-Year Study in Postmenopausal Women With Low Bone Density’, Journal of Bone and Mineral Research, 25 (2009), 091029141139034–41 <http://dx.doi.org/10.1359/jbmr.091035>

Strontium

Atteritano, Marco, Antonino Catalano, Domenico Santoro, Antonino Lasco, and Salvatore Benvenga, ‘Effects of Strontium Ranelate on Markers of Cardiovascular Risk in Postmenopausal Osteoporotic Women’, Endocrine, 2015 <http://dx.doi.org/10.1007/s12020-015-0721-8>

Donneau, A. F., and J. Y. Reginster, ‘Cardiovascular Safety of Strontium Ranelate: Real-Life Assessment in Clinical Practice’, Osteoporosis International, 25 (2014), 397–98 <http://dx.doi.org/10.1007/s00198-013-2583-3>

Reginster, J Y, ‘Cardiac Concerns Associated with Strontium Ranelate’, Expert Opinion on Drug Safety, 13 (2014), 1209–13 <http://dx.doi.org/10.1517/14740338.2014.939169>

13

Additional Resources

• Vibration therapy:• de Zepetnek JOT, Giangregorio LM, Craven BC. Whole-body vibration as a potential

intervention for people with low bone mineral density and osteoporosis: a review. J Rehab Research and Development 2009; 46: 529-542

• Rubin C, Turner AS, Bain S, Mallinkcrodt C, McLeod K. Low mechanical signals strengthen long bones. Nature 2001; 412: 603-4

• Slatkovska L, Alibhai SMH, Beyene J, Hu H, Demaras A, Cheung AM. Effect of 12 months of whole-body vibration therapy on bone density and structure in postmenopaus al women. Ann Intern Med 2011; 155: 668-79

• Wysocki A, Butler M, Shamliyan T, Kane R. Whole-body vibration therapy for osteoporosis: state of the science. Ann Intern Med 2011; 155: 680-6

Documents

Disclosures New Drugs for Osteoporosis and Bone Disorders · 1 New Drugs for Osteoporosis and Bone Disorders Edward Hsiao, MD, PhD University of California, San Francisco Division