Disease-modifying osteoarthritis drug

A disease-modifying osteoarthritis drug (DMOAD) is a drug that would inhibit or even reverse the progression of osteoarthritis.[1] Since the main hallmark of osteoarthritis is cartilage loss, a typical DMOAD would prevent the loss of cartilage and potentially regenerate it. Other DMOADs may attempt to help repair adjacent tissues by reducing inflammation. A successful DMOAD would be expected to show an improvement in patient pain and function with an improvement of the health of the joint tissues[2].

Approved for human use

There are currently no DMOADs approved for human use.

Drugs with undergoing human trials
Drug Mechanism of Action Status Investigator(s)
SM04690 / Lorecivivint[3] Wnt pathway inhibitor Phase 2 study completed, showing improvement in pain, function and joint space width.[4]

Phase 3 study started in May 2019.[5]

 Samumed
KA34 / Kartogenin Induces MSCs to differentiate into chondrocytes[6] Phase 1 study started in May 2018 to evaluate safety of kartogenin in humans.[7] Calibr[8]
UBX0101 p53/MDM2 inhibitor, induces apoptosis of senescent cells to create a favourable healing environment[9] Phase 1 study complete in June 2019,[10] results were encouraging leading to plans for a phase 2 study. Unity Biotechnology
BMP7 Supports transcription of osteogenic genes[11] Phase 1 study completed in 2010.[12]

Phase 2 study completed in 2015,[13] suggesting the ability to prevent cartilage loss.

 Ember Therapeutics[14]
FGF-18 / Sprifermin Promote chondrogenesis through fibroblast growth factor receptor FGFR3[15] Phase 2 study completed in 2017, with results failing to show improvement in pain or function. It did however show prevention of cartilage loss meaning it may be able to be used as a prevention. Merck

Nordic Biosience

TPX-100 23-amino acid peptide that induces articular cartilage proliferation[16] A study of 93 patients revealed only 10% of them observed an increase in articular cartilage thickness but ~60% decreased their use of pain medication.[17] OrthoTrophix
LNA043 Chondrogenesis enhancer[18] Phase 1 study started in 2015.[19] Novartis
GLPG1972 ADAMTS-5 inhibitor Phase 1 study completed in 2019.

Phase 2 study started in 2019.[20]

 Galapagos
MIV-711 Cathepsin K inhibitor[21] Phase 2 study completed in 2019, showing prevention of cartilage damage but did not show reduction in patient pain.[22] Medivir
Invossa-K Cell/Gene therapy Human studies halted by FDA for false ingredient claim.[23][24] Kolon Life Science
Amniotic fluid allograft (ReNU, Palingen InovoFlo, AmnioFix, Clarix Flo) Note: Amniotic fluid is not a single drug and instead contains around 226 growth factors,[25] including BMP7.

Inflammation reducer[26] and cartilage growth enhancer.[27]

 Initial 6 patient study in 2015 showed improvement in pain and function.[28] A randomised controlled trial of 200 patients completed in 2019,[29] also showing improved pain and function.

A 2019 non-randomised study in 20 patients showed improvement in joint tissue health.[30]

 Organogenesis

Amnio Technology

MiMedx

Amniox Medical, Inc.

Drugs under investigation
Drug Mechanism of Action Status Investigator(s)
A2M Protect chondrocytes from damage A2M inhibited catabolic activity in rats.[31]

Note: Cytonics offers autologous A2M therapy in humans but no randomised human trials have been published to date. A human trial is underway at NYU.[32]

 Cytonics
SS-31 Mitoprotective peptide Study done on 2 horses[33] showed protective effects in vivo. Cornell
TD-198946 Chondrogenic factor[34] Basic science studies being carried out. University of Tokyo[35]
M6495 ADAMTS-5 inhibitor[36] Shown to protect against cartilage breakdown in cartilage and synovial joint tissue explant models[37] Merck
B001-5 ADAMTS-5 and ADAM-17 inhibitor[38] To be submitted to FDA in early 2020.[38] Guangzhou Institutes of Biomedicine and Health

