Clinical Trials

Phase 3: Extension Study Evaluating the Safety and Efficacy of a Second Year of Use of Lorecivivint in Subjects With Osteoarthritis of the Knee

Phase 3: A Study Utilizing Patient-Reported Outcomes to Evaluate the Safety and Efficacy of Lorecivivint (SM04690) for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis (STRIDES-1)

Phase 3: A Phase 3 Study Utilizing Patient-Reported and Radiograhic Outcomes and Evaluating the Safety and Efficacy of Lorecivivint (SM04690) for the Treatment of Moderately to Severely Symptomatic Knee Osteaoarthritis (STRIDES-X-ray)

Phase 2: A Study Evaluating the Safety, Tolerability and Efficacy of Two Injections of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis

Phase 2: A Study Utilizing Imaging Techniques and Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis

Phase 2: An Observational Study Evaluating the Safety, Tolerability, and Efficacy of Treatment of SM04690 or Placebo Previously Injected in the Target Knee Joint of Subjects With Moderately to Severely Symptomatic Osteoarthritis 

Phase 2: A Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis 

Phase 2: A Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects 

Phase 1: Drug-Drug Interaction Study of Lorecivivint and Triamcinolone Acetonide in Healthy Volunteers

Phase 1: Phase 1, Dose Escalation Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SM04690 in Moderate to Severe Knee Osteoarthritis (OA)

Corporate Memberships and Collaborations

ORBIT Registry (Brigham and Women’s Hospital)

Samumed is sponsoring the Osteoarthritis Registry of Biomarker and Imaging Trajectories (ORBIT). The data from this study will enhance our understanding of the natural history of knee osteoarthritis. This registry was developed in collaboration with investigators at Brigham and Women’s Hospital at Harvard Medical School.

PROGRESS OA (Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium)

Samumed is a partner on the FNIH Biomarkers Consortium’s PROGRESS OA Project: Clinical Evaluation and Qualification of Osteoarthritis Biomarkers. The project seeks to qualify imaging and biochemical biomarkers with the FDA as prognostic biomarkers of disease progression in knee osteoarthritis.

Osteoarthritis Research Society International (OARSI)

Samumed is proud to be a Corporate Member of OARSI, the leading medical society for advancing the understanding, early detection, treatment, and prevention of osteoarthritis through its exclusive dedication to research. OARSI is the only organization that is exclusively dedicated to advancing osteoarthritis research.

International Cartilage Regeneration & Joint Preservation Society (ICRS)

Samumed is proud to be a Corporate Member of the ICRS, the main forum for international collaboration in cartilaginous tissue research and joint preservation. The ICRS seeks to improve patients’ quality of life, decrease their disability, and reduce the impact of degenerative joint disease on healthcare systems worldwide.

Early OA Consortium (KU Leuven)

Samumed is providing financial support to an international consortium led by Prof. Frank P. Luyten (KU Leuven, BE) and Prof. S. Lohmander (Lund, SWE) in their initiative to develop and validate classification criteria for early-stage osteoarthritis (OA) of the knee. This task force aims to define the patient with early knee OA and is considered a critical contribution to ongoing efforts in the field of OA for patient stratification, proposing early disease as a window of opportunity to better understand the disease process, reduce the burden of OA disease, and potentially prevent disease progression. This initiative is interdisciplinary, connecting the work of basic researchers, physician scientists, and clinicians and aims to go across continents and professional disciplines including general practitioners, rheumatologists, orthopedic surgeons, and physiotherapists, while also involving patient organizations.

STEpUP OA (Oxford University)

Samumed is pleased to support Synovial fluid To define molecular EndotyPes by Unbiased Proteomics in OA (STEpUP OA), an Oxford University-led effort, which has created a partnership to characterize the synovial fluid protein signatures of osteoarthritis patients. Data generated as part of this endeavor may potentially guide clinical decision-making by allowing for better characterization of osteoarthritis disease stages and risk of progression.

