OSTEOPROTECT: a new therapy of osteoporosis based on sphingosin-1-phosphate and analogues

Prof. Bodo Levkau Institute for Pathophysiology, University Hospital Essen

bodo.levkau@uni-due.de

8.9 million yearly fractures: 1 every 3 seconds

200 million people worldwide are currently suffering from osteoporosis

Longer life span and the increasingly aging population have turned osteoporosis into a major burden on public health

More days in a hostipal in women over 45 than than due to diabetes, cardiovascular disease or breast cancer

1 in 3 women over the age of 50 years and 1 in 5 men will experience an osteoporotic fracture in their lifetime

International Osteoporosis Foundation (2016) Cosman, F., et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int 25, 2359-2381 (2014). Wright, N.C., et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29, 2520-2526 (2014).

Osteoporosis – a globale epidemic

Normal balance between bone formation and bone degradation

Osteoporosis: reduced bone formation and increased bone degradation

Current therapy of osteoporosis

• Early diagnosis difficult: no clinical manifestations until a fracture occurs

• Drug therapy consists ONLY of anti-resorptive agents that inhibit bone degradation bisphosphonates, estrogen, estrogen receptor modulators, RANKL antibodies

• No drugs that stimulate new bone formation – the ‘holy grail’ in the

treatment of osteoporosis human parathyroid hormone (Teriparatide®) restricted to special patient groups and a ‘black box’ warning

• Novel osteoanabolic drugs and therapies are dearly sought for

Ceramide Sphingosine S1P S1P lyase

Sph kinases 1 and 2

SPPases

CDase

CerS

Sphingomyelin

SMS

Glucosylceramide GCase

GCS

SMase

UV radiation Chemotherapy Death receptors

Heat stress UV radiation Chemotherapy Death receptors

Growth factors (PDGF, IGF, VEGF) Cytokines (TNF, IL-1) oxLDL immune complexes Hypoxia, Fc receptor

CS

100 30.000 3.000 1

• immunomodulation (multiple sclerosis, Gilenya®) • angiogenesis and tumor angiogenesis

(Sphingomab) • cardiovascular functions

SPT

Sphingosin-1-phosphate (S1P)

Modified from Hannun and Obeid Principles of bioactive lipid signalling: lessons from Sphingolipids NATURE REVIEWS MOLECULAR CELL BIOLOGY 2008 Harayama, NATURE REVIEWS MOLECULAR CELL BIOLOGY 2018

Ethanolamine phosphate

+ Hexadecenal

Palmitoyl CoA +Serine

molecules per cell

O H

N H 2

O P O H O

O H

Association between serum S1P and bone health in 4,091 participants of the population-based SHIP-Trend study

Clinical bone formation marker

Weske, Nature Medicine 2018

High S1P levels increase bone mass in mice

Cre+Cre-

Exon1 Exon8 Exon9 Exon15

loxP

Exon7

loxP

Sgpl loxP/loxP β-actCreERT2

S1P S1P lyase

ethanolamine phosphate

+ hexadecenal

4-deoxypyrodoxin (DOP)

8 months 4 months

Micro-computed tomography Micro-computed tomography

Weske, Nature Medicine 2018

High S1P increases bone mineral density and mechanical strength

Force (N)

cortical thickness

bone mineral density mechanical strength

Corticalis at femoral midshaft

three-point bending tests

Weske, Nature Medicine 2018

PS1P

S1P2

OPG osteoclast differentiation

osteoblast differentiation

adipocytedifferentiation

adipocyte/osteoblast precursor

osteoclast precursor

OPG

RANKL

RANK

High bone FORMATION Suppressed bone DEGRADATION +

Denosumab (Prolia®, XGEVA®; Amgen)

= more and better bone

Mechanism: pro-osteoanabolic and anti-resorptive

Successful therapy of osteoporosis using S1P lyase inhibitors

NaCl

OVX

DOP

OVX

iPTH

OVX

Ovariectomy

OPG-/-

control

OPG-/-

DOP

OPG

RANKL

RANK

Denosumab (Prolia®, XGEVA®)

Genetic osteoporosis (M. Paget Typ 1)

Teriparatide® DOP or

LX2931 (Lexicon)

control

Osteoporosis due to estrogen deficiency (e.g. after menopause)

DOP OPG knockout

Weske, Nature Medicine 2018

Successful therapy of osteoporosis using S1P receptor-specific agonists

CYM5520

S1P receptor 2

Satsu, Bioorg Med Chem..2013 l

Control CYM5520

Ovariectomy

CYM5520

S1P

Weske, BONE 2019

Osteoporosis due to estrogen deficiency (e.g. after menopause)

CYM5520

Publications Weske, S. et al. (2018): Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss. Nat. Med. 24(5): 667-678 Weske, S. et al. (2019): Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy for the treatment of osteoporosis in mice. BONE, 2019 Apr 24

PCT-patent application has been filed (March 2019) Broad response in the general population TV (WDR), Newspapers (BILD, NZZ), Apothekenrundschau; more than 200 volunteers for clinical studies Current Pipeline: Successful synthesis of a new and more potent lead substance

Current status

Tasks: retrosynthesis and modifications in vitro and preclinical testing biodistribution, pharmacokinetics, toxicity studies, further patenting

CYM5520 S1P S1P

JV490

Commercial Opportunities: start up, access to rights for commercial use, opportunity for further co-development

Acknowledgements

Mithila Vaidya, Alina Reese, Karin von Wnuck Lipinski, Petra Keul, Gerd Heusch Institut für Pathophysiologie, Westdeutsches Herz- und Gefäßzentrum, Universitätsklinikum Essen Julia K Bayer, Jens W Fischer, Ulrich Flögel Institut für Pharmakologie und Klinische Pharmakologie, Heinrich Heine Universität Düsseldorf Jens Nelsen, Matthias Epple, Gebhard Haberhauer Institute für Anorganische und Organische Chemie, Universität Duisburg-Essen Marta Scatena Department of Bioengineering, University of Washington, Seattle, WA, USA Edzard Schwedhelm, Universitätsklinikum Hamburg-Eppendorf Bernhard H Rauch, Anke Hannemann, Henry Völzke Universitätsmedizin Greifswald Markus H. Gräler, Universitätsklinikum Jena

SFB 656