References
  1. "Disease-modifying osteoarthritis drugs (DMOADs): what are they and what can we expect from them?". Medicographia. 2013-10-31. Retrieved 2020-01-24.
  2. "New targets in osteoarthritis are about more than just pain". Biocentury Innovations.
  3. Deshmukh, V.; Hu, H.; Barroga, C.; Bossard, C.; Kc, S.; Dellamary, L.; Stewart, J.; Chiu, K.; Ibanez, M.; Pedraza, M.; Seo, T. (2018-01-01). "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. 26 (1): 18–27. doi:10.1016/j.joca.2017.08.015. ISSN 1063-4584. PMID 28888902.
  4. Yazici, Y.; McAlindon, T. E.; Gibofsky, A.; Lane, N. E.; Clauw, D. J.; Jones, M. H.; Bergfeld, J.; Swearingen, C. J.; DiFrancesco, A.; Tambiah, J. R.; Hochberg, M. (2018-04-01). "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". Osteoarthritis and Cartilage. Abstracts from the 2018 OARSI World Congress on Osteoarthritis. 26: S293–S294. doi:10.1016/j.joca.2018.02.589. ISSN 1063-4584.
  5. Horsley, Erich (May 2, 2019). "Samumed Launches Phase 3 Lorecivivint (SM04690) Clinical Program in Knee Osteoarthritis". Samumed.
  6. Kwon, Ji Ye; Lee, Seung Hoon; Na, Hyun-Sik; Jung, KyungAh; Choi, JeongWon; Cho, Keun Hyung; Lee, Chang-Yong; Kim, Seok Jung; Park, Sung-Hwan; Shin, Dong-Yun; Cho, Mi-La (2018-09-14). "Kartogenin inhibits pain behavior, chondrocyte inflammation, and attenuates osteoarthritis progression in mice through induction of IL-10". Scientific Reports. 8 (1): 13832. Bibcode:2018NatSR...813832K. doi:10.1038/s41598-018-32206-7. ISSN 2045-2322. PMC 6138726. PMID 30218055.
  7. "A Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of KA34 in Subjects With Knee Osteoarthritis - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-01-24.
  8. "Calibr | Scripps Research". www.scripps.edu. Retrieved 2020-01-24.
  9. "Safety, Tolerability, Pharmacokinetics, and Clinical Outcomes Following Single-Dose IA Administration of UBX0101, a Senolytic MDM2/p53 Interaction Inhibitor, in Patients with Knee OA". ACR Meeting Abstracts. Retrieved 2020-01-24.
  10. "UNITY Biotechnology, Inc. Announces Plan for Phase 2 Clinical Study of UBX0101 in Osteoarthritis of the Knee". Unity Biotechnology. Retrieved 2020-01-24.
  11. Honsawek, Sittisak; Chayanupatkul, Maneerat; Tanavalee, Aree; Sakdinakiattikoon, Manoon; Deepaisarnsakul, Benjamad; Yuktanandana, Pongsak; Ngarmukos, Srihatach (August 2009). "Relationship of plasma and synovial fluid BMP-7 with disease severity in knee osteoarthritis patients: a pilot study". International Orthopaedics. 33 (4): 1171–1175. doi:10.1007/s00264-009-0751-z. ISSN 0341-2695. PMC 2898966. PMID 19301001.
  12. Hunter, David J; Pike, Marilyn C; Jonas, Beth L; Kissin, Eugene; Krop, Julie; McAlindon, Tim (2010-10-10). "Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis". BMC Musculoskeletal Disorders. 11: 232. doi:10.1186/1471-2474-11-232. ISSN 1471-2474. PMC 2958989. PMID 20932341.
  13. Inc, Ember Therapeutics. "Ember Therapeutics Announce Initial Positive Results From a Phase 2 Trial of BMP-7 in Patients with Moderate Osteoarthritis of the Knee". www.prnewswire.com. Retrieved 2020-01-24.
  14. "Ember Therapeutics". www.embertx.com. Retrieved 2020-01-24.