Press

Publications

Osteoarthritis and Cartilage | February 12, 2021

  • A Phase 2b Randomized Trial of Lorecivivint, a Novel Intra-articular CLK2/DYRK1A Inhibitor and Wnt Pathway Modulator for Knee Osteoarthritis

    Osteoarthritis and Cartilage. doi: 10.1016/j.joca.2021.02.004


    Yusuf Yazici, MD, Timothy E. McAlindon, MD, MPH, Allan Gibofsky, MD, JD, Nancy E. Lane, MD, Christian Lattermann, MD, Nebojsa Skrepnik, MD, PhD, Christopher J. Swearingen, PhD, Ismail Simsek, MD, Heli Ghandehari, MS, Anita DiFrancesco, BS, BA, Jamielle Gibbs, MPH, Jeyanesh Tambiah, MD, Marc C. Hochberg, MD, MPH

    Article

American College of Rheumatology (ACR) Convergence | November 02 - 05, 2020
Virtual Meeting

  • The Patient Journey in Knee OA: Variations in Patient Characteristics and Treatment by Physician Specialty
    Poster
  • Patient Characteristics and Factors Affecting Decision-Making Regarding Total Knee Replacement by Different Types of Physicians Treating Patients with Knee OA
    Poster

World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases | August 20 - 22, 2020
Virtual Meeting

  • Items Driving WOMAC Pain Subscore Changes Due to Lorecivivint, a Potential Disease-Modifying Treatment for Knee Osteoarthritis: A Post Hoc Analysis of Phase 2b Trial Data
    Poster

Journal of Medical Economics | August 13, 2020

  • Health care resource utilization and burden of disease in a U.S. Medicare population with a principal diagnosis of osteoarthritis of the knee

    Journal of Medical Economics. doi: 10.1080/13696998.2020.1801453


    Fang Chen, Wenqing Su, Angela V. Bedenbaugh & Arman Oruc

    Article

European League Against Rheumatism (EULAR) | June 03 - 06, 2020
Virtual Meeting

  • Safety Profile of the Novel, Intra-articular Agent Lorecivivint (LOR; SM04690), a CLK/DYRK1A Inhibitor That Modulates the Wnt Pathway, in Subjects with Knee Osteoarthritis
    Slides
  • Lorecivivint (SM04690), an Intra-articular, Small-Molecule CLK/DYRK1A Inhibitor that Modulates the Wnt Pathway, as a Potential Treatment for Meniscal Injuries
    Abstract

Arthritis & Rheumatology | May 20, 2020

  • Lorecivivint, a Novel Intra‐articular CLK/DYRK1A Inhibitor and Wnt Pathway Modulator for Treatment of Knee Osteoarthritis: A Phase 2 Randomized Trial

    Arthritis & Rheumatology. doi: 10.1002/art.41315


    Yusuf Yazici, Timothy E. McAlindon, Allan Gibofsky, Nancy E. Lane, Daniel Clauw, Morgan Jones, John Bergfeld, Christopher J. Swearingen, Anita DiFrancesco, Ismail Simsek, Jeyanesh Tambiah, Marc C. Hochberg

    Article

European Workshop for Rheumatology Research (EWRR) | February 13 - 15, 2020
Leuven, Belgium

  • Lorecivivint (SM04690), a Potential Disease-Modifying Treatment for Knee Osteoarthritis, Demonstrated Cartilage-Protective Effects on Human Osteoarthritic Explants
    Poster

American College of Rheumatology (ACR) | November 08 - 13, 2019
Atlanta, GA

  • Lorecivivint (SM04690), a Potential Disease-Modifying Osteoarthritis Drug, Inhibits CLK2 and DYRK1A, Novel Molecular Regulators of Wnt Signaling, Chondrogenesis, and Inflammation
    Slides
  • The Novel, Intra-articular CLK/DYRK1A Inhibitor Lorecivivint (LOR; SM04690), Which Modulates the Wnt Pathway, Improved Responder Outcomes in Subjects with Knee Osteoarthritis: A Post Hoc Analysis from a Phase 2b Trial
    Poster
  • Subject Enrichment Criteria for Phase 3 Studies of Lorecivivint (SM04690), a Potential Disease-Modifying Knee Osteoarthritis Drug: A Post Hoc Study on the Effects of Baseline Comorbid Pain and Joint Space Width on Patient-Reported Outcomes
    Poster