  15. Davidson, David; Blanc, Antoine; Filion, Dominic; Wang, Huifen; Plut, Paul; Pfeffer, Gerald; Buschmann, Michael D.; Henderson, Janet E. (2005-05-27). "Fibroblast Growth Factor (FGF) 18 Signals through FGF Receptor 3 to Promote Chondrogenesis". Journal of Biological Chemistry. 280 (21): 20509–20515. doi:10.1074/jbc.M410148200. ISSN 0021-9258. PMID 15781473.
  16. McGuire, D.; Lane, N.; Segal, N.; Metyas, S.; Barthel, H.; Miller, M.; Rosen, D.; Kumagai, Y. (2018-04-01). "TPX-100 leads to marked, sustained improvements in subjects with knee osteoarthritis: pre-clinical rationale and results of a controlled clinical trial". Osteoarthritis and Cartilage. 26: S243. doi:10.1016/j.joca.2018.02.502. ISSN 1063-4584.
  17. "Clinical Benefits of TPX-100 in Knee Osteoarthritis Patients are Associated with Improvements in Knee Cartilage Structure Modification". www.orthotrophix.com. August 13, 2018. Retrieved 2020-01-25.
  18. "LNA043: Chondrogenesis inducer for cartilage repair" (PDF). Meet Novartis Management NIBR.
  19. "First-in-human Single Ascending Dose Study of LNA043 in Patients Scheduled for Total Knee Replacement - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-01-24.
  20. "A Study to Assess Efficacy and Safety of GLPG1972/S201086 in Patients With Knee Osteoarthritis - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-01-25.
  21. Conaghan, Philip G.; Bowes, Michael A.; Kingsbury, Sarah R.; Brett, Alan; Guillard, Gwenael; Rizoska, Biljana; Sjögren, Niclas; Graham, Philippa; Jansson, Åsa; Wadell, Cecilia; Bethell, Richard (2019-12-31). "Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized, Placebo-Controlled Study". Annals of Internal Medicine. doi:10.7326/M19-0675. ISSN 1539-3704. PMID 31887743.
  22. "A Study to Evaluate the Efficacy, Safety and Tolerability of MIV-711 in Osteoarthritis Patients - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-01-30.
  23. "Prosecutors seek to arrest 2 Kolon execs for false Invossa data - Korea Biomedical Review". www.koreabiomed.com (in Korean). 2019-10-31. Retrieved 2020-01-31.
  24. "Kolon TissueGene feared to be delisted due to cancellation of Invossa approval". Korea IT Times (in Korean). 2019-05-29. Retrieved 2020-01-31.
  25. Koob, Thomas (2016). A Primer on Amniotic Membrane Regenerative Healing (PDF). Color House Graphics. p. 60. ISBN 978-0-692-51694-2.
  26. Kimmerling, Kelly A.; Gomoll, Andreas H.; Farr, Jack; Mowry, Katie C. (2019). "Amniotic Suspension Allograft Modulates Inflammation in a Rat Pain Model of Osteoarthritis". Journal of Orthopaedic Research. n/a (n/a). doi:10.1002/jor.24559. ISSN 1554-527X. PMID 31814175.
  27. Willett, Nick J; Thote, Tanushree; Lin, Angela SP; Moran, Shamus; Raji, Yazdan; Sridaran, Sanjay; Stevens, Hazel Y; Guldberg, Robert E (2014). "Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development". Arthritis Research & Therapy. 16 (1): R47. doi:10.1186/ar4476. ISSN 1478-6354. PMC 3978824. PMID 24499554.
  28. Vines, Jeremy B.; Aliprantis, Antonios O.; Gomoll, Andreas H.; Farr, Jack (2015). "Cryopreserved Amniotic Suspension for the Treatment of Knee Osteoarthritis". The Journal of Knee Surgery. 29 (6): 443–450. doi:10.1055/s-0035-1569481. ISSN 1938-2480. PMID 26683979.
  29. Farr, Jack; Gomoll, Andreas H.; Yanke, Adam B.; Strauss, Eric J.; Mowry, Katie C.; ASA Study Group (2019). "A Randomized Controlled Single-Blind Study Demonstrating Superiority of Amniotic Suspension Allograft Injection Over Hyaluronic Acid and Saline Control for Modification of Knee Osteoarthritis Symptoms". The Journal of Knee Surgery. 32 (11): 1143–1154. doi:10.1055/s-0039-1696672. ISSN 1938-2480. PMID 31533151.