Cartilage Regeneration & Joint Preservation Society (ICRS) World Congress | October 05 - 08, 2019
Vancouver, Canada

  • Wnt Pathway Modulation via CLK2 and DYRK1A Inhibition by Lorecivivint, a Potential Disease-Modifying Treatment for Knee Osteoarthritis
    Slides
  • Prospective Comparison of Sham vs. Placebo Injections: Data from a Trial of Lorecivivint, a Wnt Pathway Inhibitor for Knee Osteoarthritis
    Slides

Gordon Research Conference (GRC) - Wnt Signaling Networks in Development, Disease and Regeneration | August 11 - 16, 2019
Mount Snow, VT

  • Lorecivivint (SM04690), a Potential Disease-Modifying Osteoarthritis Drug, Inhibits CLK2 and DYRK1A, Novel Molecular Regulators of Wnt Signaling, Chondrogenesis, and Inflammation
    Poster

European League Against Rheumatism (EULAR) | June 12 - 15, 2019
Madrid, Spain

  • Comparison of Knee Osteoarthritis Treatment Patterns by Rheumatologists vs. Other Providers in a U.S. Administrative Claims Database
    Poster
  • Efficacy and Safety from a Phase 2b Trial of Lorecivivint (SM04690), a Novel Intra-articular Wnt Pathway Inhibitor for the Treatment of Osteoarthritis of the Knee
    Poster

Osteoarthritis and Cartilage | May 24, 2019

  • Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

    Osteoarthritis and Cartilage. doi: 10.1016/j.joca.2019.05.006


    V. Deshmukh, A.L. O'Green, C. Bossard, T. Seo, L. Lamangan, M. Ibanez, A. Ghias, C. Lai, L. Do, S. Cho, J. Cahiwat, K. Chiu, M. Pedraza, S. Anderson, R. Harris, L. Dellamary, S. KC, C. Barroga, B. Melchior, B. Tam, S. Kennedy, J. Tambiah, J. Hood, Y. Yazici

    Article

International Society for Pharmaeconomics and Outcomes Research (ISPOR) | May 18 - 22, 2019
New Orleans, LA

  • An Analysis of Treatment Patterns in Knee Osteoarthritis in a U.S. Administrative Claims Database
    Poster

Academy of Managed Care Pharmacy (AMCP) | March 25 - 28, 2019
San Diego, CA

  • An Analysis of the Burden of Illness and Treatment in Knee Osteoarthritis in a U.S. Administrative Claims Database
    Poster

American Academy of Orthopaedic Surgeons (AAOS) | March 12 - 16, 2019
Las Vegas, NV

  • A 52-Week, Randomized, Double-Blind, Phase 2 Study of an Intra-articular Wnt Pathway Inhibitor (SM04690) for Osteoarthritis
    Poster

Orthopaedic Research Society (ORS) | February 02 - 05, 2019
Austin, TX

  • SM04690, a Potential Disease-Modifying Treatment for Knee Osteoarthritis, Functions Through Inhibition of CLK2 and DYRK1A, Novel Molecular Regulators of Wnt Signaling, Chondrogenesis, and Inflammation
    Poster

International Cartilage Regeneration & Joint Preservation Society (ICRS) Summit | January 17 - 18, 2019
San Diego, CA

  • Efficacy and Safety from a Phase 2b Trial of SM04690: A Novel, Intra-Articular Wnt Pathway Inhibitor for the Treatment of Knee Osteoarthritis
    Poster

American College of Rheumatology (ACR) | October 19 - 24, 2018
Chicago, IL

  • Efficacy and Safety from a Phase 2b Trial of SM04690, a Novel, Intra-Articular, Wnt Pathway Inhibitor for the Treatment of Osteoarthritis of the Knee
    Poster
  • Assessment of Health-Related Quality of Life in a 52-Week, Phase 2, Randomized, Controlled Trial of a Novel, Intra-Articular, Wnt Pathway Inhibitor (SM04690) for Treatment of Knee Osteoarthritis
    Poster

Asia Pacific League of Associations for Rheumatology (APLAR) | September 06 - 09, 2018
Kaohsiung, Taiwan

  • Results from a 52-week, phase 2a study of an intra-articular, small molecule Wnt pathway inhibitor, SM04690, for knee osteoarthritis
    Slides

European League Against Rheumatism (EULAR) | June 13 - 16, 2018
Amsterdam, Netherlands

  • Radiographic outcomes were associated with pain and function responses: post-hoc analysis from a phase 2 study of a Wnt pathway inhibitor, SM04690, for knee osteoarthritis treatment
    Poster
  • Potential Nociceptive Pain Relief of Intra-Articular Saline Control in Clinical Trials of Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Trials
    Poster
  • Treatment of Knee Osteoarthritis with SM04690 Improved WOMAC A1 “Pain on Walking” – Results from a 52 week Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of a Novel, Intra-Articular, Wnt Pathway Inhibitor
    Slides

Osteoarthritis Research Society International (OARSI) World Congress | April 26 - 29, 2018
Liverpool, United Kingdom

  • Radiographic Outcomes Were Concordant with Outcome Measures in Rheumatology Osteoarthritis Research Society International (OMERACT-OARSI) Strict Response: Post-Hoc Analysis from a Phase 2 Study of a Wnt Pathway Inhibitor, SM04690, for Knee Osteoarthritis Treatment
    Poster
  • Joint Space Width Inclusion Criteria Can Reduce Knee Osteoarthritis Trial Heterogeneity: Post-Hoc Data from a Phase 2 Trial of Wnt Pathway Inhibitor, SM04690
    Poster

World Congress on Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases | April 19 - 22, 2018
Krakow, Poland

  • SM04690, a small molecule Wnt pathway inhibitor, appeared to have no deleterious effects on bone, joint, and tissue health in knee OA models
    Poster
  • SM04690 caused dose-dependent Wnt pathway modulation within a homeostatic range in a rat model of knee osteoarthritis
    Poster

International Cartilage Repair Society (ICRS) | April 09 - 12, 2018
Macao, China

  • A 52 Week Randomized, Double-Blind Phase 2 Study of Intra-Articular, Wnt Pathway Inhibitor (SM04690) for Osteoarthritis
    Slides
  • Joint Space Width Criteria Can Reduce Knee OA Trial Heterogeneity: P2 Post-Hoc Data from Wnt Pathway Inhibitor, SM04690
    Slides
  • Radiographic Outcomes Were Concordant with Pain and Function Response: Post-Hoc Analysis from a Phase 2 Study of SM04690, a Wnt Pathway Inhibitor for Knee Osteoarthritis Treatment
    Slides
  • SM04690, a Wnt Pathway Inhibitor: Anti-Inflammatory and Cartilage Protective Effects in Preclinical OA Models
    Slides

American College of Rheumatology (ACR) | November 03 - 08, 2017
San Diego, CA

  • Results from a 52 Week Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of a Novel, Intra-Articular, Wnt Pathway Inhibitor (SM04690) for the Treatment of Knee Osteoarthritis
    Slides
  • Reducing Heterogeneity in OA Clinical Trials: Data from a Phase 2 Study of SM04690, a Novel, Intra-Articular, Wnt Pathway
    Inhibitor in Knee Osteoarthritis
    Poster