  30. Castellanos, Ramon; Tighe, Sean (2019-11-01). "Injectable Amniotic Membrane/Umbilical Cord Particulate for Knee Osteoarthritis: A Prospective, Single-Center Pilot Study". Pain Medicine. 20 (11): 2283–2291. doi:10.1093/pm/pnz143. ISSN 1526-2375. PMC 6830267. PMID 31418794.
  31. Zhang, Yang; Wei, Xiaochun; Browning, Shawn; Scuderi, Gaetano; Hanna, Lewis S.; Wei, Lei (2017). "Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection". Arthritis Research & Therapy. 19 (1): 175. doi:10.1186/s13075-017-1363-4. ISSN 1478-6354. PMC 5526282. PMID 28743292.
  32. "Reduction of Pro-Inflammatory Synovial Fluid Biomarkers in Osteoarthritis of the Knee With Alpha-2 Macroglobulin - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-01-25.
  33. Delco, Michelle L.; Bonnevie, Edward D.; Szeto, Hazel S.; Bonassar, Lawrence J.; Fortier, Lisa A. (2018-02-22). "Mitoprotective Therapy Preserves Chondrocyte Viability and Prevents Cartilage Degeneration in an Ex Vivo Model of Posttraumatic Osteoarthritis". Journal of Orthopaedic Research. 36 (8): 2147–2156. doi:10.1002/jor.23882. ISSN 0736-0266. PMC 6105558. PMID 29469223.
  34. Chijimatsu, Ryota; Yano, Fumiko; Saito, Taku; Kobayashi, Masato; Hamamoto, Shuichi; Kaito, Takashi; Kushioka, Junichi; Hart, David A.; Chung, Ung-Il; Tanaka, Sakae; Yoshikawa, Hideki (March 2019). "Effect of the small compound TD-198946 on glycosaminoglycan synthesis and transforming growth factor β3-associated chondrogenesis of human synovium-derived stem cells in vitro". Journal of Tissue Engineering and Regenerative Medicine. 13 (3): 446–458. doi:10.1002/term.2795. ISSN 1932-7005. PMID 30650248.
  35. Yano, Fumiko; Hojo, Hironori; Ohba, Shinsuke; Fukai, Atsushi; Hosaka, Yoko; Ikeda, Toshiyuki; Saito, Taku; Hirata, Makoto; Chikuda, Hirotaka; Takato, Tsuyoshi; Kawaguchi, Hiroshi (2013). "A novel disease-modifying osteoarthritis drug candidate targeting Runx1". Annals of the Rheumatic Diseases. 72 (5): 748–753. doi:10.1136/annrheumdis-2012-201745. ISSN 1468-2060. PMID 23041841.
  36. Balchen, T.; Strotmann, R.; Bihlet, A. Reinstrup; Sonne, J.; Ladel, C.; Moreau, F.; Guehring, H. (2018-04-01). "Study design of a phase I, placebo-controlled, First-in-human trial to assess safety and tolerability, immunogenicity, and pharmacokinetics and pharmacodynamics of single ascending doses of the anti-ADAMTS-5 Nanobody®, M6495, in healthy male subjects". Osteoarthritis and Cartilage. 26: S276–S277. doi:10.1016/j.joca.2018.02.561. ISSN 1063-4584.
  37. Siebuhr, A.; Bay-Jensen, A.-C.; Thudium, C. T.; Karsdal, M. A.; Serruys, B.; Werkmann, D.; Michaelis, M.; Ladel, C.; Lindemann, S. (2018-04-01). "The anti-ADAMTS-5 nanobody®, M6495, protects against cartilage breakdown in cartilage and synovial joint tissue explant models". Osteoarthritis and Cartilage. 26: S187. doi:10.1016/j.joca.2018.02.402. ISSN 1063-4584.
  38. Malfait, A.-M.; Tortorella, M.D. (2019-09-17). "The "elusive DMOAD": Aggrecanase inhibition from laboratory to clinic". Clinical and Experimental Rheumatology. 37.

Disease-modifying Osteoarthritis Drug (DMOAD)
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