Osteoarthritis and Cartilage | September 15, 2017

  • A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee

    Osteoarthritis and Cartilage. doi: 10.1016/j.joca.2017.08.015


    V. Deshmukh, H. Hu, C. Barroga, C. Bossard, S. KC, L. Dellamary, J. Stewart, K. Chiu, M. Ibanez, M. Pedraza, T. Seo, L. Do, S. Cho, J. Cahiwat, B. Tam, J.R.S. Tambiah, J. Hood, N.E. Lane, Y. Yazici

    Article

Gordon Research Conference: Wnt Signaling | August 06 - 11, 2017
Stowe, VT

  • Discovery of a Small Molecule Inhibitor of the Wnt Pathway (SM04690) as a Potential Disease Modifying Treatment for Knee Osteoarthritis
    Poster - Slides

Osteoarthritis and Cartilage | July 13, 2017

  • A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study

    Osteoarthritis and Cartilage, 25(10), 1598-1606. doi: 10.1016/j.joca.2017.07.006


    Y. Yazici, T.E. McAlindon, R. Fleischmann, A. Gibofsky, N.E. Lane, A.J. Kivitz, N. Skrepnik, E. Armas, C.J. Swearingen, A. DiFrancesco, J.R.S. Tambiah, J. Hood, M.C. Hochberg

    Article

International Cartilage Repair Society Heritage Summit | June 29 - Jul 01, 2017
Gothenburg, Sweden

  • Cartilage Regeneration in a Rat Model of Knee OA by SM04690, a Potential Disease Modifying Wnt Pathway Inhibitor
    Poster

European League Against Rheumatism (EULAR) | June 14 - 17, 2017
Madrid, Spain

  • Clinical Outcomes from a Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of a Novel, Intra-Articular, Injectable, Wnt Pathway Inhibitor (SM04690) for the Treatment of Knee Osteoarthritis: Week 26 Interim Analysis
    Poster
  • Radiographic Outcomes from a Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of a Novel, Intra-Articular, Injectable, Wnt Inhibitor (SM04690) in the Treatment of Osteoarthritis of the Knee: Week 26 Interim Analysis
    Slides

International Society for Pharmacoeconomics and Outcomes (ISPOR) | May 20 - 24, 2017
Boston, MA

  • A Statistical Analysis Plan to Understand Osteoarthritis Patient Journey by Linking Medicare Claims Across Care Delivery Settings
    Poster
  • Health Care Resource Use of Medicare Beneficiaries With Primary Osteoarthritis (OA) Of The Knee – A Claims Data Analysis
    Poster

Osteoarthritis Research Society International (OARSI) | April 27 - 30, 2017
Las Vegas, NV

  • Anti-inflammatory Properties of SM04690, a Small Molecule Inhibitor of the Wnt Pathway as a Potential Treatment for Knee Osteoarthritis
    Poster

American College of Rheumatology (ACR) | November 11 - 16, 2016
Washington D.C.

  • A Small Molecule, SM04690, has Inhibitory Effects on the Wnt Pathway and Inflammation In Vitro, With Potential Implications For the Treatment of Osteoarthritis
    Poster

Royal Society of Medicine's 13th Medical Innovations Summit | September 17, 2016
London, United Kingdom

  • Samumed's Regenerative Medicine Platform
    Slides

Osteoarthritis Research Society International (OARSI) | March 31 - Apr 03, 2016
Amsterdam, Netherlands

  • OMERACT-OARSI ‘Strict Responders’ Analysis from Results of a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of a Novel, Intra-Articular, Injectable Wnt Inhibitor (SM04690) in the Treatment of Osteoarthritis of the Knee
    Poster
  • Discovery of a Small Molecule Inhibitor of the Wnt Pathway (SM04690) as a Potential Disease Modifying Treatment for Knee Osteoarthritis
    Slides

American College of Rheumatology (ACR) | November 06 - 11, 2015
San Francisco, CA

  • Safety, Efficacy and Biomarker Outcomes of a Novel, Intra-Articular, Injectable, Wnt Inhibitor (SM04690) in the Treatment of Osteoarthritis of the Knee: Interim, Exploratory Analysis of Results from a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study
    Abstract - Poster
  • Magnetic Resonance Imaging Outcomes Using an Intra-Articular Injection (SM04690) in the Treatment of Osteoarthritis of the Knee: Interim, Exploratory Analysis of Results from a Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study
    Abstract - Poster
  • Discovery of an Intra-Articular Injection Small Molecule Inhibitor of the Wnt Pathway (SM04690) As a Potential Disease Modifying Treatment for Knee Osteoarthritis
    Abstract - Slides

Award Winning

Overview: Osteoarthritis of the Knee

Arthritis is the most common cause of disability among adults, and osteoarthritis (OA) is the most common type of arthritis, accounting for much of this burden.1

  • The global prevalence of symptomatic knee OA has been estimated at 3.8% (4.8% for females and 2.8% for males).2
  • Current estimates indicate that there are 14 million U.S. adults with symptomatic knee osteoarthritis.3 The overall number of U.S. adults affected by OA in any joint has increased during recent decades and is estimated to affect 30 million U.S. adults today, primarily due to an aging population and an ever-increasing prevalence of obesity.1
  • The combination of direct medical costs, pain and suffering, and loss of workplace productivity elevates OA to a major socioeconomic problem for health systems, the economy, and suffering patients.4

OA is characterized by the destruction of articular cartilage and structural changes in bone, which contribute to pain and loss of joint function.5 The Wnt signaling pathway plays a central role in the processes that direct the lineage fate of stem cells, that are resident in the joint, toward bone (osteoblasts) or cartilage (chondrocytes).6,7

  • In OA joints, elevated Wnt activity has been shown to cause these stem cells to become osteoblasts instead of chondrocytes and to lead to the production of proteases that degrade cartilage.8,9,10
  • Inhibition of Wnt signaling in OA joints may drive stem cells to become chondrocytes and block protease-mediated cartilage degradation, resulting in cartilage regeneration.8,11
  • Therapies that target the Wnt pathway may therefore have potential in treating OA.8

References

    1. Centers for Disease Control and Prevention. Osteoarthritis. Available at https://www.cdc.gov/arthritis/basics/osteoarthritis.htm.
    2. Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323-30.
    3. Deshpande BR, Katz JN, Solomon DH, et al. Number of persons with symptomatic knee osteoarthritis in the US: impact of race and ethnicity, age, sex, and obesity. Arthritis Care Res (Hoboken). 2016;68(12):1743-50.
    4. Wier LM, Levit K, Stranges E, et al. HCUP facts and figures: statistics on hospital based care in the United States, 2008. Rockville, MD: Agency for Healthcare Research and Quality, 2010. Available at http://www.hcup-us.ahrq.gov/reports/factsandfigures/2008/pdfs/FF_report_2008.pdf.
    5. Glyn-Jones S, Palmer AJR, Agricola R, et al. Osteoarthritis. Lancet. 2015;386(9991):376-87.
    6. Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014;346(6205):1248012.
    7. Blom AB, Brockbank SM, Van Lent PL, et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum. 2009;60(2):501-12.
    8. Monteagudo S, Lories RJ. Cushioning the cartilage: a canonical Wnt restricting matter. Nat Rev Rheumatol. 2017;13(11):670-81.
    9. Gelse K, Ekici AB, Cipa F, et al. Molecular differentiation between osteophytic and articular cartilage – clues for a transient and permanent chondrocyte phenotype. Osteoarthritis Cartilage. 2012;20(2):162-71.
    10. Corr M. Wnt-beta-catenin signaling in the pathogenesis of osteoarthritis. Nat Clin Pract Rheumatol. 2008;4(10):550-6.
    11. Zimmerman ZF, Moon RT, Chien AJ. Targeting Wnt pathways in disease. Cold Spring Harb Perspect Biol. 2012;4(11):a008086.